CA2421315A1

CA2421315A1 - Novel polypeptides and nucleic acids encoding the same

Info

Publication number: CA2421315A1
Application number: CA002421315A
Authority: CA
Inventors: William I. Wood; Austin L. Gurney; Audrey Goddard; Kevin P. Baker; Jian Chen; Jean Yuan
Original assignee: Individual
Current assignee: Genentech Inc
Priority date: 1998-03-10
Filing date: 1999-03-08
Publication date: 1999-09-16
Also published as: CA2421329A1; CA2421322A1; CA2421339C; CA2421372A1; CA2421388A1; CA2421333A1; CA2421364A1; CA2421345A1; CA2421394A1; CA2421339A1; CA2421375A1; CA2421319A1

Abstract

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Description

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NOVEL POLYPEPTTDES AND NUCLEIC ACIDS ENCODING THE SAME
FIELD OF THE INVEN~'ION
The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides encoded by that DNA.
BACKGROUND OF THE 1NVEN~ON
Extracellular proteins play an important role in the formation, differentiation and maintenance of multicelluiar organisms, The fate of many individual cells, e.g., proliferation, migration; differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate envirorutient. This information is ofren transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrornbolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see; for example, Klein et al., ProcLNatl,,~pcad.
Vii., Q3:'710&7113 (1996); U.S. Patent No. 5,536,53'].
Membrane-bound proteins and receptors can play an important role in the formation; differentiation and maintenance of multicellular organisms. The fate of many individual cells, c.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and itttezpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and III receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, ttansdtxtion of that regulate cell growth and differentiation is regulated in part by phosphorylation of various _. cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor itttmunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mamtnatian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
We herein describe the identification and characterization of novel secreted and transmembrane polypeptides and novel nucleic acids encoding those polypeptides.
1. PR0213 Human growth arrest-specific gene 6 (gash) encodes a protein that is expressed in a variety of different tissues and which has been reported to be highly expressed during periods of serum starvation and negatively regulated during growth induction. See Manfioletti et al., Mol. Cell. Biol.
13(8):4976-4985 (1993) and Stitt et al., Cell 80:661-670 (1995). Manfioletti et al. (1993), supra, have suggested that the gash protein is member of the vitamin K-dependent family of proteins, wherein the members of the latter family of proteins (which include, for example, Protein S, Protein C and Factor ?~ all play regulatory roles in the blood coagulation pathway. Thus, it has been suggested that gash may play a role in the regulation of a protease cascade relevant in growth regulation or in i5 the blood coagulation cascade.
Given the physiological importance of the gash protein, efforts are currently being undertaken by both industry and academia to identify new, native proteins which are homologous to gash. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins, specifically those having homology to gash. Examples of such screening methods and techtuques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad.
~," X3:7108 7113 (1996); U.S. Patem No. 5,536,637)]. We herein describe the identification of a novel polypeptide which has homology to the gash polypeptide.

2. PR_ 0274 The 7-transmembrane ('"7T'NI") proteins or receptors, also referred to in the literature as G-protein coupled receptors, are specialized proteins designed for recognition of ligands and the subsequent signal transduction of information contained within those ligands to the machinery of the cell. The primary purpose of cell surface receptors is to discriminate appropriate.Iigands from the various extracellular stimuli which each cell encounters, then to activate an effector system that produces an intracellular signal, thereby controlling cellular processes. [Dohlinan, H. Ann. I~,ev. Biochem., øQ:653 (1991)]. The ability of 7TM receptors to bind ligand to a recognition domain and allosierically transmit the information to an intracellular domain is a specialized feature of 7TM proteins [Kenakin, T., p,~armacQl. Rev., 4$:413 (1996)]. The gene family which encodes the 7TM
receptors or G-protein linked receptors encode receptors which recognize a large number of ligands, including but not limited to; CSa, interieukin 8 and related chemokines. Research in this area suggests that distinct signals at the cell surface feed into common pathways of cell activation. [Getard, C. and Gerard, N.,Curr. O~. Immtmol., 6_:140 (1994), Gerard, C. and Gerald, N.,A~tm. Rev. hmttunol., j,~:775 (1994)]. The superfamily of 7TM or G-protein coupled receptors contains several hundred members able to recognize various messages such as photons, ions and amino acids among others [Schwartz, T.W., et al., H.,Trendt in Phartnacoi. Sci., 17 :213 (1996)].
[Dohltnan, H.,Ann. Rev. Biochem., x.1:653 (1991)]. [Schwartz. T.W., et al., H.,Fur J. Pharm. Sci., 2_:85 (1994)].

We describe herein the identification of a novel polypeptide (designated herein as PR0274) which has homology to the 7 uansmembrane segment receptor proteins and the Fn54 protein.

3. PR
The Diff 33 protein is over-expressed in mouse testicular tumors. At present its role is unclear, however, it may play a role in cancer. Given the medical importance of understanding the physiology of cancer, efforts are currently being under taken to identify new, native proteins which are involved in cancer. We describe herein the identification of a novel polypeptide which has homology to Diff 33, designated herein as PR0300.

4. PR0284 Efforts arre currently being undertaken to identify and characterize novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide, designated herein as PR0284.

5. PR0296 Cancerous cells often express numerous proteins that are not expressed in the corresponding normal cell type or are expressed at different levels than in the corresponding normal cell type. Many of these proteins are involved in inducing the transformation from a normal cell to a cancerous cell or in maintaining the cancer phenotype.
As such, there is significant interest in identifying and characterizing proteins that are expressed in cancerous cells.
We herein describe the identification and characterization of a novel polypeptide having homology to the sarcoma-amplified protein SAS, designated herein as PR0296.

6. P_R0329 immunoglobulin molecules play roles in many important mammalian physiological processes. The structure of immunogIobulin molecules has been extensively studied and it has been well documented that intact immunoglobulins possess distinct domains, one of which is the constant domain or F~ region of the immunoglobulin molecule. The F~ domain of an immunoglobulin, while not being directly involved in antigen recognition and binding, does mediate the ability of the imrnunoglobulin molecule, either uncomplexed or complexed with its respective antigen, to bind to F~ receptors either circulating in the serum or on the surface of cells. The ability of an F~ domain of an immunoglobuIin to bind to an F~ receptor molecule results in a variety of important activities, including for example, in mourtzing an immune response against unwanted foreign particles.
As such, there is substantial interest in identifying novel F~ receptor proteins and subunits thereof. We herein describe the identification and characterization of a novel polypeptide having homology to a high affinity immunoglobulin F~ receptor protein, designated herein as PR0329.

7. PR0362 Colorectal carcinoma is a malignant neoplastic disease which has a high incidence in the Western world, particularly in the United States: Tumors of this type often metastasize through lymphatic and vascular channels and result in the death of some 62>000 persons in the United States annually.

Monoclonal antibody A33 (mAbA33) is a marine immunoglobulin that has undergone extensive preclinical analysis and localization studies in patients inflicted with colorectal carcinoma (Welt et aL, J. Clln. Oncol. 8:1894-1906 (1990) and Welt et al.; J. Clin. Oncol. 12:1561-1571 (1994)). mAbA33 has been shown to bind to an antigen found in and on the surface of normal colon cells and colon cancer cells. In carcinomas originating from the colonic mucosa, the A33 antigen is expressed homogeneously in more than 95 % of the cases. The A33 antigen, however, has not been detecting in a wide range of other normal tissues, i.e., its expression appears to be rather organ specific Therefore, the A33 antigen appears to play an important role in the induction of colorectal cancer.
Given the obvious importance of the A33 antigen in tumor cell formation andlor proliferation, there is substantial interest in identifying homologs of the A33 antigen. In this regard, we herein describe the identification and characterization of a novel polypeptide having homology to the A33 antigen protein, designated herein as PR0362.

8. 80363 The cell surface protein HCAR is a membrane-bound protein that acts as a receptor for subgroup C of the adenoviruses and subgroup B of the coxsackieviruses. Thus, HCAR may provide a means for mediating viral infectiam of cells in that the presence of the HCAR receptor on the cellular surface provides a binding site for viral particles, thereby facilitating viral infection.
In light of the physiological importance of membrane-bound proteins and spcficially those which serve a cell surface receptor for viruses, efforts are currently being undertaken by both industry and academia to identify new, native membrane-bound reeptor proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe a novel membrane-bound polypeptide having homology to the cell surface protein HCAR
and to various tumor antigens including A33 and carcinoembryonic antigen, designated herein as PR0363, wherein this polypeptide may be a novel cell surface virus receptor or nunor antigen.

9. P80868 Control of cell numbers in mammals is believed to be determined, in part, by a balance between cell proliferation and cell death. One form of cell death, sometimes referred to as necrotic cell death, is typically characterized as a pathologic form of cell death resulting from some uauma or cellular injury. In contrast, there is another, "physiologic" form of cell death which usually proceeds in an orderly or controlled tnatirter. This orderly or controlled form of cell death is often referred to as "apoptosis" [see, e.g., Barr et al., BiolTechrtology, 12:487-493 (1994); Steller et al., Scie~e, x:1445-1449 (1995)]. Apoptotic cell death naturally occurs in many physiological processes, including embryonic development and clonal selection in the immune system [Itoh et al., ell, 66:233-243 (1991)). Decreased levels of apoptotic cell death have been associated with a variety of pathological conditions, including cancer, lupus, and herpes virus infection [Thompson, ci nce, x:1456-1462 (1995)]. Increased levels of apoptotic cell death may be associated with a variety of other pathological conditions, including AIDS, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, retinitis pigmentosa, cerebellar degon, aplastic anemia, myocardial infarction, stroke, reperfusion injury, and toxin-induced liver disease [see, Thotnpson, suoral. ' Apoptotic cell death is typically accompanied by one or more characteristic morphological and biochemical changes .in cells, such as condensation of cytoplasm, loss of plasma membrane microvilli, segmentation of the nucleus, degradation of chromosomal DNA or loss of mitochondria) function. A
variety of extrinsic and intrinsic signals are believed to trigger or induce such morphological and biochemical cellular changes [Raff, atu , 'l 6:397-400 (1992); Steller, supra; Sachs et al., Blood, 82:15 (1993)]. For instance, they can be triggered by hormonal stimuli, such as glucocorticoid hormones for immature thymocytes, as well as withdrawal of certain growth factors [Watanabe-Fukunaga et al., Na r , ,~,~5 :314-317 (1992)]. Also, some identified oncogenes such as myc, re), and EIA, and tumor suppressors, like p53, have been reported to have a xole in inducing apoptosis. Certain chemotherapy drugs and some forms of radiation have likewise been observed to have apoptosis-inducing activity [Thompson, supra).
Various molecules, such as tumor necrosis factor-a ("TNF-a"), tumor necrosis factor-/3 ("TNF-Vii" or "lymphotoxin-a~), lymphotoxin-(3 ("L'IT~i"), CD30 ligand, CD27 ligand, CD401igand, OX-40 ligand, 4-1BB ligand, Apo--I Iigand (also referred to as Fas ligand or CD95 ligand), and Apo-2 ligand {also referred to as TRAIL) have been identified as members of the tumor necrosis factor ("TNF") family of cytokines [See, e.g., Gross and Dower, Blood, X5:3378 3404 (1995; Pith et al., J. Biol. Chem., x:12687-12690 (1996); Wiley et al., mmu ' , 3_:673-682 (1995);
Browning et at., ~e , 22:847-856 (1993); Armitage et al. tore, 357:80-82 (1992), WO 97101633 published January 16, 1997; WO 97125428 published July 17, 1997]. Among these molecules, TNF-a, TNF-~3, CD30 ligand, 4-1BB
ligand, Apo-I ligand, and Apo-2 ligand {TRAIL) have been reported to he involved in apoptotic cell death. Both TNF-a and TNF-[3 have been reported to induce apoptotic death in susceptible tumor cells [Schmid et al., Proc~Natl.
d, l , 83:1881 (198; Dealtry et al., Eur. J~,,, X7:689 (1987)]. Zheng et al.
have reported that TNF-a is involved in post stimulation apoptosis of CD8-positive T cells [Zheng et al., Ngrure, 3:348-351 (1995)]. Other investigators have reported that CD30 ligand may be involved in deletion of self reactive T cells in the thymus (Amakawa et al., Cold Spring Harbor Laboratory Symposium on Programmed Cell Death, Abstr. No. 10, (1995)].
Mutations in the mouse FaslApo-1 receptor or ligand genes (called Ipr and gld, respectively) have been associated with some autoimmune disorders, indicating that Apo-1 ligand may play a role in regulating the clonal deletion of self reactive lymphocytes in the periphery [Krammer et al., Curr.
O~i lrnmunoi., ø:279-289 (1994);
Nagata et al., 'Sctettce, 2:1449-1456 (1995)]. Apo-l ligand is also reported to induce post-stimulation apoptosis in CD4-positive T lymph~ytes and in $ lymphocytes, and may be involved in the elimination of activated lymphocytes when their function is no longer needed [Kratnmer et al., ~unra;
Nagata et al., su . Agonist rtmuse monoclonal antibodies specifically binding to the Apo-1 receptor have been reported to exhibit cell killing activity that is comparable to or similar to that of-TNF-a [Yonehara ei al., 3. Exo.
Med., 19:1747-1756 (1989)].
Induction of various cellular responses mediated by such TNF fanuly cytokines is believed to be initiated by their binding to specific cell receptors. Two distinct TNF receptors of approximately 55-kDa (TNFRl) and 75-kDa (1'NFRZ) have been identified [Hohtnan et al., J. Biol. Chem:, x:14927-14934 (1989): Brockhaus et al., Proc.
Nat). Acad. Sci., $2:3127-3131 (1990); EP 417,563, published March 20, 1991]
and human and mouse cDNAs corresponding to both receptor types have been isolated and characterized [Loetscher et al., Ce]l, ~3,:351 (1990);
_. Schali et al., ~g ji , ø1;361 (1990); Smith et al., S 'enc , x:1019-1023 (1990); Lewis et al., Proc. Nat). Acad. Scs, $$:2830-2834 (1991); Goodwin et al., Mol. Cell: Bioj" ~:3020-3026 (1991)].
Extensive polymorphisms have been .. associated with both TNF receptor genes (see, e.g., Takao et al., lmmunoeenetics, x:199-203 (1993)]. Both TNFRs share the typical structure of cell surface receptors including extracellular, uansmembrane and inuacellular regions.

The extracellular portions of bath receptors are found naturally also as soluble TNF-binding proteins [Nophar, Y.
et al., EMBO J., _9:3269 (1990); and Kohno, T. et al., Proc. Nat!. Acad. Sci.
U S.A., 87:8331 (1990)]. More recently, the cloning of recombinant soluble TNF receptors was reported by Hale et al. [J. Cell. Biochem.
Supplement 15F, 1991, p. 113 {P424)].
The extracellular portion of type 1 and type 2 TNFRs (TNFRl and TNFR2) contains a repetitive amino acid S sequence pattern of four cysteitte-rich domains (CRDs) designated 1 through 4, starting from the NH~-terminus. Each CRD is about 40 amino acids long and contains 4 to 6 cysteine residues at positions which are well conserved [Schail et al., ~; Loetscher et al., supra; Smith et al., su r ; Nophar et al., su r ;
Kohno et al., su ra . In TNFRl, the approximate boundaries of the four CRDs are as follows: CRDI- amino acids 14 to about 53; CRD2- amino acids from about 54 to about 97; CRD3- amino .acids from about 98 to about 138; CRD4-amino acids from about 139 to about 167. In TNFR2, CRDI includes amino acids 17 to about 54; CRD2- amino acids from about 55 to about 97;
CRD3- amino acids from about 98 to about 140; and CRD4- amino acids from about 141 to about 179 [banner et al., gel , x:431-435 (1993)]. The potential role of the CRDs in ligand binding is also described by Banner et al., a ra.
A similar repetitive pattern of CRDs exists in several other cell-surface proteins, including the p75 nerve growth factor receptor (NGFR) [3ohnson et al., Cell, 47:545 (1986); Radeke et al., Nature, 325:593 (1987)], the B
cell antigen CD40 [Stamenkovic et al., EM O ., _8:1403 (1989)], the T cell antigen OX40 [Mallet et al., M)_ BO J., Q:1063 {1990)] and the Fas antigen [Yonehara et al., supra and Itoh et al., Cell, 66:233-243 (199I)]. CRDs are also found in the soluble TNFR (sTNFR)-like T2 proteins of the Shope and myxoma poxviruses [Upton et al., ViroloQV, 160:20-29 (1987); Smith et al., Biochem Biophvs Resj Commun., x:335 (1991);
Upton et al., ViroloQV, ,x:370 (1991)). Optimal alignment of these sequences indicates that the positions of the cysteine residues are well conserved.
Tlxse receptors are sometimes collectively referred to as members of the TNF/NGF receptor superfamily. Recent studies on p75NGFR showed that the deletion of CRDI [Weicher, A.A. et al., Proc. Nat!. Acad. Sci. USA, 8$:159-163 {1991)] or a 5-amino acid insertion in this domain [Yan, H. and Chao, M.V., 1. Biol. Chem., 266:12099-12104 (1991)] had little or no effect on NGF binding [Yan, H. and Chao, M.V., a ra .
p75 NGFR contains a proline-rich stretch of about 60 amino acids, between its CRD4 and transmembrane region, which is not involved in NGF binding [Peetre, C. et al., Eur. 1. Hematol., 4:414-419 (1988); Seckinger, P. et al., 1. Biol. Chem:, 264:11966-11973 (I989); Yan, H. and Chao, M.V., su . A similar proline-rich region is found in TNFR2 but not in TNFRi.
The TNF family ligands identified to date, with the exception of lymphotoxin-a, are type 11 transmembrane proteins, whose C-terminus is ex>racellular. 1n contrast, most receptors in the TNF receptor ('TNFR) family identified to date are type I transmembrane proteins. In both the TNF ligand and receptor families, however, homology identified between family members has been found mainly in the extracellular domain ("ECD "). Several of the TNF
family cytokines, including TNF-a, Apo-1 Iigand and CD40 ligand, are cleaved proteolytically at the cell surface;
the resulting protein in each case typically forms a homotrimeric molecule that functions as a soluble cytokine. TNF
receptor family proteins are also usually cleaved proteolytically to release soluble receptor ECDs that can function as inhibitors of the cognate cytokines.
Recently, other members of the TNFR family have been identified. Such newly identified members of the TNFR family include CART, HVEM and osteoprotegerin (OPG) [Brojatsch et al., Cep, x:845-855 (1996);
Moragomery et al., r,e,], ]x'1:427-436 (1996); Marsters et al., J. Biol.
Chem., 2:14029-14032 (1997); Simonet et al., ~, $Q:309-319 (1997)]. Unlike other known TNFR-like molecules, Simonet et al:, swra, report that OPG
contains no hydrophobic cransmembrane-spanning sequence.

Moreover, a new member of the TNF/NGF receptor family has been identified in mouse, a receptor referred to as "GITR" for "glucocorticoid-induced tumor necrosis factor receptor family-related gene" [Nocentini et al., Proc.
Natl. Acad. Sci. USA 94:6216-6221 (1997)). The mouse GITR receptor is a 228 amino acid type I transrnembrane protein that is expressed in normal mouse T lymphocytes from thymus, spleen and lymph nodes. Expression of the mouse GITR receptor was induced in T lymphocytes upon activation with anti-CD3 antibodies, Con A or phorbol 12-myristate 13-acetate. It was speculated by the authors that the mouse GITR
receptor was involved in the regulation of T cell receptor-mediated cell death.
1n Marsters et al., Curr. Biol., ø:750 (1996), investigators describe a full length native sequence human polypeptide, called Apo-3, which exhibits similarity to the TNFR family in its extracellular cysteine-rich repeats and resembles TNFRI and CD95 in that it contains a cytoplasmic death domain sequence [see also Marsters et al., C~trr.
Biol., 6_:1669 (1996)). Apo-3 has also been referred to by other investigators as DR3, wsl-1 and TRAMP
[Chinnaiyan et al., Science, 274:990 {1996); Kitson et al., Na re, x_4:372 (1996); Bodmer et al., Immunitv, ø:79 (1997)].
Pan et al. have disclosed another TNF receptor family member referred to as "DR4" [Pan et al., Science, 27:111-113 (1997)]. The DR4 was reported to contain a cytoplasmic death domain capable of engaging the cell suicide apparatus. Pan et al. disclose that DR4 is believed to be a receptor for the ligand known as Apo-2 ligand or TRAIL.
In Sheridan et al., cience, 277:818-821 (1997) and Pan et al., Science, 277:815-818 (1997), another molecule believed to be a receptor for the Apo-2 ligand (TRAIL) is described.
That molecule is referred to as DR5 (it has also been alternatively referred to as Apo-2). Like DR4, DR5 is reported to contain a cytoplasmic death domain and be capable of signaling apoptosis In Sheridan et al., supra, a receptor called DcRl (or alternatively, Apo-2DcR) is disclosed as being a potential decoy receptor for Apo-2 Iigand (TRAIL). Sheridan et al. report that DcRl can inhibit Apo-2 ligand function in vitro. See also, Pan et al., ~Dra, for disclosure on the decoy receptor referred to as TRID.
For a review of the TNF family of cytokines and their receptors, see Gruss and Dower, supra.
As presently understood, the cell death program contains at least three important elements - activators, inhibitors, and effectors; in C. elegans, these elements are encoded respectively by three genes, Ced-4, Ced 9 and Ced 3 [Steller, Science, x:1445 (1995); Chinnaiyan et al., cienee, x:1122-1126 (1997); Wang et al., 11, Q~:1-20 (1997)]. Two of the TNFR family members, TNFRl and Fas/Apol (CD95), can activate apoptotic cell death [Chinnaiyan and Dixit, Current Biology, ø:555-562 (1996); Fraser and Evan, ell; $5_:781-784 (1996)]. TNFRl is also known to mediate activation of the transcription factor, NF-tcB
jTartaglia et al., ,~, 74:845-853 (1993); Hsu et al., Cg[j, $4:299-308 (1996)). In addition to some ECD homology, these two receptors share homology in their intracellular domain (ICD) in an oligometization interface known as the death domain [Tartaglia et al., supra; Nagata, t~, 88:355 (1997)]. Death domains are also found in several metazoan proteins that regulate apoptosis, namely, the Drosophila protein, Reaper, and the trtatntnalian proteins referred to as FADD/MORTI, TRADD, and RIP
[Cleaveland and Ihle, t~g[l_, x:479-482 (1995)).
<, Upon ligand binding and receptor clustering, TNFR1 and CD95 are believed to recruit FADD into a death-inducing signalling complex. CD95 purportedly binds FADD directly, while TNFRI
binds FADD indirectly via TRADD [Chinnaiyan et al., ~, $j,:505-512 (1995); Boldin et al., J. Biol.
Chem., X0:387-391 {1995); Hsu et al., supra; Chinnaiyan et al., J. Biol. Chem.; x:4961-4965 (1996)]. It has been reported that FADD serves as an adaptor protein which recruits the Ced-3-related protease, MACHa/FLICE
(caspase 8), into the death signalling complex [Boldin et al., Cell, $5_:803-8i5 (1996); Muzio et al., Cell, x:817-827 (1996)]. MACHa/FLiCE appears to be the trigger that sets off a, cascade of apoptotic proteases, including the interieukin-1 p converting enryme (ICE) and CPP321Yama, which may execute some critical aspects of the cell death programme [Eraser and Evan, su ra .
It was recently disclosed that programmed cell death involves the activity of members of a family of cysteine proteases related to the C. elegans cell death gene, ced 3, and to the mammalian IL-1-converting enzyme, ICE. The activity of the ICE and CPP32/Yama proteases can be inhibited by the product of the cowpox virus gene, crmA [Ray et al., C~el , 69:597-604 (1992); Tewari et al., CeII, 81:801-809 (1995)].
Recent studies show that CrmA can inhibit TNFRI- and CD95-induced cell death [Enari et al., Nature, 75:?8-81 (1995};
Tewari et al., ~. Biol. Chem., X70:3255-3260 (1995)].
As reviewed recently by Tewari et al., TNFRl, TNFR2 and CD40 modulate the expression of proittflammatory and costirrtulatory cytokines, cytokine receptors, and cell adhesion molecules through activation of the transcription factor, NF-xB [Tewari et al., Curr. Op. Genet. Develop., f:39-44 (1996)]. NF-xB is the prototype of a family of dimeric transcription factors whose subunits contain conserved Rel regions [Verma et al., Genes ev to , 9_:2723-2735 (1996); Baldwin, Ann. Rev. Immunol., 14:649-681 (1996)].
In its latent form, NF-xB is compIexed with members of the IxB inhibitor family; upon inactivation of the IxB in response to certain stimuli, released NF-xB translocates to the nucleus where it binds to specific DNA
sequences and activates gene transcription.

10. gR0382 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized, including the serine proteases which exhibit specific activity toward various serine-containing proteins. The mammalian protease enzymes play important roles in biological processes such as, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
In light of the important physiological roles played by protease enzymes, efforts are currently being undertaken by both industry and academia to identify new, native protease homologs. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, HIein et al., Proc. Natl. Acad. Sci., Q~:7108-7113 (1996);
U.S. Patent No. 5,536,637)]. We herein describe the identification of novel polypeptides having homology to serine protease enzymes, designated herein as PR0382 polypeptides.

11. PR0545 The ADAM (A Disincegtin And Metalioprotease) family of proteins of which meltrin is a member may have an important role in cell interactions and in modulating cellular responses.
[see, for example, Gilpin et al., J. Biol.
to , 273(1):157-166 (1998)]. The ADAM proteins have been implicated in carcinogenesis. Meltrin-a (ADAM 12) is a myoblast gene product reported to be required for cell fusion. [Harris et al., J. Cell. Biochem., 67(11:136-142 (i997), Yagami-Hirotnasa et al., Nature, X7:652-656 (1995)]. The meitrins contain disintegrin and metailoprotease domains and are implicated in cell adhesive events involved in development, through the integrin-binding disintegrin domain, but also have an anti-adhesive function through a zinc-dependent metalloprotease domain. [Alfandari et al., Devel: Biol., 18212):314-330 (1997)]. Given the medical importance of cell fusion and modulation of cellular responses in carcinogenesis and other disease mechanisms, efforts are currently being under taken to identify new, native proteins which are involved in cell fusion and modulation of cellular responses. We describe herein the identification of a novel polypeptide which has homology to meitrin, designated herein as PR0545.

12. PR 17 CD24 is a protein that is associated with the cell surface of a variety of different cells of the marrurtalian immune system, including for example, neutrophils, monocytes and some lymphocytes, for example, B lymphocytes.
CD24 has been shown to be a ligand for the platelet-associated surface glycoprotein P-selectin (also known as granule membrane protein-140 or GMP-140), a glycoprotein that is constitutively synthesized in both platelets and endothelial cells and becomes exposed on the surface of platelets when those cells become activated. In this way, P-selectin mediates the calcium-dependent adhesion of activated platelets and endothelial cells to the various cells of the immune system that express one or more iigands for the P-selectin molecule, particularly CD24. This mechanism allows for recruitment of immune system cells to locations where they are most needed, for example, sites of injury. Thus, there is substantial interest in identifying novel polypeptides that exhibit homology to the cell surface antigens of the immune system cells. We herein describe the identification and characterization of a novel polypeptide having homology to the CD24 protein, wherein that novel polypeptide is herein designated PR0617.

13. P80700 Protein-disulfide isomerase (PDn is a catalyst of disulfide formation and isomerization during protein folding. It has two catalytic sites housed in two domains homologous to thioredoxin, one near the N terminus and the other near the C terminus. [See for example, Gilbert HF, J.Biol.Chem., 47:29399-29402 (1997), Hayfield K,I, Science, 278:1954-1957 (1997) and Puig et al., .l.Biol.Chem., 52:32988-32994 (1997)]. PDI is useful for formation of natural type disulfide bonds in a protein which is produced in aprokaryotic cell. (See also, U.S. Patent Nos.
5,700,659 and 5>700,678).
Thus, PDI and molecules related thereto are of interest, particularly for ability to catalyze the formation of disulfide bonds. Moreover, these molecules are generally of interest in the study of redox reactions and related processes. PDI and related molecules are further described in Darby, et al., Biochemistry 34, 11725-I 1735 (1995).
We herein describe the identification and charactezization of novel polypeptides having homology to protein disulfide isomerase, designated herein as PR0700 polypeptides 14. P80702 Conglutinin is a bovine serum protein that was originally described as a vertebrate lectin protein and which belongs to the family of C-type lectins that have four characteristic domains, (1) an N-termirtai cysteine-rich domain, {2) a collagen-like domain; (3) a neck domain and (4) a carbohydrate recognition domain (CRD). Recent reports have demonstrated that bovine conglutinin can inhibit hemagglutination by influenza A viruses as a result of their lectin properties (F.da et al., Biochem. J. 316:43-48 {1996)). h has also been suggested that lectins such as conglutinin can function as immunoglobulin-independent defense molecules due to complement-mediated mechanisms. Thus, conglutinin has been shown to be useful for purifying immune complexes in vitro and for removing circulating immune complexes from patients plasma in vivo (Lim etaL, Biochem. Bio~hvs.
Res. Commun. 218:260-266 (1996)).
We herein describe the identification and characterization of a novel polypeptide having homology to the conglutinin protein, designated herein as PR0702.

15. PR0703 Very-long-chain acyl-CoA synthetase ("VLCAS") is a long-chain fatty acid transport protein which is active in the cellular transport of long and very long chain fatty acids. [see for example, Uchida et al., J Biochem (Tokyo) 119(3):565-571 (1996) and Uchiyama et al., J Biol Chem 271(48):30360-30365 (1996). Given the biological importance of fatty acid transport mechanisms, efforts are currently being under taken to identify new, native proteins which are involved in fatty acid transport. We describe herein the identification of a novel polypeptide which has homology to VLCAS, designated herein as PR0703.

16. PR0705 The glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored proteoglycans that, by virtue of their cell surface localization and possession of heparin sulfate chains, may regulate the responses of cells to numerous heparin-binding growth factors, cell adhesion molecules and extraceliular matrix components. Mutations in one glypican protein cause of syndrome of human birth defects, suggesting that the glypicans may play an important role in development (Litwack et al., v. D n 211:72-87 (1998)). Also, since the glypicans may interact with the various extracelhtlar matrices, they may also play important roles in wound healing (McGrath et al., Pa o1.
183:251-252 (1997)). Furthermore, since glypicans are expressed in neurons and glioma cells, they may also play an important role in the regulation of cell division and survival of cells of the nervous system (Liang et al., J. ell iol. 139:851-864 (1997)). It is evident, therefore, that the glypicans are an extremely important family of proteoglycans. There is, therefore, substantial interest in identifying novel polypeptides having homology to members of the glypican family. We herein describe the identification and characterization of a novel polypeptide having homology to K-glypican, designated herein as PR0705.

17. PR0708 Aryl sulfatases are enzymes that exist in a number of different isoforms, including aryl sulfatase A (ASA), aryl suifatase B (ASB) and aryl sulfatase C (ASC), and that function to hydrolyze a variety of different aromatic sulfates. Aryl sulfatases have been isolated from a variety of different animal tissues and microbial sources and their structures and functions have been extensively studied (see, e.g., Nichol and Roy, ~. Biochem. 55:643-651 (1964)).
ASA deficiency has been reported to be associated with metachromatic leukodystrophy (MLD) (tiles et al., re DiaQn. 7(4):245-252 (1987) and I~ierska et al., Am. J. Med. ('~gnet. 26(3):629-635 (1987)). Additionally, other groups have reported that aryl sulfatases have been found in high levels in natural killer cells of the immune system and have hypothesized a possible role for these enzymes in NK cell-mediated cellular lysis (see, e.g., Zucke:-Franklin et al., Proc. rlatl. Acad. Sci. USA 80(22):6977-6981 (1983)). Given the obvious physiological importance of the aryl sulfatase enzymes, there is a substantial interest in identifying novel aryl sulfatase homolog polypeptides. We herein describe the identification and characterization of novel polypeptides having homology to the aryl sulfatases, wherein these novel polypeptides are herein designated PR0708 polypeptides.

18. PR 320 Fibulin-1 is a cysteine-rich, calcium-binding extracellular matrix (ECM) component of basement membranes and connective tissue elastic fibers and plasma protein, which has four isoforms, A-D, derived from alternative splicing. Fibulin-1 is a modular glycoprotein with amino-temlinai anaphlatoxin-like modules followed by nine epidermal growth factor (EGF)-like modules and, depending on alternative splicing, four possible carboxyl termini.
Fibulin-2 is a novel extracellular matrix protein frequently found in close association with microfibrils containing either fibronectin or fibrilIin. There are multiple forms of fibulin-1 that differ in their C-terminal regions that are produced through the process of alternative splicing of their precursor RNA.
(see for example Tran et al., atrix '~ol, 15(7):479-493 (1997).]
Northern and Western blotting analysis of l6 cell lines established from tumors formed in athymic mice and malignant cell lines derived from patients indicate that low expression of fibulin-1D plays a role in tumor formation and invasion. [Qing et al., Oncooge_ne, 18:2159-2168 (1997)]. Ovarian-cancer cells are charactet''tzed by their ability to invade freely the peritoneal cavity. It has been demonstrated that estradiol stimulates the proliferation of estrogen-receptor (ER)-positive ovarian-cancer cells, as well as expression of fibulin-1. Studies on the effect of fibulin-1 on motility of the MDA-MB231 breast-cancer cell line, indicated inhibition of haptotactic migration of MDA-MB231 cells, and the authors concluded that fibulin-1 can inhibit cancer cell motility in vitro and therefore has the potential to inhibit tumor invasion. [Hayashido et al., Int J Cancer , 75(4):654-658 {1998)]
Thus, fibulin, and molecules related thereto are of interest, particularly for the use of preventing cancer.
Moreover, these molecules are generally of interest in the study of connective tissue and attachment molecules and related mechanisms. Fibulin and related molecules are further described in Adams, et al., J. Mol. B_'~,., 272(2):226-36 {1997); Kielry and Shuttleworth, ~icrosc. Res. Tech., 38(4):413-27 (1997); and Child. J. Card. Surg..
12(2Supp.):i31-5 (1997).
We herein describe the identification and characterization of novel polypeptides having homology to fibulin;
designated herein as PR0320 polypeptides.

19. R 24 Oxidoreductases are enzymes that catalyze a reaction in which two molecules of a compound interact so that one molecule is oxidized and the other is reduced, with a molecule of water entering the reaction. There are many different types of oxidoreductase enzymes that play very important physiological roles in the mammalian organism.
Some of the most important oxidoreductases include, for example, lyases, lactases, cholesterol oxidases, and the like.
These enzymes play roles in such essential processes as digestion, signal transduction, maintenance of ionic homeostasis, and the like. As such, given that oxidoreductase enzymes fmd various essential uses in the mammalian organism, there is a substantial interest in identifying novel oxidoreductase enzyme homologs. We herein describe the identification and characterization of a novel polypeptide having homology to oxidoreductases, designated herein as PR0324.

20. PR 51 Prostasin is a novel human serine proteinase purified from human seminal fluid. Immunohistochemical localization reveals that prostasin is pzesent in epithelial cells and ducts of the prostate gland. The cDNA for prostasin has been cloned and characterized. Southern blot analysis, following a reverse transcription polymerase chain reaction. indicates that prostasin mRNA is expressed in prostate, liver, salivary gland. kidney, lung, pancreas, colon, bronchus, renal proximal tubular cells, and prostate carcinoma LNCaP
cells. Cellular localization of prostasin mRNA was identified within epithelial cells of the human prostate gland by in situ hybridization histochemistry. [See for example, Yu et al., yiol Chem. (1994) 2b9(29):I8843-18848, and Yu et al., J Biol Chem. (1994) 270(22):13483-13489] .
Thus, prostasin, and molecules related thereto are of interest, particularly for the study, diagnosis and treatment of medical conditions involving the prostate. Prostasin and related molecules are further described in Yu et al., Genomics (i996) 32(3):334-340. We herein describe the identification and characterization of novel polypeptides having homology to prostasin, designated herein as PR0351 polypeptides.

21. RP 0352 Buryroplvlin is a milk glycoprotein that constitutes more than 40% of the total protein associated with the fat globule membrane in mammalian milk. Expression of buryrophilin mRNA has been shown to correlate with the onset of milk fat production toward the end pregnancy and is maintained throughout kactation. Butyrophilin has been identified in bovine, murine and human (see Taylor et al., Biochim. BioQh~s.
Acta 1306:1-4 (1996), Ishii et al., Biochim. Bio h~vsy,Ac,la 1245:285-292 (1995), Mather et al., J. Daiy Sci.
76:3832-3850 (1993) and Banghart et al., J. Biol. Chem. 273:4171-4179 (1998)) and is a type I transmembrane protein that is incorporated into the fat globulin membrane. It has been suggested that buryrophilin may play a role as the principle scaffold for the assembly of a complex with xanthine dehydrogenase/oxidase and other proteins that function in the budding and release of milk-fat globules from the apical surface during lactation (Banghart et al., s r Given that butyropliiIin plays an obviously innportant role in mammalian milk production, there is substantial interest in identifying novel buryropltilin homologs, We herein describe the identification and characterization of a novel polypeptide having homology to buryrophilin> designated herein as PRO352.

22. RP 0381 Tile immunophilins are a family of proteins that function as receptors for immunosuppressant drugs, such as cyclosporin A,1x506, and rapamycin. The immunophilins occur in two separate classes, (1) the FK506-binding proteins (FKBPs), which bind to FIC506 and rapamycin, and (2) the cyclophilins, which bind to cyclosporin A. With regard to the FI~506-binding proteins, it has been reported that the FK506IFKBP complex functions to inhibit the activity of the serine/threonine protein phosphatase 2B (calcineurin), thereby providing immtmosuppressant activity (Gold, Mol. Neur bo ioI. 15:285-306 (1997)). It has also been reported that the FKBP immunoplulins are found in the marnrttalian nervous system and may be involved in axonal regeneration in the central nervous system through a tnechanasm that is it>depettdent of the process by which immunosuppression is achieved (Gold, supra). Thus, there is substantial interest in identifying novel polypeptides having homology to the FKBP immunopltilins. We herein describe the identification and characterization of a novel polypeptide having homology to an FKBP immunophiiin protein, designated herein as PR0381.

23. PR0386 Mammalian cell membranes perform very important functions relating to the structural integrity and activity of various cells and tissues. Of particular interest in membrane physiology is the study of transmembrane ion WO 99/46281 PCT/US99/05~28 channels which act to directly control a variety of physiological, pharmacological and cellular processes. Numerous ion channels nave been identified including calcium (Ca); sodium (Na) and potassium (K) channels, each of which have been analyzed in detail to determine their roles in physiological processes in vertebrate and insect cells.
One type of cell membrane-associated ion channel, the sodium channel, plays an extremely important role in a cell's ability to maintain ionic homeostasis as well as transmit intracellular and extracellular signals. Voltage-gated sodium channels in brain neurons have been shown to be complexes of a pore-forming alpha unit with smaller beta-1 and beta-2 subunits psom et al., Cell 83:433-442 (1995)). Given the obvious importance of sodium channels in cellular homeostasis and other important physiological functions, there is a significant interest in identifying novel polypeptides having homology to soditun channel subunits. We herein describe the identification and characterization of a novel polypeptide having homology to the beta-2 subunit of the rat sodium channel, designated herein as PR0386.

24. P~,,0540 Lecithin~holesterol acyltransferase ("LCAT"), also known as phosphatidylcholine-sterol acyltransferase is a key e~ in the inuavascular metabolism of high density lipoproteins, specifically in the process of cholesterol metabolism. [see, for example, Brousseau et al., J. Lig~d Res., 38(12):2537-2547 (1997), Hill et al., Biochem. J., 294:879-884 (1993), and Drayna et al., Na a 327 (6123):632-634 (1987)]. Given the medical importance of lipid metabolism, efforts are currently being under taken to identify new, native proteins which are involved in lipid transport. We describe herein the identification of a novel polypeptide which has homology to LCAT, designated herein as PR0540.

25. I5 Synaptogyrin is a synaptic vesicle protein that is uniformly distributed in the nervous system. The cDNA
encoding synaptogyrin has been cloned and sequenced and the sequence predicts a protein with a molecular mass of 25,900 D with four membrat~-sparming domains. Synaptogyrin has been implicated in membrane traffic to and from the plasma membrane. Stenius et al., J. Cell: Biol. I31(6-2):1801-1809 (1995).
In addition, a novel isoform of synaptogyrin called cellugyrin exhibits sequence identity with synaptogyrin.
In rat tissues, cellugyrin and synapwgyriru are expressed in mirror image patterns. Cellugyrin is ubiquitously present in all tissues tested with the lowest levels in brain tissue, whereas synaptogyrin protein is only detectable in brain. In rat tissues, cellugyrin and synaptogyrinc are expressed in mirror image patterns. The synaptic vesicle protein synaptogyrin may be a specialized version of a ubiquitous protein, cellugyrin, with the two proteins sharing structural similarity but differing in locati~ation. This finding supports the emerging concept of synaptic vesicles as the simplified and specialized form of a generic trafficllong organelle. (lanz et al., J. Biol. Chem. 273(5):2851-285? (1998)] . The sequence for cellugyrin derived from the Norway rat, Rattus norvegicus has been deposited in the Genbank database on 23 December 1997, designated accession number AF039085. See also, lanz et al., J.
Biol. Chem. 273 (1998), in press.
Give the medical importance of synaptic transmission, efforts are currently being under taken to identify new, native proteins that may be part of a simplified and specialized generic trafficking organelle in the form of synaptic vesicles. We descn'be herein the identification of a novel polypeptide which has homology to synaptogyrin, designated herein as PR06I5.

26. PR 618 Enteropeptidase is a key enzyme in the intestinal digestion cascade specifically cleaves the acidic propeptide from trypsinogen to yield active trypsin. This cleavage initiates a cascade of proteolytic reactions leading to the activation of many pancreatic zymogens.
See, for example, Matsushima et al., J. Biol. Chem. 269(31):19976-19982 (1994), Kitamoto et al., Proc. Nat. Acad.
Sci., 91(16):7588-7592 (1994). Enterokinase (enteropeptidase) is a related to mammalian serine proteases involved in digestion, coagulation, and ftbrinolysis. LaVallie et al., J Biol Chem., 268(31):23311-23317 (1993).
Given the medical importance of digestive processes, efforts are currently being under taken to identify new, native proteins that may be involved in digestion, coagulation, and fibrinolysis. We describe herein the identification of a novel polypeptide which has homology to enteropeptidasc, designated herein as PR0618.

27. PRQ'119 Lipoprotein lipase is a key enzyme that mediates the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins (Dugi et al., J. Biol. Chem._ 270:25396-25401 (1995)). Moreover, lipoprotein lipase has been shown to mediate the uptake of lipoproteins into cells, wherein cellular uptake of lipoproteins is initiated by binding of lipoprotein lipase to cell surface proteoglycans and to the low density lipoprotein (LDL) receptor-related protein (Krapp et al., J. Lipid Res. 36:2362-2373 (1995)).
Thus, it is clear that lipoprotein lipase plays an extremely important role in lipoprotein and cholesterol metabolism.
There is, therefore, substantial interest in identifying novel polypeptides that share sequence homology andlor biological activity with lipoprotein lipase. We herein describe the identification and characterization of a novel polypeptide having sequence homology to Lipoprotein lipase H, designated heein as PR0719.

28. PR0724 The low density lipoprotein (LDL) receptor is a membrane-bound protein that plays a key role in cholesterol homeostasis, mediating cellular uptake of lipoprotein particles by high affinity binding to its ligands, apolipoprotein (apo) B-100 and apoE. The ligand-binding domain of the LDL receptor contains 7 cysteine-rich repeats of approximately 40 amino acids, wherein each repeat contains 6 cysteines, which form 3 infra-repeat disulfide bonds.
Terse unique strucaual features provide the LDL receptor with its ability to specifically interact with apo B-100 and apoE, thereby allowing for tratuport of these lipoprotein particles across cellular membranes and metabolism of their co»potrettts. Soluble fragments containing the extracellular domain of the LDL
receptor have been shown to retain tl~ ability to interact with its specific lipoprotein ligands (Simmons et al., ~i Biol. ,~Iem. 272:25531-25536 (I997)).
Thus, it is clear that the LDL receptor is intimately involved in important physiological activities related to cholesterol metabolism. As such, there is substantial interest in identifying novel LDL
receptor homolog proteins. We herein describe the identification and characterization of a novel polypeptide having homology to the human LDL receptor protein, designated herein as PR0724..

29. PR0772 Expression of the human gene A4 is enriched in the colonic epithelium and is transcriptionally activated on differentiation of coIonie epithelial cells in vitro (Oliva et al., Arch.
Bioc,~em_Bionhvs. 302:183-192 (1993) and Oliva et al., Am. J~ltvsiol. 272:C957-C965 (1997)). A4 cDNA contains an open reading frame that predicts a polypeptide WO 99/46281 PCTlUS99/05028 of approximately 17 kilodaltons in size. Hydropathy analysis of the A4 protein revealed four putative membrane-spanning.alpha-helices. lmmunocytochemical studies of cells expressing A4 protein indicated that expression is localized to the endoplasmic, reticulum. The four membrane-spanning domains and the biophysical characteristics of the A4 protein suggest that it belongs to a family of integral membrane proteins called proteolipids, some of which muitimerize to form ion channels. In fact, preliminary evidence has suggested that A4 may itself multimerize and take on the properties of an ion channel (Oliva et al., Am. ~,~hysiol.
272:C957-C965 (1997)}. Given the importance of ion channels in maintaining cellular homeostasis, there is a significant interest in identifying novel polypeptides having homology to known and putative ion channels. We herein describe the identification and characterization of a novel polypeptide having homology to the putative ion channel protein, A4, designated herein as PR0772.

30. PR0852 Proteases are enzymatic proteins which are involved in a Large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different rnaimnalian and non-mammalian organisms have been both identified and characterized. The marntnalian protease enzymes play important roles in many different biological processes including, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
In light of the important physiological roles played by protease enzymes, efforts are currently being undertaken by both industry and academia to identify new, native protease homologs. Many of these efforts are focused on the screening of tnatnntalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Aeg~l. Sci., Q~:7I08-7113 (1996); U,S. Patent No.
5,536,637)]. We herein describe the identification of novel polypeptides having homology to various protease enzymes, designated herein as PR0852 polypeptides.

31. PR0853 Studies have reported that the redox state of the cell is an important detertrtinattt of the fate of the cell.
Furthermore, reactive oxygen species have been reported to be eytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy.
Thus, the coturol of oxidation and reduction is important for a number of reasons, including the control and prevention of strokes, heart attacks, oxidative stress, hypertension and tray be associated with the development of malignancies. The levels of antioxidant enzymes, such as reductases, which catalyze the conversion of reactive oxygen species to water have been shown to be low in cancer cells. In particular, malignant prostate epithelium may have lowered expression of such antioxidant enzymes [faker et ., Pros a 32(4):229-233 (1997)]. In this regard, reductases, are of interest. In addition, the transcription factors, NF-kappa B and AP-1, are known to be regulated by redox state and to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis and diabetic complications. Publications further describing this subject matter include Engman et al., Anticancer Res. lGreecel, 17:4599-4605 (1997), Kelsey, et al., Br. J. Cancer, 76('n:852-4 (1997);
Friedrich and Weiss, J. Theor. J iol., 187(4):529-40 (1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997).
Given the physiological importance of redox reactions in vitro, efforts are currently being under taken to identify new, 1~

native proteins which are involved in redox reactions. We describe herein the identification of a novel prostate specific polypeptide which has sequence similarity to reductase, designated herein as PR0853.
32. R 86 Neurofascin is a member of the LI subgroup of the cellular adhesion molecule ("CAM") family of nervous system adhesion molecules and is involved in cellular aggregation. Cell-cell recognition and patterning of cell contacts have a critical role in mediating reversible assembly of a wide variety or transcelluiar complexes in the nervous system. Cell interactions may be regulated through modulation of ankyrin binding to neurofascin. See, for example, Tuvia et al., Proc. Nat Acad. Sci., 94(24) 12957-12962 (1997).
Neurofascin has been described as a member of the Ll subgroup of the immunoglobulin superfamily implicated in neurite extension during embryonic development for which numerous isoforms have been detected at various stages of development. See also Hassel et al., J. Biol. Chem., 272(45) 28742-28749 (1997), Gtvmet., dell. Tissue Res.
290(2) 423-428 (1997), Garver et al., J. Cell,. Biol., 137:703-714 (1997), and Lambent et al., J. Neurosci., I7:7025-7-36 (1997),.
Given the physiological importance of cellular adhesion molecules and development of the nervous system in vivo, efforts are currently being under taken to identify new, native proteins which are involved in regulation of cellular interactions in the nervous system. We describe herein the identification and characterization of a novel polypeptide which has sequence similarity to neurofascin, designated herein as PR0860.

33. R 84 The CMRF35 monoclonal antibody was used to identify a cell membrane antigen, designated CMRF35, which is present on the surface of monocytes, neutrophils, a proportion of peripheral blood T and B lymphocytes and lymphocytic cell lines. The CMRF35 cDNA encodes a novel integral membrane glycoprotein member of the immunoglobulin (Ig) gene superfamily. The molecule comprises (a) a single extracellular Ig variable domain remarkably similar to the Fc receptor for polymeric IgA and IgM, (b) a membrane-proximal domain containing a high proportion of proline, serine and threonine residues that was predicted to be heavily O-glycosylated, (c) an unusual transmembrane anchor that contained a glutamic acid and a proline residue and (d) a short cytoplasmic tail.
Transcripts encoding the CMRF35 protein have been detected in early monocytic cell lines, in peripheral blood T
cells and in some B lymphoblastoid cell lines, conftrtning the results of immunocytological staining. Jackson et al., Eur. 1. Irrunurtol. 22(5):1157-1163 (1992). CMRF-35 molecules are differentially expressed in hematopoietic cells, and the expression of the antigen was shown to be markedly influenced by stimulation with mitogens and cytokines.
See, for example, Clark et al., Exp. Hematol. 25(8):759 (1997), Daish et al., Immunol. 79(1):55-63 (1993), and Clark et al., Tissue Antiee_ns 48:461 (1996).
Given the physiological importance of the immune system and antigens associated with various immune system cells, efforts are currently being under taken to identify new, native proteins which are expressed on various cells of the immune system. We describe herein the identification of a novel polypepfide which has sequence similarity to CMRF35, designated herein as PR0846.

34. PR0862 Lysozyme is a protein which is widely distributed in several human tissues and secretions including milk, tears and saliva. It has been demonstrated to hydrolyze linkages between N-aceryiglucosamines. It has been WO 99!46281 PCTIUS99J05028 demonstrated to be an inhibitor of chemotaxis and of the production of toxic oxygen free radicals and tray also have some role in the calcification process. As such, there is substantial interest in identifying novel polypeptides having homology to lysozyme. We describe herein the identification of a novel polypeptide which has sequence similarity to lysozyme.

35. PR0864 Wnt-4 is a secreted glycoprotein which correlates with, and is required for, kidney tubulogenesis. Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchytnal and ureteric development are unaffected. Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development. Stark et al., N re ;372(6507):679-683 (1994). In addition, members of the Wnt gene family code for cystsine-rich, secreted proteins, which are differentially expressed in the developing brain and possibly act as intercellular signaling molecules. A Wnt gene, e.g., Wnt-1 is known to be essential for specification of the tnidbrain cell fate. Y~hioka et al., ~ochem. Bioghvs.
Res. Cornmun. 203(3):1581-1588 (1994).
Several member of the Wnt family of secreted factors are strongly implicated as regulators of matnrnaty cellular growth and differentiation. Shimizu et al., C~1_Growth iffer. 8(12) 1349-1358.
Wnt-4 is normally expressed in IS early pregnancy. Wnt-4 may therefore be a local signal driving epithelial branching in pregnancy. Edwards PA, Biochem Soc Symv.63:21-34 (1998). See also, Lipschutz JH, Am. J. Kidney I~s.
31(3):383-397, (1998). We describe herein the identification and characterizaton of a novel polypeptide which has sequence similarity to Wnt-4, designated herein as PR0864.

36. PR0792 At least two cell-derived signals have been shown to be necessary for the induction of immunoglobulin isotype switching in Bells. The first signal is given by either of the soluble lymphokines, interleukin (IL)-4 or IL-13, which induce getmline epsilon transcript expression, but this alone is insufficient to nigger secretion of immunoglobulin E (IgE). The second signal is provided by a physical interaction between B-cells and activated T-cells, basophils and mast cells, and it has been shown that the CD40/CD40 ligand pairing is crucial for mediating IgE synthesis. Additionally, amongst the numerous pairs of surface adhesion molecules that are involved in IgE
synthesis, the CD23lCD21 pair appears to play a key role in the generation of IgE. CD23 is a protein that is positively and negatively regulated by factors which increase or decrease IgE
production, respectively. Antibodies to CD23 have been shown to inhibit IL-4-induced human IgE production in vitro and to inhibit antigen-specific IgE
responses in a rat model, in an isotype selective manner (Bont>efoy et al., Eur. Resnir. 1. Su~~ 22:63S-66S (1996)).
CD23 interacts with CD21 on B-cells, preferentially driving IgE production.
Given that the CD23 protein plays an extremely important role in the induction of a mammalian IgE response, there is significant interest in identifying novel polypeptides having homology to CD23. We herein describe the identification and characterization of a novel polypeptide having homology to CD23, designated herein as PRU792.

37. PR0866 Mitxlirt and spondin proteins are secreted proteins that are structurally related to one another and which have been identified in a variety of organisms. For example, Higashijima et al., Dev Biol. 192:211-227 (1997) have reported the identification of spondin and mindin expression in floor plate cells in the zebrafish embryonic axis, thereby suggesting that minrfin and spondin prtoteins play important roles in embryonic development. This same group has reported that minrfin and spondin proteins function as extracellular matrix proteins that have a high affinity for the basal lamina. (Id.). It has been reported that F-spondin is a secreted protein that promotes neural adhesion and neurite extension (Klan et al., Cell 69:95-110 (i992) and that M-spondin is an extracellular matrix protein that localizes to muscle attachment sites in Drosophila {tJmemiya et al., ev. l 1.
186:165-176 (1997)). Thus, there is significant inteest in identifying novel polypeptides having homology to the minrfin and spondin proteins. We herein describe the identification and characterization of a novel polypeptide having homology to mindin2 and mindinl , designated herein as PR0866.

38. PR0871 , Cyclophilins are a family of proteins that bind to cyclosporin A and possess peptidyl-prolyl cis-traps isomerase activity (Sherry et al., Proc. Natl. Acad. Sci. USA 95:1758-1763 (1998)). In addition, cyclophilins are secreted by activated cells and act in a cytokine-like manner, presumably via signaling through a cell surface cyclophilin receptor. Host cell-derived cyclophilin A has been shown to be incorporated into HIV-1 virions and its irxorporation has been shown to be essential for viral infectiviry. Thus, one or more the cyclophilins may be directly associated with HIV-I infectiviry. Given the obvious importance of the cycloghilin proteins; there is substantial interest in identifying novel polypeptides which have sequence homology to one or more of the cyclophilin proteins.
We herein describe the identification and characterization of a novel polypeptide having homology to cyclophilin-like protein CyP-60, designated herein as PR0871.

39. PR0873 Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the biosynthesis of macromolecules, the controlled release and utilization of chemical energy, and other processes necessary to sustain life. Enzymes have also been shown to play important roles in combating various diseases and disorders. For example, liver carboxylesterases have been reported to assist in sensitizing human tumor cells to the cancer prodrugs. Danks et al., report that stable expression of the cDNA
encoding a carboxylesterase in Rh30 human rhabdomyosarcoma cells increased the sensitivity of the cells to the CPT-11 cancer prodtug 8.1-fold. Cancer Res.
(1998} 58(1):20-22. The authors propose that this prodruglenzyme combination could be exploited therapeutically in a manner analogous to approaches currently under investigation with the combinations of ganciclovir/herpes simplex virus thytnidine kirtase and 5-fluorocytosine/cytosine deaminase. van Pelt et al. demonstrated that a 55 kD
human liver carboxylesterase inhibits the invasion of Plasmodium falciparum malaria sporozoites into primary human hepatocytes in culture. a a of (1997) 27(4):688-698.
Carboxylesterases have also been found to be of importance in the detoxification of drugs, pesticides and other xenobiotics. Purified htm~an liver carboxylesterases have been shown to be involved in the metabolism of various drugs including cocaine and heroin. Prindel et al. describe the purification and cloning of a broad substrate specificity human liver carboxylesterase which catalyzes the hydrolysis of cocaine and heroin and which may play an important role lm the degradation of these drugs in human tissues. J. Biol.
Chem. (1997) 6:272(23):147b9-14775.
Bizentinsla et al. describe a spectrophotometric competitive inhibition assay used to identify drug or environmental esters that are metabolized by carboxyiesterases. p~ Metab Dj~pos (199?) 25(9):1089-1096.

In light of the important physiological roles played by carboxylesterases, efforts are being undertaken by both industry and academia to identify new, native carboxylesterase homologs.
We herein describe the identification and characterization of a novel polypeptide having homology to carboxylesterase, designated herein as PR0873.

40. PR0940 CD33 is a cell-surface protein that is a member of the sialoadhesin family of proteins that are capable of mediating sialic-acid dependent binding with distinct specificities for both the type of sialic acid and its linkage to subterminai sugars. CD33 is specifically expressed in early myeloid and some monocyte cell lineages and has been shown to be strongly associated with various myeloid tumors including, for example, acute non-lymphocytic leukemia (ANLL). As such, CD33 has been suggested as a potential target for the treatment of cancers associated with high level expression of the protein. There is, therefore, significant interest in the identification of novel polypeptides having homology to CD33. In fact, one CD33 homolog (designated CD33L) has already been identified and described (see Takei et al., Cyr_oge_net. Cell Genet. 78:295-300 (1997)). We herein describe the identification of another novel polypeptide having homology to CD33; designated herein as PR0940. The novel polypeptide described herein also exhibits significant homology to the human OB binding proteins designated HSU71382 1 and HSU7I383_1 in the Dayhoff database (version 35.45 SwissProt 35).

41. 941 Cadherins are a large fatnt3y of transmembrane proteins. Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multicellular organisms.
At least cadherins 1-13 as well as types B; E, EP, M, N, P and R have been identified and characterized. Among the functions cadherins are known for, with some exceptions, are that cadherins participate in cell aggregation arHi are associated with cell-cell adhesion sites. Recently, it has been reported that while all cadherins share multiple repeats of a cadherin specific motif believed to correspond to folding of extracellular domains, members of the cadherin superfamily have divergent structures and, possibly, functions. In particular it has been reported that members of the cadherin superfamily are involved in signal transduction. See, Suzuki, i<. Cell Bioch~r~., 61(4):531-542 (1996). Cadherins are furtlxr described in Tanihara et al., . e1 '., 107(6):1697-1704 (1994), Aberie et al., J. Cell Biochem., 61(4):514-523 (1996) and Tattihara et al., Cell Adhes.
Commun., 2(1):15-26 (1994). We herein describe the identification and characterization of a novel polypeptide having homology to a cadherin protein, designated herein as PR0941.

42. PR0944 Clostridium perfringens enterotoxin (CPE) is considered to be the virulence factor responsible for causing the symptoms of C. perfringens type A food poisoning and may also be involved in other human and veterinary illnesses (McCtane, Taxicon. 34:1335-1343 (1996)). CPE carries out its adverse cellular functions by binding to an approximately 50 kD cell surface receptor protein designated the Clostridium perfringens enterotoxin receptor (CPE-R) to form an approximately 9(1,000 kD complex on the surface of the cell, cDNAs encoding the CPE-R protein have been identified characterized in both human and mouse (Katahira et al., .l.
Cell Biol. 136:1239-1247 (1997) and Katahira et al., J. .8iol. t'fiem. 272:26652-26658 (1997)). Since the CPE
toxin has been reported to cause a variety of illnesses in mammalian hosts and those illnesses are initiated by binding of the CPE toxin to the CPE-R, there is significant interest in identifying novel CPE-R homologs. We herein describe the identification and characterization of a novel polypeptide having homology to the CPE-R, designated herein as PR0944.

43. PR0~83 Membrane-bound proteins include not only cell-surface membrane-bound proteins, but also proteins that are found on the surface of intracellular vesicles. These vesicles are involved in exocytosis, which is the fusion of .
secretory vesicles with the cellular plasma membrane, and have two main functions. One is the discharge of the vesicle contents into the extracellular space, and the second is the incorporation of new proteins and lipids into the plasma membrane itself. Exocytosis can be either constitutive or regulated.
All eukaryotic cells exhibit constitutive exocytosis, which is marked by the immediate fusion of the secretory vesicle after formation. In contrast, regulated exocytosis results in the accumulation of the secretory vesicles that fuse with the plasma membrane upon receipt of an appropriate signal by vesicle-associated membrane proteins. Usually, this signal is an increase in the cytosolic free CaZ' concentration. However, regulated exocytosis that is independent of C~+ has been reported (see, e.g.
Fujita-Yoshigaki et al. J.~iol. Chem. (1996) 31:271(22):13130-13134).
Regulated exocytosis is crucial to marry specialized cells, including neurons (neurotransmitter release from synaptic vesicles), adrenal chromaffm cells IS (adrenaline secretion), pancreatic acittar cells (digestive enzyme secretion), pancreatic ~i-cells (insulin secretion), mast cells (histamine secretion), mammary cells (milk protein secretion), sperm (enzyme secretion), egg cells (creation of fertilization envelope) and adipocytes {insertion of glucose transporters into the plasma membrane).
Disorders involving exocytosis are known. For example, inflammatory mediator release from mast cells leads to a variety of disorders, including asthma. Similarly, Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease in which neutrophils, monocytes and lymphocytes contain giant cytoplasmic granules. Accordingly, the proteins involved in exocytosis are of paramount interest and efforts are being undertaken by both industry and academia to identify new, vesicle-associated proteins. For example, Skehel et al. identified a 33-kilodalton membrane protein in Aplysia, termed VAP-33, which is required for the exocytosis of neurotransmitter. Sc' nc (1995) 15:269(5230):1580-1583, and Neuro~hatrnacoloev (1995) 34(11):1379-1385. Many efforts are focused on tree screening of matnmalian recombinant DNA libraries to identify the coding sequences for novel vesicle- associated membrane proteins. It is an object of the invention to provide proteins having homology to the vesicle associated protein, VAP-33, designated herein as PR0983.

44. PR01057 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enrymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized. The mammalian protease enzymes play important roles in many different biological processes including, for example, protein digestion, activation. inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzyates.
In light of the important physiological roles played by protease enzymes;
efforts are currently being undertaken by both industry and academia to identify new, native protease homologs. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. AcadiSci., X3:7108-7113 (1996); U.S. Patent No.
5,536,637)]. We herein describe the identification of novel polypeptides having homology to various protease enrytnes, designated herein as PRO1057 polypeptides.

45. PR 1071 Thrombospondin-1 is a trimeric high molecular weight glycoprotein that is released from platelet aIpha-granules in response to thrombin stimulation and that is also a transient component of the extracellular matrix in developing arid repairing tissues (Adams, nt, J. Biochem. Cell Biol. 29:861-865 (1997) and Qian et al., Proc. Soc.
Ex~. Biol. Med. 212:199-207 (1996)). A variety of factors regulate thrombospondin expression and the protein is degraded by both extracellular and intracellular routes. Thrombospondin-1 functions as a cell adhesion molecule and also modulates cell movement, cell proliferation, neurite outgrowth and angiogenesis. As such, there is substantial interest in identifying novel polypeptides having homology to thrombospondin.
We herein describe the identification and characterization of a novel polypeptide having homology to thrombospondin, designated herein as PR01071.

46. R 1 72 Studies have reported that the redox state of the cell is an important determinant of the fate of the cell.
Furthermore, reactive oxygen species have been reported to be cytotoxic, causing inflammatory disease, including tissue t~ecx~is, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy.
Thus, the control of oxidation and reduction is important for a number of reasons, including the control and prevention of strokes, heart attacks, oxidative stress, hypertension and may be associated with the development of malignancies. The levels of antioxidant enzymes, such as reductases, which catalyze the conversion of reactive oxygen species to water have been shown to be low in cancer cells. In particular, malignant prostate epithelium may have lowered expression of such antioxidant enzymes [Baker et al., ostat 32(4):229-233 (1997)J. In this regard, reduciases, are of interest. In addition, the transcription factors, NF-kappa B and AP-1, are known to be regulated by redox state and to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AmS, cancer, atlterosclerosis and diabetic complications. Publications further describing this subject matter include Engitart et al., Anticancer lltes. (Greece), 17:4599-4605 (1997), Kelsey, et al., Br. J. Cancer, 76(7):852-854 (1997);
Friedrich arid Weiss, J. Theor. Biol., 187(4):529-40 (1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997).
Given the physiological importance of redox reactions in tdvo, efforts are currently being under taken to identify new, native proteins which are involved in redox reactions. We describe herein the identification of a novel polypeptide which has sequence similarity to reductase enzymes, desiignated herein as PR01072.

47. R ~ S
Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation.
Protein disulfide isomerase was initially idenrified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J. Biol.
Chern. 239:1406-1410 (1964) and Epstein et al., Cold Sprring Harbor Sump.
Quara. Biol. 28:439-449 {1963)).
Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus.
Given the importance of disulfide bond-forming enzymes and their potential uses in a number of different applications, for example in increasing the yield of correct refolding of recombinantly produced proteins, efforts are currently being undertaken by both industry and academia to identify new;
native proteins having homology to protein disulfide isomerase. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996);
U.S. Patent No. 5,536,637)]. We herein describe a novel polypeptide having homology to protein disulfide isomerase, designated herein as PR01075.

48. P 0181 In Drosophila, the dorsal-ventral polarity of the egg chamber depends on the localization of the oocyte nucleus and the gurken RNA to the dorsal-anterior comer of the oocyte. Gurken protein presumably acts as a ligand for the drosophila EGF receptor (torpedo/DER) expressed in the somatic follicle cells surrounding the oocyte.
Cornichon is a gene required in the germline for dorsal-ventral signaling ~(Roth et al., Cell 81:967-978 (1995)).
Comichon, gurken and torpedo also function in an earlier signaling event that establishes posterior follicle cell fates and specifies the anterior-posterior polarity of the egg chamber. Mutations in any or all of these genes prevent the formation of a correctly polarized nvcrotubule cytoskeleton required for proper localization of the anterior and posterior determinants bicoid and oskar and for the asymmetric positioning of the oocyte nucleus. Thus, it is clear that the cornichon gene product plays an important role in early development.
We herein describe the identification and characterization of a novel polypeptide having homology to the cornichon protein, designated herein as PR0181.

49. ROl Efforts ante currently being undertaken to identify and characterize novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide, designated herein as PR0195.

50. ~R0865 Efforts acre currently being undertaken to identify and characterize novel secreted proteins. We herein descn-be the identification and characterization of a novel secreted polypeptide, designated herein as PR0865.

51. ~~Q827 VLA-2 is an cell-surface integrity protein that has been identified and characterized in a number of mammalian organisms, including both mouse and human. VLA-2 has been shown to be a receptor on the surface of cells for echovitvs-1 (EV-I) which mediates infection of VLA-2-expressing cells by EV-I (Zhang et al., ViT
235{2):293-301 (1997) and Bergelson et al., , cience 255:1718-1720 (I992)).
VLA-2 has also been shown to mediate the interaction of collagen with endothelium during in vitro vascular tube formation {3ackson et al., Cell Biol. Int.
18(9):859-867 (1994)). Various other integrity proteins that share various degrees of amino acid sequence homology with VLA 2 have been identified and characterized in a variety of mammalian organism. These integrins have been reported to play important roles in a variety of different physiological functions. Therefore, there is significant interest in identifying novel polypeptides having homology to one or more of the integrity proteins. We herein describe the identification and characterization of a novel polypeptide having homology to VLA-2 integrity protein, Zz WO 99/46281 PCTlUS99/05028 designated herein as PR0827.

52. PR 1114 Many important cytokine proteins 'have been identified and characterized and shown to signal through specific cell surface receptor complexes. For example, the class 11 cytokine receptor fanlily (CRF2) includes the interferon receptors, the interleukin-10 receptor and the tissue factor CRFB4 (Spencer et al., J. Exp. Med 187:571-578 (1998) and Kotenko et al., M~, BQ J. 16:5894-5903 (199?)). Thus, the multitude of biological activities exhibited by the various cytokine proteins is absolutely dependent upon the presence of cytokine receptor proteins on the surface of target cells. There is, therefore, a significant interest in identifying and characterizing novel polypeptides having homology to one or more of the cytokine receptor family. We herein describe the identification and characterization of a novel polypeptide having homology to cytokine receptor family-4 proteins, designated herein as PR01117.
Interferons (IFNs) encompass a large family of secreted proteins occurring in vertebrates. Although they were originally named for their antiviral activity, growing evidence supports a critical role for IFNs in cell growth and differentiation (Jaramillo et al:, Cancer lmestigation 13(3):327-338 (1995)). IFNs belong to a class of negative growth factors having the ability to inhibit the growth of a wide variety of cells with both normal and transformed phenotypes. 1FN therapy has been shown to be beneficial in the treatment of human malignancies such as Karposi's sarcoma, chronic myelogenous leukemia, non-Hodgkin's lymphoma, and hairy cell leukenua as well as in the treatment of infectious diseases such as hepatitis B (Gamliel et al., Scanrvng Microscopy 2(1):485-492 (1988), Einhorn et al., Med. Oncol. & Tumor Pharmacother. 10:25-29 (1993), Ringenberg et al., Missouri Medicine 85(1):21-26 (1988), Saracco et al., Journal of Gastroenterology and Hepatology 10:668-673 (1995), Gonzalez-Mateos et al., Hepato- astro serology 42:893-899 (1995) and Malaguamera et al., ~harmacotherapy 17(5):998-1005 (1997)).
Iruerferons can be classified ituo two major groups based upon their primary sequence. Type I interferons, IFN-a and IFN-j3, are enrnded by a superfamily of intronless genes consisting of the IFN-a gene family and a single IFN-p gene that are thought to have arisen from a common ancestral gene. Type I interferons may be produced by most cell types. Type II IFN, or IFN-y, is restricted to lymphocytes (T cells and natural killer cells) and is stimulated by nonspecific T cell activators or specific antigens in vi o.
Although both type I and type D IFNs produce similar antiviral and antiproliferative effects, they act on distinct cell surface receptors, wherein the binding is generally species specific (Larger et al., Immunol. Todav 9:393-400 (1988)). Both IFN-a and IFN-(3 bind competitively to the same high affinity type l receptor, whereas IFN-y binds to a distinct type II receptor. The presence and number of IFN receptors on the surface of a cell does not generally reflect the sensitivity of the cell to IFN, although it is clear that the effects of the IFN protein is mediated through binding to a cell surface interferon receptor. As such, the identification and characterization of novel interferon receptor proteins is of exueme interest.
We herein describe the identification and characterization of novel interferon receptor polypeptides, designated herein as "PR01114 interferon receptor° polypeptides. Thus, the PR01114 polypeptides of the present invention represents a novel cell surface interferon receptor.

53. PR023?
Carbonic anhydrase is an enzymatic protein that which aids carbon dioxide transport and release in the mammalian blood system by catalyzing the synthesis (and the dehydration) of carbonic acid from (and to) carbon dioxide and water. Thus, the actions of carbonic anhydrase are essential for a variety of important physiological reactions in the mammal. As such, there is significant interest in the identification and characterization of novel polypeptides having homology to carbonic anhydrase. We herein describe the identification and characterization of a novel polypeptide having homology to carbonic anhydrase, designated herein as PR0237.

54. PR0541 Numerous trypsin inhibitory proteins have been identified and characterized (see, e.g., Yamakawa et al., Biochim. Biophys_. Acta 1395:202-208 (1998) and Mizuki et al., Mammalian Genome 3:274-280 (1992)). Trypsin inhibitor proteins play important roles in a variety of different physiological and biological pathways and are specifically involved in such processes as the regulation of protein degradation; digestion. and the like. Given the important roles played by such enzymatic proteins, there is significant interest in identifying and characterizing novel polypeptides having homology to known trypsin inhibitor proteins. We herein describe the identification and characterization of a novel polypeptide having homology to a trypsin inhibitor protein, designated herein as PR0541.

55. PR_ 0273 Leukocytes include monocytes, macrophages, basophils, and eosinophils and play an important role in the immune response. These cells are important in the mechanisms initiated by T
andlor B lymphocytes and secrete a range of cytokines which recruit and activate other inflammatory cells and conuibute to tissue destruction.
Thus, investigation of the regulatory processes by which leukocytes move to their appropriate destination and interact with other cells is critical. Currently, leukocytes are thought to move from the blood to injured or inflamed tissues by rolling along the endothelial cells of the blood vessel wall. This movement is mediated by transient interactions between selectuts and their ligands. Next, the leukocyte must move through the vessel wall and into the tissues. This diapedesis and exuavasation step involves cell activation which promotes a more stable leukocyte-endothelial cell interaction, again mediated by integrins and their Iigands.
Chemokines are a large family of structurally related polypeptide cytokines.
These molecules stimulate leukocyte movement and may explain leukocyte trafficking in different inflammatory situations. Chemokines mediate the expression of particular adhesion molecules on endothelial cells, and they produce chemoattractants which activate specific cell types. In addition, the chemokines stimulate proliferation and regulate activation of specific cell types.
In both of these activities, chemokines demonsuate a high degree of target cell specificity.
The cherrtolarte family is divided into two subfamilies based on whether two amino terminal cysteine residues are immediately adjacent (C-C) or separated by one amino acid (C-X-C).
Chemokines of the C-X-C family generally activate rteutrophils and fibroblasts while the C-C chemokines act on a more diverse group of target cells including mottocyteslmacrophages, basophils, eosinophils and T lymphocytes. The known chemokines of both subfamilies are synthesized by many diverse cell types as reviewed in Thotnson A: (1994) The Cytokine Handbook, 2 d Ed.
Academic Press, N.Y. Chemokines are also reviewed in Schall TJ (1994) Chemotactic Cytokines: Targets for Therapeutic Development. International Business Communications, Southborough Mass. pp 180-270; and in Paul Wfi (1993) Fundamental Immunology, 3rd Ed. Raven Press, N.Y. pp 822-826.

WO 99!46281 PCTIUS99/05028 Known chemokines of the C-X-C subfamily include macrophage inflammatory proteins alpha and beta (MIP-1 and MIP-2 ), interleukin-8 (IL-8), and growth regulated protein (GRO-alpha and beta).
MIP 2 was first identified as a 6 kDa heparin binding protein secreted by the mouse macrophage cell line RAW 264.7 upon stimulation with lipopolysaccharide (LPS): MIP-2 is a member of the C-X-C (or CXC) subfamily of chemokines. Mouse M1P-2 is chemotactic for human neutrophils and induces local neutrophil infiltration when injected into the foot pads of mice. Rat MIP-2 shows 86% amino acid homology to the mouse MIP-2 and is chemotacFic for rat neutrophils but does not stimulate migration of rat alveolar macrophages or human peripheral blood eosinophiIs or lymphocytes. 1n addition, the rat MIP-2 has been shown to stimulate proliferation of rat alveolar epittielial cells but not fibroblasts.
Current techniques for diagnosis of abnormalities in inflamed or diseased issues mainly rely on observation of clinical symptoms or serological analyses of body tissues or fluids for hon~twnes, polypeptides or various metabolites. Problems exist with these diagnostic techniques. First, patients may not manifest clinical symptoms at early stages of disease. Second, serological tests do not always differentiate between invasive diseases and genetic syndromes. Thus, the identification of expressed chemokines is important to the development of new diagnostic techniques, effective therapies, and to aid in the understanding of molecular pathogenesis.
IS To date, chemokines have been implicated in at least the following conditions: psoriasis, inflammatory bowel disease, renal disease, arthritis, immune-mediated alopecia, stroke, encephalitis, MS, hepatitis, and others.
In addition, non-BLR-containing chemokines have been implicated in the inhibition of angiogenesis, thus indicating that these chemokines have a rule in tumor vascularization and tumorigenesis.
Therefore it is the object of this irneiroon to identify polypeptides and nucleic acids encoding the same which have sequence identity and similarity with cytokine-induced neutrophil chemoattractants, MIP-1, M1P-2, and other related proteins. The efforts of this object are provided herein.

56. PR0701 Beta neurexins and neuroligins are plasma iiiembrane proteins that are displayed on the neuronal cell surface Neuroligin 1 is enriched in synaptic plasma membranes and acts as a splice site-specific ligand for beta neurexins as described in Ichtchenko, et al., ell, 81(3):435-443 (1995). The extracellular sequence of neuroligin 1 is composed of a catalytically inactive esterase domain homologous to acetylcholinesterase. Neuroligin 2 and 3 are similar in structure and sequerxe to neuroligin 1. AU newoligins contain an N-terminal hydrophobic sequence with the characteristics of a cleaved signal peptide followed by a large esterase homology domain, a highly conserved single trausmembrane region, and a short cytoplasmic domain. The three neuroligins are alternatively spliced at the same position and are expressed at high levels only in the brain. Tight binding of the three neuroligins to beta neurexins is observed only for beta ~urexins lacking an insert in splice site 4. Thus, neuroligins constitute a multige~ family of brain-specific proteins with distinct isoforms that may have overlapping functions in mediating recognition processes between neurons, see ichtchenko, et al., 3. Bjpl: Chem., 271(5):2676-2682 (1996). Moreover, neurexins and neuroligins have been reported as functioning as adhesion molecules in a Ca2'' dependent reaction that is regulated by alternative splicing of beta neurexins, i.e.; see Nguyen and Sudhof, J.
Biol. Chem., 272(41):26032-26039 (I997):
Given the foregoing, membrane bound proteins are of interest. More generally, membrane-bound proteins and receptors can play an important role in the formation; differentiation and maintenance of multicellular organisms.
The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often uansmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor ltinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can aiso act as growth factor receptors.
Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial appiications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-hound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Efforts are being undertaken by both industry and acadenua to identify new, native membrane-bound receptor proteins, particularly those having sequence identity and/or similarity with neuroligins 1, 2 and 3. Many efforts are focused on the screening of matrunalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., x:7108-7113 (1996); U.S. Patent No.
5,536,637)]. The results of such efforts are provided herein.

57. PR0704 VIP36 is localized to the Golgi apparatus and the cell surface, and belongs to a family of legume lectin homologues in the animal secretory pathway that night be involved in the uafficlortg of glycoproteins, glycoiipids, or both. It is farther believed that VIP36 binds to sugar residues of glycosphingoiipids and/or gycosylphosphatidyl-inositol anchors and might provide a link between the extracellularlluminal face of glycolipid rafts and the cytoplasmic protein segregation machinery. Further regarding VIP36, it is believed that there is a signal at its C-terminus that matches an internalization consensus sequence which confers its ability to cycle between the plasma membrane and Golgi. See, Fiedler, et al, ~MBO ., 13(7):1729-1740 (1994); Fiedler and Simons, J. Cell Sci., 109(1):271-276 (1996); Itin, et al., [yIBO J., 14(10):2250-2256 (1995}. It is believed that V1P36 is either the same as or very closely related to the human GP36b protein: VIP36 andlor GP36b are of interest.
More generally, vesicular, cytoplasmic, extracellular and membrane-bound proteins play important roles in the Formation, differentiation and maintenance of multicellular organisms.
The fate of many individual celis, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogerlic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in tum, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreaetors. In fact, most protein drugs available at present, such as thrombolyt3c agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and imegrins. Transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Efforts are being undertaken by both industry and academia to identify new, native vesicular, cytoplasmic, secreted and membrane-bound receptor proteins, particularly those having sequence identity and/or similarity with ViP36. Many efforts are focused on the screening of mammalian recombinant DNA
libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl.
Acad. Sci., X3,:7108-7113 (1996); U.S.
Patent No. 5,536,637)).

58. PR0706 Acid phophatase proteins are secreted proteins which dephophorylate terminal phosphate groups tinder acidic pH conditions. Acid phophatases contain a RHGXRXP amino acid sequence, which is predicted to be mechanistically sigirificant. Acid phosphatases may have important futxtions in the diagnosis and treatment of human diseases. For example, prostatic acid phosphatase is a secreted protein uniquely expressed in prostatic tissue and prostate cancer.
The level of prostatic acid phosphatase is a potential prognostic factor for local and biochemical control in prostate cancer patients treated with radiotherapy, as' described in Lankford et al., I
tt. J. Radiat. Oncol. Biol. Ph ~~s. 38(2):
327-333 (1997). Research suggests that a cellular immune response to prostatic acid phosphatase may mediate destructive autoimtttune prostatitis, and that xenogeneic forms of prostatic acid phosphatase may prove useful for itntnunotherapy of prostate cancer. See Fong et al.; J: Immuno,,, 169(7): 3113-3117 (1997). Seminal prostatic acid phosphatase levels correlate significantly with very low sperm levels (oligospermia) in individuals over 35, see Singh et aL, Singapore Med. J. 37(6): 598-599 (I99~. Thus, prostatic acid phosphatase has been implicated in a variety of human diseases, and'may have an important function in diagnosis and therapy of these diseases. A series of aminobenzylphosphatic acid compounds are highly potent inhibitors of prostatic acid phosphatast:, as described in Beers et al:, Bioore. Med. Chem. 4(10): 1693-1701 (1996).
More generally, extracellular paoteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the ittitztediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) wbich are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the exuacellular e~ironment. -~

Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at presem, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytoltines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those having sequence identity with prostate acid phosphatase precursor and lysosomal acid phosphatase precursor and in some cases, those having identity with DNA found in fetal heart. Many efforts are focused on the screening of mammalian recombinant DNA
fbraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc_ Natl.
Acad. Sci., x:7108-7I13 (1996); U-.S.
Patent No. 5,536,637)).

59. PR07 7 Cadhetins are a large family of transmembrane proteins. At least cadherins I-I3 as well as types B, E, EP, M, N, P and R have been characterized. Among the functions cadherins are known for, with some exceptions, cadherins participate in cell aggregation and are associated with cell-cell adhesion sites. Cadherins are further described in Tanihara, et al., 1. Cell Sci., 107(6):1697-I704 (1994) and Tanihara, et al., Cell Adhes. Commun., 2{1):15 26 {1994). Moreover, it has been reported that some members of the cadherin superfamily are involved in general cell-cell interaction processes including uansduction. See, Suzuki, .1. Cell Biochem., 61(4):531-542 (1996).
Therefore, novel members of the cadherin superfamily are of interest.
More generally, all novel proteins are of interest, including membrane-bound proteins. Membrane-bound proteins and receptors can play an important role in the formation, differentiation and maintenance of muhicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, m turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, uansduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various indusuial applications, including as phmimaceutiucal and diagnostic agents. Receptor irruttunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly membrane bound proteins having identity with cadherins. The results of such efforts are provided herein.

WO 99!46281 PCTIUS99/05028 60. P 03 Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different marnrnalian and non-mammalian organisms have been both identified and characterized, including the serine proteases which exhibit specific activity toward various serine-containing proteins. The mammalian protease enzymes play important roles in biological processes such as, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
Neuropsin is a novel serine protease whose mRNA is expressed in the central nervous system. Mouse neuropsin has been cloned, and studies have shown that it is involved in the hippocampal plasticity. Neuropsin has also been indicated as associated with extraceLlular matrix modifications and cell migrations. See, generally, Chen, et al., eu osci., 7(2):5088-509? (1995) and Chen, et al., J. Histochem.
~rtoct~gm., 46:313-320 (1998).
Efforts are being undertaken by both industry and academia to identify new, native membrane-bound or secreted proteins, particularly those having homology to neuropsin; serine protease, neurosin and trypsinogen. Many efforts are focused on the screening of mammalian recombinant DNA Libraries to identify the coding sequences for novel secreted aril membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., 1'soc. Nat!. cac~,, Sci., ,23:7108-7113 (I996); U.S, Patent No.
5,536,637)x.

61. PR0526 Protein-protein interactions inchrde those involved with receptor and antigen complexes and signaling mechanisms. As more is Irnown about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.
All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions.
Ixucine-rich repeats are shoe sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglobular shape. These two features have lien indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(1.0):415-421 (Oct. 1994).
A study has been reported on leueine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogemr and are involved in pathological processes such as wound healing; tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol.
Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev.
Fr. Hematol. (Gerr~y); 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Souiier syndrome; Chlemetson, K. J., ~romb.
Haemost. (Germatry), 74(1}:111-116 (July 1995), reporting that platelets have leucine rich repeats and Ruoslahti, E. L, et al., W0911072'7-A by La Jolla Cancer Research Foundation reporting that decorin binding to transforming growth factor[3 has involvement in a treatment for cancer, wound healing and scarring. Related by function to this group of proteins is the insulin like growth factor (IGf), in that it is useful in wound healing and associated therapies concerned with re-growth of tissue, such as connective tissue, skin and bone; in promoting body growth in humans and animals; and in stimulating other growth-related processes. The acid labile subunit (ALS) of IGF is also of interest in that it increases the half life of IGF and is pan of the IGF complex in vivo. ALS is further described in Leong and Baxter, Mol. EndocrinoL, 6(6):870-87fi (1992); Baxter,1 Biol. Chem., 264{20):11843-I 1848 {1989): and Khosravi, et al., J. Clin. Endocrinol.
Metab., 82(12):3944-3951 (1997).
Another protein which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S.
and Rothberg, J. M., W09210518-A1 by Yale University. Also of interest is LIG-1, a membrane glycoprotein that is expressed specifically in glial cells . in the mouse brain, and has leucine rich repeats and immtmoglobulin-like domains. Suzuki, et al., 1. BioI Chem.
(IJ.S.), 271(37):22522 {1996). Other studies reporting on the biological functions of proteins having leucine rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., {Ireland), 125(1-2):65-70 (Dec. 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon RinshQ (Japan), 54(7):1784-1?89 (July 1996) (apoptosis involvement); Hams, P. C., et al., J. Am. Soc. Nephrol" 6(4):i 125-1133 {Oct.
1995) (kidney disease involvement).
Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and identity or similarity to known proteins having leucine rich repeats such as ALS. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound proteins having leucine rich repeats. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Nat!.
Acad. Sci., x:7108-7113 (i996); U.S.
Patent No. 5,536,637)].

62. P~Q'~
Cadherins are a large family of trattsmembrane proteins. Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of muiticellular organisms.
At least cadherins 1-13 as well as types B, E, EP, M, N, P and R have been characterized. Among the functions cadherins are known for, with some exceptions, cadherins participate in cell aggregation and are associated with cell-cell adhesion sites. Recently, it has been reported that while all cadherins share multiple repeats of a cadherin specific motif believed to correspond to folding of extracellular domains, members of the cadherin superfamily have divergent structures and, possibly, functions. In particular it has been reported that members of the cadherin superfamily are involved in signal uansduction. See, Suzuki, ~ Cell Biochem., 61(4):531-542 (1996). Cadherins are further described in Tattihara, et al., a l., 107(6):1697-1704 (1994), Aberle, et al., J Cell Biochem., 61(4):5I4-523 (1996) and Tanihara, et at., Cgll Adhes. ~ommun., 2(1):15-26 (1994).
Protocadherins are members of the cadherin superfamily which are highly expressed in the brain. In some studies, protocadherins have shown cell adhesion activity. See, Sano, et al., 1~]~., I2(6):2249-2256 (1993).
However, studies have also shown that some protocadherins, such as protocadherin 3 (also referred to as Pcdh3 or pc3), do not show strong calcium dependent cell aggregation activity. See, Sago, et al., ~~ cs, 29(3):631-640 (1995) for this study and further characteristics of Pcdh3.

Therefore, novel members of the cadherin superfatnily are of interest. More generally, all membrane-bound proteins and receptors are of interest. Such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications; including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block'receptor-Iigand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Efforts are therefore being undertaken by both industry and academia to identify new, native membrane bound proteins, particular those having sequence identity with protocadherins, especially 3 and 4. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel membrane-bound proteins. Provided herein are the results of such efforts.

63. PR0534 Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation.
Protein disulfide isomerase was initially identified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J.J. Biol.
em. 239:1406-1410 (1964) and Epstein et oh, Cold Spr-~'n-g j~;~o~~ymn. Ouant.
Biol. 28:439-449 (1963)).
Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus. Protein disulfide isomerase and related proteins are further described in Laboissiere, et al., J. Biol. Chem., 270(47:28006-28009 (1995); Jeenes, et aL, ~, 193(2):151-156 (1997; Koivunen, et al., a 'cs, 42(3):397-404 (1997); and Desilva, et al., DNA Cell Biol., 15(1):9-16 (1996). These studies indicate the importance of the identification of protein disulfide related proteins.
More generally, aril also of interest are all novel membrane-bound proteins and receptors. Such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the imtr~diate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and celhtlar adhesin molecules like selectins and integrins. For instance, uansduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Given the importance of membrane bound proteins, efforts are under way to identity novel membrane bound proteins. Moreover, given the importance,of disulfide bond-forming enzymes and their potential uses in a number of different applications, for example in increasing the yield of correct refolding of recombinantly produced proteins, efforts are currently being undertaken by both industry and academia to identify new, native proteins having sequence identity with protein disulfide isomerase. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs. We herein describe a novel polypeptide having sequence identity with protein disulfide isomerase and the nucleic acids encoding the same.

64. PR0697 Secreted frizzled related proteins (sFRPs) are related to the frizzled family of uansmembrane receptors.
The sFRPs are approximately 30 kDa in size, and each contains a putative signal sequence, a frizzled-like cysteine-rich domain, and a conserved hydrophilic carboxy-terminal domain. It has been reported that sFRPs may function to modulate Wnt signaling, or function as ligands for certain receptors.
Rattner, et al., PNAS USA, 94(7):2859-2863 (i997). Therefore, sFRPs and proteins having sequence identity andlor similarity to sFRPs are of interest.
Another secreted protein of interest is arty member of the family of secreted apoptosis-related proteins (SARPs). Expression of SARPs modifies the intracellular levels of beta-catenin, suggesting that SARPs interfere with the Wnt-frizzled proteins signaling pathway. MeIkonyan, et al., PNAS USA, 94(25):13636-13641 (1997).
Therefore, SARPs and proteins having sequence identity andlor similarity to SARPs are of interest.
In addition to sFRPs and SARPs, many extracellular proteins are of interest.
Exuacellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of marry individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells; is typically governed by information received from other cells and/or the immediate environment.
This information is often transmitted by secret$d polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the excracellular environment.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors 'and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.

Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those having seguence identity or similarity with sFRP-2 and SARP-1. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the litezature [see, for example, Klein et aL, Proc.
Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Patent No. 5,536,637)].

65. R 71 Efforts are being undertaken by both industry and academia to identify new, native uansmembrane receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts are provided herein.

66. PR0731 Cadherins are a large family of transmembrane proteins. Cadfierins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multiceIlular organisms.
At least cadherins 1-13 as well as types B, E, EP, M, N, P and R have been characterized. Among the functions IS cadherins are known for, with some exceptions, cadherins participate in cell aggregation and are associated with ceIl-cell adhesion sites. Recently, it has been reported that while all cadherins share multiple repeats of a cadherin specific motif believed to correspond to folding of extraceIlular domains, members of the cadherin superfamily have divergent structures and, possibly, functions. In particular it has been reported that members of the cadherin superfamily are involved in signal transduction. See, Suzuki, J. Cell Biochem., 61(4):531-S42 (1996). Cadherins are further described in Tanihara, et al., 1 a S '., 107(6):1697-1704 (1994), Aberle, et al., J. Cell Biochr~., 61(4):514-523 (1996) and Tanihara, et al., Cell Adh_es.,~ommun., 2(1):15-26 (1994).
Protocadherins are members of the cadherin superfamily which are highly expressed in the brain. In some studies, protocadherins have shown cell adhesion activity. See, Sano, et aL, EMB_O J,., 12(6):2249-2256. (1993).
However, studies have also shown that some protocadherins, such as protocadherin 3 (also referred to as Pcdh3 or pc3), do not show suong calcium dependent cell aggregation activity. See, Sago, et al., Genomics, 29(3):631-640 (1995) for this study and further characteristics of Pcdh3.
Therefore, novel members of the cadherin superfartlily are of interest. More generally, all membrane-bound proteins and receptors are of interest. Such proteins can play an important role in the formation, differentiation and maintenance of muldcellular organisms. The fate of marry individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the imr~diate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors;
neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
Such membrane-bound proteins and cell receptors inchrde, but are not limited to, cyiokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, uansduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kittases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.

Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immutnoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are therefore being undertaken by both industry and academia to identify new, native membrane S bound proteins, particular those having sequence identity with protocadherins, especially 4, 68, 43, 42; 3 and 3.
Many efforts are focused on the screening of matrunalian recombinant DNA
libraries to identify the coding sequences for novel membrane-bound proteins. Provided herein are the results of such efforts.

67. PR 218 : Efforts are being undertaken by both industry and academia to identify new, native membrane bound proteins, particularly those having sequence identity with membrane regulator proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.

68. PR0768 The integrins comprise a supergene family of cell-surface glycoprotein receptors that promote cellular adhesion. Each cell has numerous receptors that define its cell adhesive capabilities. Integrins are involved in a wide variety of interaction between cells and other cells or matrix components. The integrins are of particular importance in regulating movement and function of immune system cells. The platelet IIbIIIIA integrin complex is of particular importance in regulating platelet aggregation. A member of the integrin family, integrin p-6, is expressed on epithelial cells and modulates epithelial inflammation. Another integrin, leucocyte-associated antigen-1 (LFA-1) is important in the adhesion of lymphocytes during an immune response.
Of particular interest is H36-alpha 7, an integrin alpha chain that is developmentally regulated during myogenesis as described in Song, et a1.,1. CeU Biol., 117(3):643-657 {1992).
The expression pattern of the lamittin-binding alpha 7 beta 1 integrin is developmentally regulated in skeletal, cardiac, and smooth muscle. Ziober, et al., Mol. Biol. Cell, 8(9):1723-1734 (1997). It has been nyported that expression of the alpha 7-X1/X2 integrin is a novel mechanism that regulates receptor affinity states in a cell-specific context and tnay modulate integtltt-dependent events during muscle development and repair. Id. It has farther been reported that laminins promote the locomotion of skeletal myoblasts via the alpha 7 integrin receptor. In particular it was reported that, alpha 7 beta 1 receptor can promote myoblast adhesion and motility on a resuicted number of laminin isofotms and may be important in myogenic precursor recruitittent during regeneration and differentiation, Yao, et al., J ell S l., 109(13):3139-3150 (1996). Spliced variants of integrin alpha 7 are also described in Letlng, et al., Biochem Biophvs Res ~tnmun., 243(/):317-325 {1998) and Fornaro and l.anguino, Matrix Biol., Ib(4):185-I93 (1997). Moreover, it has been reported that absence of integrin alpha 7 causes a form of muscular dystrophy.
Thus integrins, particularly those related to integrin 7 and related molecules, are of interest.
In addition to the interest of integrins. mare generally, all membrane-bound proteins and receptors are of interest since such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate WO 99!46281 PCTlUS99/05428 environment. This information is often transmitted by secreted polypeptides (for instance, mitogettic factors, survival factors,; cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytolane receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin ~lecules like selectins and integrins.
For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process> can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as phatinaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Therefore, efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Marry efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts, particularly those focused on identifying new IS polypeptides having sequence identity with integrins, are provided herein.

69. PR07?l Testican is a multidomain testicular proteoglycan which .is expressed in numerous tissue types including, but not limited to neuromuscular tissue, the brain and reproductive tissues.
Testican resembles modulators of cell social behavior such as the regulation of cell shape, adhesion, migration and proliferation. [Bonnet, F. et al., J.J. Biol.
chem., X71(8):4373 (1996), Penn, J.P. et al., ~XS (Switzerland), 7:191 (1994), Alliel, P.M" et al, a J
ioc , 2 4(1):346 (1993), Charbonnier, F., et al., C. R. Seatg;es Soc. Biol.
Fl!. (France), ~1_(1):12~ (1997)].
Among other reasons, since testican has been implicated in neuronal processes and may be associated with the growth of connective tissue, testican and related molecules are of interest.
More generally, all extracellular proteins are of interest. Extracellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment. This informationis often transmitted by secreted poIypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and iruerpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have variousindustrial applications, including pharmaceuticals, diagnostics, biosensors and bioreaccors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techtuques are described in the literature (see, for example, Klein et al., Prod. Nat1 Ao~

Sci., 93:7108-7113 (1996); U.S. Patent No. 5,536,637)]. The results of such efforts, particularly those focused on identifying molecules having identity and/or similarity with testican are of interest.
'70. PRO?33 TI/ST2 is a receptor-like molecule homologous to the type I interleultin-1 receptor, believed to be involved in cell signaling. The Tl/ST2 receptor and/or putative ligands are further described in Gayle, et al., J. 13io1. Chem., 271(10):5784-5789 (1996), Kumar, et al., I. Biol. Chem., 270(46):27905-27913 (1995), and Mitcham, et al., J. iol.
Chem., 271(10):5777-5783 (1996). These proteins, and proteins related thereto are of interest.
More generally all tnembrarte-bound proteins and receptors are of interest since they can play an impor~tartt role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, ntitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts are provided herein.
71. PR 2 Panczeatitis-associated protein (PAP) is a secretory protein that is overexpressed by the pancreas during acute pancreatitis. Serum PAP concentrations have been shown to be abnormally high in patients with acute pancreatitis. Pezzilli et al., Am. J. Gastroenterol., 92(10):1887-1890 (1997).
PAP is synthesized by the pancreas due to pancreatic inflammation and has been shown to be a good serum marker for injury of the pancreas. In addition, serum PAP levels appear to strongly correlate with creatinine clearance measurements. In patients with a pancreas lodney transplantation, PAP may prove to be a useful biological and histological marker of pancreatic graft rejection. Van der Pijl et al., ~~n nlantation, 63(7):995-1003 (1997).
Further, PAP has been shown to be useful in screening neonates for cystic fibrosis. In fact, PAP may discriminate cystic fibrosis neonates with better specificity than the current immunoreactive trypsis assay. lovanna et al., ~. R. , e,cad. Aci. III, 317(6):561-564.
Secreted proteins such as PAP have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other eytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature (see, for example, Klein et al., Prod; Natl. Acad. Sci., 23:7108-7113 (I996); U.S.
Patent No. 5,536,637)). The results of such efforts are presented herein.
72. PRO'788 Anti-neoplastic urinary protein (ANUP) was identified as the major protein present in a fraction of human urine which exhibits antiproliferative activity against human tumor cell lines without affecting the growth of several normal diploid cell lines or tumor cells of mouse or hamster origin. Sloane et al., J3iocher2 J., 234(2):355-362 (I986).
ANUP is a unique cytokine that has been found in human granulocytes. The N-terminal amino acid sequence has been shown to be unique. A synthetic peptide corresponding to the first nine residues, with Cys at positions 4 and 7, was found to be an anti-tumor agent in vitro. Ridge and Sloane, o ' e, 8(1):1-5 (1996).
Secreted proteins such as ANUP have various itulustrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the literature (see, for example, Klein et al., r c Natl. Acad. Sci., X3:7108-?113 (1996); U.S. Patent No. 5,536,637)) 73. PR0100$
Dickkopf I (dkk-1) is a member of a family of secreted proteins and functions in head induction. Dkk-I
is an inducer of Spetnarut organizer in amphibian embryos. Glinka, et al., Nature, 391 (6665):357-362 (1998). Dkk-I
is a potent antagonist of Wnt signalling, suggesting that dkk genes encode a family of secreted Wnt inhibitors. Thus, dkk-1 family members and related molecules are of interest.
More generally, all extraceilular proteins are of interest since they can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of marry individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate envirotunent. This information is often transmitted by secreted polypeptides (for instance, n>itogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Mast protein drugs available at present, such as thrombolytic agents, interferons, interleukins, WO 99/46281 PCTlUS99/U5028 erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those related to dkk-1. Many efforts are focused on the screening of mammalian recombinant DNA
libraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the literature jsee, for example, Klein et al., Proc. Natl.
Acad. Ski., X3:7108-7113 (1996); U.S.
Patent No. 5,536,637)). The results of such efforts to identify molecules related to dkk-1 are provided herein.
74. PROI 12 Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation.
Protein disulfide isomerase was initially identified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J. l 1.
Chem. 239:1406-1410 (1964) and Epstein et al., Cold S~ring_Harbor Symp. Ouant.
Biol. 28:439-449 (1963}).
Protein disulfide isomerase has been shown to be a resident enzyme 'of the endoplasmic reticulum which is retained in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus. Protein disulfide IS isomerase and related proteins are further described in Laboissiere, et al., J. Biol. Chem., 270(47:28006-28009 (1995}; 3eenes, et al., a ~ , 193(2):151-156 (1997; Koiwnen, et al., Gepomics, 42(3):397-404 (1997); and Desilva, et aL, DNA Cell Biol., 15(1):9-16 (1996). These studies indicate the importance of the identification of protein disulfide related proteins.
More generally, the identification of all exuacellular and membrane-bound proteins is of interest since they play important roles in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment.
This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropepiides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracelluIar environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreactors. In fact, most protein drugs available at present, such as thrombolytic agents, interferons, ituerleukms, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins, Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor itnmunoadhesiUts, for instance, can be employed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules Like selectins and integrins. Transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.

Of particular interest are cellular proteins having endoplasmic reticulum (ER) retention signals. These proteins are retair~d in the cell and function closely with endoplasmic reticuium in protein production. Such proteins have been described previously, i.e., see Shorrosh and Dixon, Plant J., 2(1):51-58 (1992).
Efforts are being undertaken by both industry and academia to identify new.
native secreted and membrane-bound receptor proteins, and in particular, cellular proteins having ER
retension signals. Many efforts are focused S an the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature (see, for example, Klein et al., roc. Natl. Acad. Sci" Q3_:7108-7113 (1996);
U.S. Patent No. 5,536,637)]. T'he results of such efforts, particularly the identification of novel polypeptides and nucleic acids encoding the same, which have sequence identity and similarity to protein disulfide isomerase are presented herein.
75. PR01014 Oxygen free radicals and antioxidants appear to play an important role in the cenual nervous system after cerebral ischemia and reperfusion. Moreover, cardiac injury, related to ischaemia and reperfusion has been reported to be caused by the action of free radicals. Additionally, studies have reported that the redox state of the cell is a pivotal determinant of the fate of the cells. Furthermore, reactive oxygen species have been reported to be cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging; mutations and malignancy. Thus, the control of oxidation and reduction is important for a number of reasons including for control and prevention of strokes, heart attacks, oxidative stress and hypertension. In this regard, reductases, and particularly, oxidoreductases, ate of interest.
Publications further describing this subject matter include Kelsey, et al., Br. J. Cancer, 76('n:852-4 (1997); Friedrich and Weiss, ). Theor. Biol., 187(4):529-40 (1997) and Pieulie, et a1.,1. Bacteriol., 179(18):5684-92 (1997).
In addition to reductases in particular, novel polypeptides are generally of interest. Extracellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells andlor the immediate environment:
This informadan is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides; ami hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have various industrial applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, irnerleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry atxl acadtmia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature (see, for example, Klein et al., Proc. Natl. Asad.
,~j,., x:7108-7113 (1996); U.S. Patent No. 5,536,637)7. The results of such efforts, patvcularly those identifying polypeptides having sequence identity with reduetases, and the nucleic acids encoding the same, are presented herein.

76. PR01017 Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the biosynthesis of macromolecules, the controlled release and utilization of chemical energy, and other processes necessary to sustain Life. Sulfotransferases are enzymes which transfer sulfate from a sulfate donor to acceptor substrates, particulazly those containing terminal glucoronic acid. The NNK-1 carbohydrate epitope is expressed on several neural adhesion glycoproteins and a glycolipid, and is involved in cell interactions. The glucuronyltransferase and sulfotransferase are considered to be .the key enzymes in the biosynthesis of this epitope because the rest of the structure occurs often in giycoconjugates. HNK-1 sulfotransfererase is further described in Bakker, H., et al., J. Biol.Chem., 272(47):29942-29946 (1997).
In addition to HNK-1 sulfotransfererase, and novel proteins related thereto, all novel proteins are of , interest. Extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the irt>irtediate environment. This information is often transmitted by secreted golypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins.
These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreactors. In fact, most protein drugs available at present, such as thrombolytic agents, interferons, interlettldns, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immtmoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like seleciins and integrins. Transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Efforts are being urxlertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly those having sequence identity with HNK-1 sulfotransferase. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane=bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., roc. N~tl. Acad.. Sci., x:7108-7113 (I996); U.S. Patent No.
5,536,637)j, The results of such efforts are provided herein.
77. PR 74 Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the _ biosynthesis of macromolecules, the controlled release and utilization of chemical energy, and other processes WO 99146281 PCTIUS99l05028 necessary to sustain life. Glucose dehydrogenase functions in the oxidation of glucose to gluconate to generate metabolically useful energy. The regulation of the PQQ-linked glucose dehydrogenase in different organisms is reviewed in Neijssel, et al.,. Antonie Van Leeuwenhoek, 56(1):51-61 (1989).
Glucose dehydrogenase functions as an auxiliary energy generating mechanism, because it is maximally synthesized under conditions of energy stress.
In addition to molecules related to glucose dehydrogenase, all novel proteins are of interest. Extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicelluIar organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the itnmediate environment. This information is often transmitted by secreted polypeptides {for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretary pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.
Secreted proteins have various industrial applications, including use as pharmaceuticals, diagnostics, biosensors and bioreactors. In fact, most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane-bound proteins, also have potential as therapeutic or diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction.
Membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction. Such membrane-bound proteins and cell receptors include, but are not lin>ited to, eytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. Transduction of signals that regulate cell growth and differentiation is regulated in pan by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane bound receptor proteins, and particularly cellular proteins and those related to dehydrogenase or oxidoreductase.
Many efforts are focused on the screening of tnamtnalian recombinant DNA
libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature jsee, for example, IClein et al., Proc. NatliAcad.
Sci., 9, x:7108-7113 (1996); U.S. Patent No. 5,536,637)]_ The results of such efforts are presented herein.
78. PR ~ 1 It has been reported that the cytokine interleukin 37 (~1'~ stimulates epithelial, endothelial, and fibroblastic cells to secrete cywkines stxh as II,-6, IL-8, and granuIocyte-colony-stimulating factor, as well as prostaglandin E2.
Moreover, it has been shown that when cultured in the presence of IIrl7, fibroblasts could sustain proliferation of CD34+ preferential maturation into neutrophils. Thus it has been suggested that IL-17 constitutes an early initiator of the T cell-dependent inflammatory reaction andJor an element of the cytokine network that bridges the immune system to hematopoiesis. See, Yao, et al., ,T~~j., I55{12):3483-5486 (1995);
Fossiez, et al., J. Exn. Med., 1830:2593-2603 (1996); Ketmedy, et al., J. InterferotL~'Lvtokine Res., 16{8):6I 1-617 (1996). Thus, proteins related to IL-17 are of interest.
More generaily, all novel proteins are of interest. Excracellular proteins play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the exaacellular environment.
Secreted proteins have various indusuiai applications, including pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins, particularly those related to IL-17. Many efforts are focused on the screening of matr>zna)ian recombinant DNA
libraries to identify the coding sequences for novel secreted proteins.
Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Prod. Nat!.
Acad. Sci., x:7108-7113 (1996); U.S.
Patent No. 5,536,637)j. The results of such efforts are presented herein.
79. PR0938 Protein disulfide isotnerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation:
Protein disulfide isomerase was initially identified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J_;B_iol.
Chem. x:1406-1410 {1964) and Epstein et aL, Fold S.prin~ Harbor Svmn Quant Biol. 28:439-449 (1963)).
Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus. Protein disulfide isomerase and related proteins are further described in Laboissiere, et al., J. Biol. Chem., 270 47 :28006-28009 {i995); Jeenes, et al., C;er e, ~Q312~:151-156 {199?); Koivunen, et al., enomics, 42:397-404 (1997); Desilva, et al,, DNA Cell Bigl., ~,.5 1~:9-lb (1996); Freedman, et al. Trends in Biochem.
Sci. x:331-336 (1994); Bulleid, N.J.
A~gattces in Prot. Chem. 44:125-50 (1993); and Noiva, R., Prot Ex~. and Purification ~:1-13 (1994). These studies indicate the importance of the identification of protein disulfide related proteins.
More generally, and also of interest are all novel membrane-bound proteins and receptors. Such proteins can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cycotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membratre-bound proteins. Such mertrbrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, aansduction of signals that regulate cell growth and WO 99!46281 PCTNS99/05028 differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, cart also act as growth factor receptors, Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Given the importance of membrane bound proteins, efforts are under way to identity novel membrane bound proteins. Moreover, given the importance of disulfide bond-forming enzymes and their potential uses in a number of different applications, for example in increasing the yield of correct refolding of recombinantly produced proteins, effons are currently being undertaken by both industry and academia to identify new, native proteins having sequence identity with protein disulfide isomerase. Many of these efforrs are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs.
We herein describe the identification and characterization of a novel polypeptide having homology to protein disulfide isomerase.
IS
88. PR01082 The low density lipoprotein (LDL) receptor is a membra~-bound protein that plays a key role in cholesterol homeostasis, mediating cellular uptake of lipoprotein particles by high affinity binding to its ligands, apolipoprotein (apo) B-100 and apoE. The ligand-binding domain of the LDL receptor contains ?
cysteine-rich repeats of approximately 40 amino acids, wherein each repeat contains 6 cysteines, which form 3 intra-repeat disulfide bonds.
These unique structural features provide the LDL receptor with its ability to specifically interact with apo B-100 and apoE, thereby allowing for transport of these lipoprotein particles across cellular membranes and metabolism of their corr~portents. Soluble fragments containing the extracellular domain of the LDL receptor have been shown to retain the ability to interact with its specific lipoprotein ligands (Simmons et al., liBiiol. Chem. 272:25531-25536 (1997)).
LDL receptors are further descn'bed inJavitt, ~SEB ., 9(13):1378-1381 (1995) and Herz and Willnow, nAn~NY
d ci., ?37:14-19 (1994). Thus, proteins having sequence identity with LDL
receptors are of interest.
More generally, all membrane-bound proteins and receptors can play an important role in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the irritaediate envirorntient. 'Ibis information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors; neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors inchtde, but are not limited to; cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in'cell-yell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in pan by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor. Of particular interest are membrane bound proteins that have type II transmembrane domains.

Membrane-bound proteins and receptor molecules have various indusuial applications, including as gharnaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are thus being undertaken by both industry and academia to identify new, native proteins, particularly membrane bound proteins including type II transmembrane bound proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
The results of such efforts are provided herein.
81: PR01083 Of particular interest are membrane bound proteins that belong to the seven transmembrane (7TM) receptor superfamily. Examples of these receptors include G-protein coupled receptors such as ion receptors. Another example of a 7TM receptor superfanvly member is described in Osterhoff, et al., DNA Cell Biol., 16(4):379-389 (1997).
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor imtnunoadhesins, for instance, can be employed as therapeutic agents to block receptor-Ggand interaction. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptorlligand interaction.
Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. The results of such efforts are presented herein.
82. ~'R0200 Polypeptides involved in survival, proliferation andlor differentiation of cells are of interest. Polypeptides known to be involved in the survival, proliferation and/or differentiation of cells include VEGF and members of the bone morphogenetic protein family. Therefore, novel polypeptides which are related to either VEGF or the bone morphogeztetic protein are of interest.
The heparin-binding endothelial cell-growth factor, VEGF, was identified and purified from media conditioned by bovine pituitary follicular or folliculo-stellate cells over several years ago. See Ferrara et al., Biaphys. Res. Conutt. 161, 851 (1989). VEGF is a naturally occurring compound that is produced in follicular or folliculo-stcllate cells t',FC), a morphologically well characterized population of granular cells. The FC are stellate cells that send cytoplasmic processes between secretory cells. .
VEGF is expressed in a variety of tissues as multiple homodinneric forms {121, 165, 189 and 206 amino acids per monomer) resulting from alternative RNA splicing. VEGF,z, is a soluble mitogen that does not bind heparin; the longer forms of VEGF bind heparin with progressively higher affinity. The heparin-binding forms of VEGF can be cleaved in the carboxy terminus by plasmin to release (a) diffusible forms) of VEGF. Amino acid sequencing of the carboxy terminal peptide identified after plasmin cleavage is Arg"o Ala",. Amino terminal "core"
protein, VEGF (I-110) isolated as a homoditner, binds neuu~alizing monoclonal antibodies (4.6.1 and 2E3) and soluble forms of FMS-like tyrosine kinase (FLT-1), kinase domain region (KDR) and fetal liver kinase (FLK) receptors wish similar affinity compared to the intact VEGF,6S homodimer.

WO 99!46281 PCT/US99105028 As noted, VEGF contains two domains that are responsible respectively for binding to the KDR and FLT-1 receptors. These receptors exist only on endothelial (vascular) cells. As cells become depleted in oxygen, because of trauma and the h'ke, VEGF production increases in such cells which then bind to the respective receptors in order to signal ultimate biological effect. The signal then increases vascular permeability and the cells divide and expand to form new vascular pathways - vasculogenesis and angiogenesis.
Thus, VEGF is useful for treating conditions in which a selected action on the vascular endothelial cells, in the absence of excessive tissue growth, is important, for example, diabetic ulcers and vascular injuries resulting from trauma such as subcutaneous wounds. Being a vascular (artery and venus) endothelial cell growth factor, VEGF
restores cells that are damaged, a process referred to as vasculogenesis, and stimulates the formulation of new vessels, a process referred to as angiogerresis.
VEGF would also find use in the restoration of vasculature after a myocardial infarct, as well as other uses that can be deduced. In this regard, inhibitors of VEGF are sometimes desirable, particularly to mitigate processes such as angiogenesis and vasculogenesis in cancerous cells.
Regarding the bone morphogenetic protein family, members of this family have been reported as being involved in the differentiation of cartilage and the promotion of vascularization and osteoinduction in preformed hydroxyapatite. Zou, et al., Sgnes Dev. (U.S.), 11(17):2191 (1997); Levine, et al., Ann: Plast. Sub., 39(2}:158 (1997). A number of related bone morphogenetic proteins have been identified, all members of the bone morphogenetic protein (BMP) family. Bone morphogenetic native and mutant proteins, nucleic acids encoding therefor, related comprnznds including receptors, host cells and uses are further described in at least: U.S. Patent Nos.
5,670,33$; 5,454,419; 5,661,007; 5,637,480; 5,631,142; 5,166,058; 5,620,867;
5,543,394; 4,877,864; 5,013,649;
55,106,748; and 5,399,677. Of particular interest are proteins having homology with bane morphogenetic protein 1, a procollagen C-proteinase that plays key roles in regulatiztg matrix deposition.
The present invention is predicated upon research intended to identify novel polypeptides which are related to VEGF and the BMP family, and in particular, polypeptides which have a role in the survival, proliferation and/or differentiation of cells. While the novel polypeptides are not expected to have biological activity identical to the known polypeptides to which they have homology, the known polypeptide biological activities can be used to determine the relative biological activities of the novel polypeptides. In particular, the novel polypeptides described herein can be used in assays which are intended to determine the ability of a polypeptide to induce survival, proliferation or differentiation of cells. In turn, the results of these assays can be used accordingly, for diagnostic and therapeutic purposes. The results of such research is the subject of the present invention.
$3. PR0285 and PR(~2t3!
The cloning of the Toll gene of Drosaphila, a maternal effect gene that plays a central role in the establishment of the embryonic dorsal-ventral pattern, has been reported by Hashirnoto et al. , et ~, 269-279 (!988). The Drosophila Toll gene encodes an integral membrane protein with an extracytoplasmic domain of 803 amino acids and a cytoplasmic domain of 269 amino acids. The extracytoplasmic domain has a potential membrane-spanning segment, and contains multiple copies of a leucine-rich segment, a structural motif found in marry transmembrane proteins. The Toll protein controls dorsal-ventral patterning in Drosophila embryos and activates the transcription factor Dorsal upon biding to its Iigand Spatzle. (Morisato and Anderson, ~1 J~C, 677-688 {1994).) In adult Drosophila, the TolllDorsal signaling pathway participates in the anti-fungal immune response. (Lenaitre et al., Cep $6, 973-983 (1996).) A human homologue of the Drosophila Toll protein has been described by Medzhitov et al., Nature ~8, 394-397 (1997). This human Toll, just as Drosophila Toll, is a type I
transmembrane protein, with an extracellular domain consisting of 21 tandemly repeated leucine-rich motifs (leucine-rich region - LRR), separated by a non-LRR
region, and a cytoplasmic domain homologous to the cytoplasntic domain of the human interleukin-1 (IL-1) receptor.
A constitutively active mutant of the human Toll transfected into human cell lines was shown to be able to induce the activation of NF-xB and the expression of NF-xB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as the expression of the constimulatory molecule B7.1, which is required for the activation of native T cells. It has been suggested that Toll functions in vertebrates as a non-clonal receptor of the immune system, which can induce signals for activating both an innate and an adaptive immune response in vertebrates. The human Toll gene reported by Medzhitov et al., supra was most strongly expressed in spleen and peripheral blood leukocytes (PBL), and the authors suggested that its expression in other tissues may be due to the presence of macrophages and dertdritic cells, in which it could act as an early-warning system for infection. The public GenBank database contains the following Toll sequences: Tolll f.DNAX# HSU88540-1, which is identical with the random sequenced full-length cDNA #HUMRSC786-1); ToIl2 (DNAX# HSU88878-1); TolI3 (DNAX# HSU88879-1); and To114 (DNAX#
HSU88880-1, which is identical with the DNA sequence reported by Medzhitov et al., supra). A partial Toll sequence (To115) is available from GenBank under DNAX# HSU88881-1.
Further human homologues of the Drosophila Toll protein, designated as Toll-like receptors (huTLRs 1-5) were recently cloned and shown to mirror the topographic structure of the Drosophila counterpart (Rock et at., I?roc.
Nab. cad. Sci. USA 9~, 588-593 [1998]). Overexpression of a constitutively active mutant of one human TLR
(Toll protein homologue - Med2hitov et al., supra; TLR4 - Rock et at., supra) leads to the activation of NF-tcB and induction of the inflammatory cytokines and constimulatory molecules.
Medzhitov et at., supra.
84. PR02I3-I. PRQ1330 and PR014d9 Cancer is characterized by the increase in the number of abnormal, or neoplastic, cells derived from a normal tissue which proliferate to form a tumor mass, the invasion of adjacent tissues by these neoplastic tumor cells, and the generation of malignant cells which eventually spread via the blood or lymphatic system to regional lymph rides and to distant sites (metastasis). In a cancerous state a cell proliferates under conditions in which normal cells would not grow. Cancer manifests itself in a wide variety of forms, characterized by different degrees of invasiveness and aggressiveness.
Alteration of gene expression is. intimately related to the uncontrolled cell growth and de-differentiation which are a common feature of all cancers. The genomes of certain well studied tumors have been found to show decreased expression of recessive genes, usuatly referred to as tumor suppression genes, which would normally function to prevent malignant cell growth, andlor overexpression of certain dominant genes, such as oncogenes, that act to promote maygnant growth. Each of these genetic changes appears to be responsible for importing some of the traits that, in aggregate, represent the full neoplastic phenotype (Hunter, Cell 64, 1129 [1991]; Bishop, Cell 64, 235-248 (1991j).
A well known mechanism of gene (e.g. ortcogene) overexpression in cancer cells is gene amplification. This is a process where in the chromosome of the ancestral ceU multiple copies of a particular gene are produced. The process involves unscheduled replication of the region of chromosome comprising the gene, followed by WO 9914b281 ~ PCT/US99105028 recombination of the replicated segments back into the chromosome (Alitalo et al., Adv. Cancer Res. 47, 23S-281 (198bv. ' It is believed that the overexpression of the gene parallels gene amplification, i.e. is proportionate to the number .of copies made.
Proto-oncogenes that encode growth factors and growth factor receptors have been identified to play important roles in the pathogenesis of various human malignancies, including breast cancer. For example; it has been S found that the human ErbB2 gene (erbB2, also known as her2, or c-erbB-2), which encodes a 18S-kd transmembrane glycoprotein receptor (pl8SHER2; HER2) related to the epidermal growth factor receptor (EGFR), is overexpressed in about 259'o to 30% of human breast cancer (Slamon et al., Science 23S:I77-I82 [1987]; Slamon et aL, Science 244-.707-712 [ 1989]).
It has been reported that gene amplification of a protooncogene is an event typically involved in the more malignant forms of cancer, and could act as a predictor of clinical outcome (Schwab et al., Genes Chromosomes Cancer 1, 181-193 [1990]; AIitaIo et al., supra). Thus, erbB2 overexpression is commonly regarded as a predictor of a poor prognosis, especially in patients with primary disease that involves axillary lymph nodes (Slamon et al.;
[1987] and [1989], supra; Ravdin and Chamness, Gene 159:19-27 [1995]; and Hynes and Stern, Biochem Biophys Acta 1198: 16S-184 [1994]), and has been linked to sensitivity and/or resistance to hormone therapy and 1S chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines tBaselga et al., Oixology 11 {3 Suppl 1): 43-48 [1997]). However, despite the association of erbB2 overexpression with poor prog~sis, the odds of HER2-positive patients responding clinically to treaunent with taxanes were greater than three times those of HER2-negative patients (lbid). A recombinant humanized anti-ErbB2 (anti-HER2) monoclonal antibody (a humanized version of the murine anti-ErbB2 antibody 4DS, referred to as rhuMAb HERZ
or Herceptin 7b) has been clinically active in patients with ErbB2-overexpressing metastatic breast cancers that had received extensive prior anticancer therapy. (Baselga et al., J. Clin. Oncol.
14:737-744 [1996]).
The protein Notch and its homologues are key regulatory zeceptors in determining the cell fate in various development processes. The protein Notch-4, also known as int-3 oncogene, was originally identified as a frequent target in mouse mammary tumor virus (MMVS). Notch-4 is believed to be a transgene which affects the differentiation capacity of stem cells and leads to neoplastic proliferation in epithelial cells. Shirayoshi et al., Genes Cells 2(3): 213-224 (1997). During embryogenesis, the expression of Notch-4 was detected in endothelial cells of blood vessels forming tissues such as the dorsal aorta, intersegmental vessels, yolk sac vessels, cephalic vessels, heart, vessels in bronchial arches, and capillary plexuses. Notch-4 expression in these tissues was also associated with flk I, the major regulatory gene of vasculogenesis and angiogenesis.
Notch-4 is also upregulated in vitrb during the differentiation of endothelial stem cell. The endothelial cell specific expression pattern of Notch-4, as well as its structural similarity to Notch suggest that Notch-4 is an endothelial cell specific homologue of Notch and that it may play a role in vaculogenesis and angiogenesis.
85. PRQ298 3S Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe the identification and characterization of novel transmembrane polypeptides, designated herein as PR0298 polypeptides.

WO 99!46281 PCT/US99l05028 86. PR 37 Neuronal development in higher vertebrates is characterized by processes that must successfully navigate distinct cellular environment_en route to their synaptic targets. The result is a functionally precise formation of neural circuits. The precision is believed to result form mechanisms that regulate growth cone pathfinding and target recognition, followed by latter refinement and remodeling of such projections by events that require neuronal activity, Goodman and Shatz, Cell/Neuron [Suppl.J 72(10): 77-98 (1993). It is further evident that different neurons extend nerve fibers that are biochemically distinct and rely on specific guidance cues provided by cell-cell, cell-matrix, and chemotrophic interactions to teach their appropriate synaptic targets, Goodman et al., supra.
One particular means by which diversity of the neuronal ceU surface may be generated is through differential expression of cell surface proteins referred to as cell adhesion molecules (CAMs). Neuronally expressed CAMs have been implicated in diverse developmental processes, including migration of neurons along radial glial cells, providing permissive or repulsive substrates for neurite extension, and in promoting the selective fasciculation of axons in projectional pathways. lessel, Neuron 1: 3-13 (1988); Edehnan and Crossin, Annu. Rev. Biochem. 60: 155-190 (1991). Interactions between CAMs present on the growth cone membrane and molecules on opposing cell membranes or in the extracellular matrix are thought to provide the specific guidance cues that direct nerve fiber outgrowth along appropriate projectional pathways. Such interactions are likely to result in the activation of various second messenger systems within the growth cone that regulate neurite outgrowth. Doherry and Walsh, Curr. Opin Neurobiol. 2: 595-601 {1992).
In higher vertebrates, mast neural CAMs have been found to be members of three major structural families of proteins: the integrins; the cadherins, and the immunoglobulin gene superfamily (IgSF). Jessel, supra.; Takeichi, Annu. Rev. Biochem. 59:.237-252 (1990); Reichardt atxi Tomaselli, Annu. Rev.
Neurosci. 14: 531-570 {1991). Cell adhesion molecules of the IgSF (or Ig-CAMs), in particular, constitute a large family of proteins frequently implicated in neural cell interactions and nerve fiber outgrowth during development, Salzer and Cohnan, Dev. Neurosci. I1:
377-390 (1989); Briimmendorf and Rathjen, J. Neurochem. 61: 1207-1219 (1993).
However, the majority of mammalian Ig-CAMs appear to be too widely expressed to specify navigational pathways or synaptic targets suggesting that other CAMs, yet to be identified, have role in these more selective interactions of neurons.
Many of the known neural Ig-CAMs have been found to be attached to the plasma membrane via a glycosyiphosphatidylinositol (GPn anchor. Additionally, many studies have implicated GP1-anchored proteins in providing specific guidance cues doting the outgrowth on neurons in specific pathways. In studies of the grasshopper neNOUS System, Creatment of embryos with phosphatidylinositol-specific phopholipase C (PIPLC), which selectively removes GPI-anchored proteins from the surfaces of cells, resulted in misdirection and faulty navigation among subsets of pioneering growth cones, as well as inhibited migratory patterns of a subset of early neurons, Chang et al., Devel. 114: 507-519 (1992). The projection of retinal fibers to the optic rectum appears to depend, in part, on a 33 kDa GPI-anchored protein, however, the precise nature of this protein is unknown. Stahl et al., Neuron 5: 735-743 (1990).
The expression of various GPI-anchored proteins has been characterized amongst the different populations of primary rat neurons amongst dorsal root ganglion, sympathetic neurons of the cervical ganglion, sympathetic neiunns of the superior cervical ganglion, and cerebeDar granule neurons.
Rosen et a1.,1. Cell Biol. 117: 617-627 (1992). In contrast to the similar pattern of total membrane protein expression by these different types of neurons, striking differences were observed in the expression of GPI-anchored proteins between these neurons. Recently, a WO 99146281 I'CT/US99105028 65 lcDa protein band known as neurotrimin was discovered and found to be differentially expressed by primary neurons (Rosen et al., supra), and restricted to the nervous system and found to be the most abundant and earliest expressed of the GPI-anchored species in the CNS. Struyk et al., J.
Neuroscience IS(3): 2141-2156 (1995). The discovery of neurotrimin has further lead to the identification of a family of IgSF members, each containing three Ig-Iike domains that share significant amino acid identity, now termed IgLON.
Struyk et al., supra; Pimento et al., Gene 170(2): 189-95 (1996).
Additional members of the IgLON subfamily include opiate binding cell adhesion molecule (OBCAM), Schofield et al., EMBO 1. 8: 489-495 (1989); limbic associated membrane protein (LAMP), Pimento et at., supra;
CEPU-1; GP55, Wilson et al., J. Cetl Sci. 109: 3129-3138 (1996); Fatr. J.
Neurosci. 9(2): 334-41 (1997); and AvGp50, Hancox et al., Brain Res. Mol. Brain Res: 44(2): 273-85 (1997).
While the expression of neurotrimin appears to be widespread, it does appear to correlated with the development of several neural circuits. For example, between E18 and P10, neurotitnin mRNA expression within the forebrain is maintained at high levels in neurons of the developing thalamus, cortical subplate, and cortex, particularly laminae V and VI (with less intense expression in 1I, II, and IV;
and minimal expression in lamina I).
Cortical subplate neurons may provide an early, temporary scaffold for the ingrowing thalamic afferents en route to their final synaptic targets in the cortex. Allendoerfer and Shatz, Annu. Rev.
Neurosci. 17: 185-218 (1994).
Conversely, subplate neurons have been suggested to be required for cortical neurons from layer V to select VI to grow into the thalamus, and neurons from layer V to select their targets in the colIiculus; pons, and spinal cord (McConnell et al., J. Neurosci. 14: 1892-190? (1994). The high level expression of neurotrimin in many of these projections suggests that it could be involved in their development.
In the hindbrain, high levels of netuotrimin message expression were observed within the pontine nucleus and by the internal granule cells and Purlcinje cells of the cerebellum. The pontine nucleus received afferent input from a variety of sources including corticopotttine fibers of layer V, and is a major source of afferent input, via mossy fibers, to the granule cells which, in turn, are a major source of afferent input via parallel fibers to Purldnje cells.
[Palay and Chan-Palay, The cerebellar cortex: cytology and organization. New York: Springer (1974]. High level expression of neurotrinvn these neurons again suggests potential involvement in the establishment of these circuits.
Neurotrimin also exhibits a graded expression pattern in the early postnatal striatum. Increased neurotrimin expression is found overlying the dorsolateral striatum of the rat, while lesser hybridization intensity is seen overlying the ventromedial striatum. Struyk et at., supra. This region of higher neurotrimin hybridization intensity does not correspond to a cytoarchiteccurally differentiable region, rather it corresponds to the primary area of afferent input from layer V1 of the contralateral sensorimotor cortex (Gerfen, Nature 311:
461-464 (1984); Donoghue and Herhenham, Brain Res. 365: 397-403 (1986)). The ventromedial striatum, by contrast, receives the majority of its afferent input from the perirhinal and association cortex. It is noteworthy that a complementary graded pattern of LAMP expression, has been observed within the striatium, with highest expression in ventromedial regions, and lowest expression dorsolaterally. Levitt, Science 223: 299-301 (1985);
Chesselet et al., Neuroscience 40: 725-733 33 (1991).
87. )0403 Type II transmembrane proteins, also lrnown as single pass transmembrane proteins have an N-terminal portion lodged in the cytoplasm while the C-terminal portion is exposed to the extracellular domain.

WO 99/46281 PCTIUS99l05028 Endothelia is a family of vasoconstrictor peptides about which much activity has been focused to better understand its basic pharmacological, biochemical and molecular biological features, including the presence and structure of isopeptides and their genes (endothelia-1, -2 and u3), regulation of gene expression, intracellular processing, specific endothelia converting enzymes (ECE), receptor subtypes (ET-A and ET-B), intracellular signal transduction following receptor activation, etc.
The endothelia (E'T) family of peptides have potent vascular, cardiac and renal actions which may be of pathophysioiogical importance in many human disease states. ET-1 is expressed as an inactive 212 amino acid prepropeptide. The prepropeptide is first cleaved at Arg52-Cys53 and Arg92-AIa93 and then the carboxy terminal Lys91 and Arg92 are uimmed from the protein to generate the propeptide big ET-1.
Endothelia is generated from inactive intermediates, the big endothelins, by a unique processing event catalyzed by the zinc metalloprotease, endothelia converting enzyme (ECE). ECE
was recently cloned, and its structure was shown to be a single pass transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. ECEs cleave the endothelia propeptide between Trp73 and Va174 producing the active peptide, ET, which appears to function as a local rather than a circulating hormone (Rubanyi, G.M. & Polokoff, M.A., Pharmachological Reviews 46: 325-415 (1994). Thus ECE activity is a potential site of regulation of endothelia production and a possible target for therapeutic intervention in the endothelia system. By blocking ECE activity, it is possible stop the production of ET-I
by inhibiting the conversion of the relatively inactive precursor, big ET-1, to the physiologically active forth.
Endothelins may play roles in the pathophysiolog~ of a number of disease states including: 1) cardiovascular diseases (vasospasm, hypertension, myocardial ischemia; reperfusion injury and acute myochardial infarction, stroke ' (cerebral ischemia), congestive heart failure, shock, atherosclerosis, vascular thickening); 2) kidney disease (acute and chronic renal failure, glomerulonephritis, cirrhosis); 3) lung disease (bronchial asthma, pulmonary hypertension);
4) gastrointestinal disorders (gastric ulcer, inflammatory bowel diseases); 5) reproductive disorders (premature labor, dysmenorhea, preeclampsia) and 6) carcinogenesis. Rubanyi & Polokoff, supra.
2,5 Si)MMARY OF THE INVENTION
1. PR0213 Applicants have identified a cDNA clone that encodes a novel poIypeptide, wherein the polypeptide is designated in the presem application as "PR02I3":
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0213 polypeptide. In one aspect, the .isolated nucleic acid comprises DNA
encoding the PR0213 polypeptide having amino acid residues 1 to 295 of Figure 2 (SEQ ID N0:2), or is complementary to such encoding nucleic acid seqe, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
In another embodiment, the invention provides isolated PRO213 polypeptide. In particular, the invention provides isolated native sequence PR0213 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 295 of Figure 2 (SEQ ID N0:2).

2. ~R0274-Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated,in the present application as " PR0274".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0274 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0274 .polypeptide having amino acid residues I to 492 of Figure 4 (SEQ ID N0:7), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
The isolated tntcleic acid sequence may comprise the cDNA insert of the DNA39987-I 184 vector deposited on April 21, 1998 as ATCC 209786 which includes the nucleotide sequence encoding PR0274.
In another embodiment, the invention provides isolated PR0274 polypeptide. In particular, the invention provides isolated native sequence PR0274 polypeptide; which in one embodiment, includes an amino acid sequence comprising residues 1 to 492 of Figure 4 (SEQ ID N0:7). An additional embodiment of the present invention is directed to an isolated extracelIuIar domain of a PR0274 polypeptide.
Optionally, the PR0274 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA39987-1184 vector deposited on Aprit 21, 1998 as ATCC 209786.
In another embodiment, the invention provides three expressed sequence tags ,(EST) comprising the nucleotide sequences of SEQ ID N0:8 (herein designated as DNA17873), SEQ ID
N0:9 (herein designated as DNA3615?) and SEQ ID NO:10 (herein designated as DNA28929) (see Figute 5-7, respactively).
3. PR030D
Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the presem application as "PR0300".
1n one embodiment, the invention provides an isolated rntcleic acid molecule comprising DNA encoding a PR0300 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0300 polypeptide having amino acid residues 1 to 457 of Figure 9 (SEQ 1D N0:19), or is complementary to such encoding nucleic acid seguence, and remains srably bound to it under arleast moderate, and optionally, under high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA40b25-I 189 vector deposited on April 21, 1998 as ATCC 209?88 which includes the nucleotide sequence encoding PR0300.
In another embodimern, the invention provides isolated PR0300 polypeptide. in particular, the invention provides isolated native sequence PR0300 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 457 of Figure 9 (SEQ ID N0:19). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0300 polypeptide.
Optionally, the PR0300 polypeptide is obtained or is obtainable by expressing the golypeptide encoded by the cDNA
insert of the DNA40625-1189 vector deposited on April 21, 1998 as ATCC 209788.
4. pR0284 Applicants have identified a cDNA clone that encodes a novel transmembrane polypeptide, wherein the poiypeptide is designated in the present application as "PR0284".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0284 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0284 polypeptide WO 99146281 ~ PCT/US99/05t)28 having amino acid residues 1 to 285 of Figure 11 (SEQ ID N0:28), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0284 polypeptide having amino acid residues about 25 to 285 of Figure 11 (SEQ ID N0:28) or 1 or about 25 to X of Figure I1 (SEQ 1D
N0:28), where X is any amino acid from 71 to 80 of Figure 11 (SEQ ID N0:28), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA23318-1211 vector deposited on April 21, 1998 as ATCC 209787 wtuch includes the nucleotide sequence encoding PR0284.
In another embodiment, the invention provides isolated PR0284 poIypeptide. In particular, the invention provides isolated native sequence PR0284 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 285 of Figure 11 (SEQ ID N0:28). Additional embodiments of the present invention are directed to isolated PR0284 polypeptides comprising amino acids about 25 to 285 of Figure 11 (SEQ ID N0:28) or 1 or about 25 to X of Figure 11 (SEQ ID N0:28), where X is any amino acid from ?1 to 80 of Figure 11 (SEQ ID
N0:28). Optionally, the PR0284 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA23318-1211 vector deposited on April 21, I998 as ATCC 209787.
IS In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12982 which comprises the nucleotide sequence of SEQ ID N0:29.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA15886 which comprises the nucleotide sequence of SEQ ID N0:30.
5. PR(~296 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the sarcoma-amplified protein SAS, wherein the polypeptide is designated in the present application as "PR029b".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0296 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0296 polypeptide having amino acid residues 1 to 204 of Figure 15 (SEQ ID N0:36), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0296 polypeptide having amino acid residues about 35 to 204 of Figure IS (SEQ ID N0:36) or amino acid 1 or about 35 to X of Figure 15 (SEQ 1D N0:36), where X is any amino acid from 42 to 51 of Figure 15 (SEQ ID
N0:36), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA39979-1213 vector deposited on April 21, 1998 as ATCC 209789 which includes the nucleotide sequence encoding PR0296.
In another embodiment, the invention provides isotated PR0296 polypeptide. In particular, the invention provides isolated native sequence PR0296 polypeptide, wlvch in one embodiment, includes an amino acid sequence comprising residues 1 to 204 of Figuze IS (SEQ ID N0:36). Additional embodiments of the present invention are directed to PR0296 polypeptides comprising amino acids about 35 to 204 of Figure 15 (SEQ ID N0:36) or amino acid 1 or about 35 to X of Figure 15 (SEQ ID N0:36), where X is any amino acid from 42 to 51 of Figuxe I S (SEQ
1D N0:36). Optionally, the PR0296 potypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA39979-1213 vector deposited on April 21, 1998 as ATCC 209789.

In another embodiment, the invention pzovides an expressed sequence tag (EST) designated herein as DNA23020 comprising the nucleotide sequence of SEQ ID N0:37.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA2I971 comprising the nucleotide sequence of SEQ ID N0:38.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as S DNA29037 comprising the nucleotide sequence of SEQ ID N0:39.
6. R 2 Applicants have identified a cDNA clog that encodes a novel polypeptide having homology to a high affinity immunoglobulin F~ receptor, wherein the polypeptide is designated in the present application as "PR0329" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0329 polypeptide: In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0329 polypeptide having amino acid residues 1 to 359 of Figure 20 (SEQ ID N0:45), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the I~NA40594-1233 vector deposited on February 5, 1998 as ATCC 209617 which includes the nucleotide sequence encoding PR0329.
1n another embodiment, the invention provides isolated PR0329 polypeptide. In particular, the invention provides isolated native sequence PR0329 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 359 of Figure 20 (SEQ ID NO:45). Optionally, the PR0329 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA40594-1233 vector deposited on February 5, 1998 as ATCC 209617.
7. PR0362 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to A33 antigen and HCAR membrane-bound protein, wherein the polypeptide is designated in the present application as "PR0362" .
In one embodiment, the invention pzovides an isolated nucleic acid molecule comprising DNA encoding a PR0362 polypeptide: In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0362 poiypeptide having amino acid residues 1 to 321 of Figure 22 (SEQ ID N0:52), or is complementary to such encoding nucleic acid sequetxe, and remaiiu stably bound to it under aL least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0362 polypeptide having amino acid residues 1 to X of Figure 22 (SEQ ID N0:52) whew X is any amino acid from amino acid 271 to 280, or is c~npiementary to such encoding nucleic acid sequence, and remains stably bound to it under at Ieast moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45416-125 t vector deposited on February 5, 1998 as ATCC 209620 which includes the nucleotide sequence encoding PR0362.
In another embodiment, the invention provides isolated PR0362 polypeptide. In particular, the invention provides isolated native sequence PR0362 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues t to 321 of Figure 22 (SEQ ID N0:52). An additional embodiment of the present invention is directed to an isolated extraeellular domain of a PR0362 polypeptide comprising amino acids 1 to X of the amino acid sequence shown in Figure 22 (SEQ ID N0:52), wherein X is any amino acid from amino acid 271 to 280.

Optionally, the PR0362 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA45416-1251 vector deposited on February 5, 1998 as ATCC
209620.
8. PRO363 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the cell surface receptor protein HCAR, wherein the polypeptide is designated in the present application as "PR0363".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0363 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0363 polypeptide having amino acid residues 1 to 373 of Figure 24 (SEQ ID N0:59), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding a PR0363 extracellular domain polypeptide having amino acid residues 1 to X of Figure 24 (SEQ ID N0:59) where X is any amino acid from amino acid 216 to amino acid 225, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45419-1252 vector deposited on February 5, 1998 as ATCC 209616 which includes the nucleotide sequence encoding PR0363.
In another embodiment, the invention provides isolated PR0363 polypeptide. In particular, the invention provides isolated native sequence PR0363 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 373 of Figure 24 (SEQ ID NO:59). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0363 polypeptide, wherein that extracellular domain may comprise amino acids 1 to X of the sequence shown in Figure 24 (SEQ 1D N0:59), where X is any amino acid from amino acid 216 to 225. Optionally, the PR0363 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA45419-1252 vector deposited on February 5, 1998 as ATCC
209616.
9. PR 8 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to tumor necrosis factor receptor, wherein the polypeptide is designated in the present application as "PR0868".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0868 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0868 poiypeptide having amino acid residues l to 655 of Figure 26 (SEQ ID N0:64), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0868 polypeptide having amino acid residues 1 to X of Figure 26 (SEQ ID N0:64), where X is any amino acid from amino acid 343 to 352 of the sequence shown in Figure 26 (SEQ ID N0:64), or is complementary to such encoding nucleic acid sequence, and rennaitts stably bound to it under at least moderate, and optionally, under high suingency conditions. In yet another aspect, the isolated nucleic acid comprises DNA encoding the PR0868 polypeptide having amino acid residues X to 655 of Figure 26 (SEQ ID N0:64), where X is any amino acid from amino acid 371 to 380 of the sequence shown in Figure 26 (SEQ ID N0:64), or is complementary to such encoding nucleic acid sequence, and ..
remains stably bound to it under at least moderate, and optionally, under high stringency conditions, The isolated nucleic acid sequence may comprise the cDNA insert of the DNA52594-1270 vector deposited on March 17, 1998 as ATCC 209679 which includes the nucleotide sequence encoding PR0868.
In another embodiment, the invention provides isolated PR0868 poiypeptide. In particular, the iztvemion provides isolated native sequence PR0868 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 655 of Figure 26 (SEQ ID N0:64). In another aspect, the isolated PR0868 polypeptide comprises amino acid residues 1 to X of Figure 26 (SEQ ID N0:64), where X is any amino acid from amino acid 343 to 352 of the sequence shown in Figure 26 (SEQ ID N0:64). In yet another aspect, the PR0868 polypeptide comprises amino acid residues X to 655 of Figure 26 (SEQ ID N0:64), where X is any amino acid from amino acid 371 to 380 of the sequence shown in Figure 26 (SEQ ID N0:64). Optionally, the PR0868 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA52594-1270 vector deposited on March 17, 1998 as ATCC 209679.
10. PR 8 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to serine proteases, wherein the polypeptide is designated in the present appIicauon as "PR0382".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0382 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO382 polypeptide having amino acid residues 1 to 453 of Figure 28 (SEQ ID NO:69), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45234-1277 vector deposited on March 5, 1998 as ATCC 209654 which includes the nucleotide sequence encoding PR0382.
In another embodiment, the invention provides isolated PR0382 poiypeptide: In particular, the invention provides isolated native sequence PR0382 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 453 of Figure 28 (SEQ ID N0:69). An additional embodiment of the present invention is directed to an isolated extracelhrlar domain of a PR0382 polypeptide, with or without the signal peptide. Optionally, the PR0382 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA45234-1277 vector deposited on March 5, 1998 as ATCC 209654.
11. ~RQS~S
Applit:ants have identified a cDNA clone that encodes a novel polypeptide having homology to meltrin, wherein the polypeptide is designated in the present application as "PR0545".
In uric embodiment, the invention provides an isolated.nucleic acid molecule comprising DNA encoding a PR0545 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROS45 polypeptide having amino acid residues 1 to 735 of Figure 30 (SEQ ID NO:74), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 5, 1998 as ATCC 209655 which includes the nucleotide sequence encoding PR0545.
In another embodiment, the invenrion provides isolated PR0545 polypeptide. In particular, the invention Provides isolated native sequence PR0545 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 735 of Figure 30 (SEQ ID N0:74). An additional embodiment of the present invention is directed to an isolated extracellular domain of a FR0545 polypeptide.
Optionaily> the PR0545 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on March 5, 1998 as ATCC 209655.
In another embodiment, the invention provides an expressed sequence tag (FST) designated herein as DNAI3217 comprising the nucleotide sequence of SEQ ID N0:75 (Figure 31).
12. 0617 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD24, wherein the polypeptide is designated in the present application as "PR06I7".
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0617 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0617 polypeptide having amino acid residues 1 to 67 of Figure 33 (SEQ ID NO:85), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, antler high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48309-1280 vector deposited on March 5, 1998 as ATCC 209656 which includes the nucleotide sequence encoding PRObl7.
In anothez embodiment, the invention provides isolated PR0617 polypeptide. In particular; the invention provides isolated native sequence PR0617 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 67 of Figure 33 (SEQ ID N0:85). Optionally, the PR0617 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA48309-1280 vector deposited on March 5, 1998 as ATCC 209656.
13. PR0700 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to protein disulfide isomerase, wherein the polypeptide is designated in the present application as "PR0700".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0700 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0700 polypeptide having amino acid residues 1 to 432 of Figure 35 (SEQ ID N0:90), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0700 polypeptide having amino acid residues from about 34 to 432 of Figure 35 (SEQ ID N0:90), oz is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency co~itions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 31, 1998 as ATCC 209'721 which includes the nucleotide sequence encoding PR0700.
In another embodiment, the invention provides isolated PR0700 polypeptide. In particular, the invention provides isolated native sequence PR0700 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 432 of Figure 35 (SEQ ID N0:90). In another embodiment, the invention provides an isolated PR0700 poIypeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about 34 to 432 of Figure 35 (SEQ ID N0:90). Optionally, the PR0700 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 31, 1998 as ATCC
209721.

WO 99/46281 PCTlUS99/05028 14. PR0702 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to conglutinin, wherein the polypeptide is designated in the present application as "PR0702".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0702 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0702 polypeptide having amino acid residues 1 to 277 of Figure 37 (SEQ ID N0:97), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0702 polypeptide having amino acid residues 26 to 277 of Figure 37 (SEQ 1D N0:97), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionahy, under high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50980-1286 vector deposited on March 3I, 1998 as ATCC 209717 which includes the nucleotide sequence encoding PR0702.
In another embodiment, the invention provides isolated PR0702 polypeptide. In particular, the invention provides isolated native sequence PR0702 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 277 of Figure 37 (SEQ ID N0:97). An additional embodiment of the present invention is directed to an isolated PR0702 polypeptide comprising amino acid residues 26 to 277 of Figure 3? (SEQ ID N0:97).
Optionally, the PR0702 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA50980-128b vector deposited on March 31, 1998 as ATCC 209717.
15. P ?0 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to VLCAS, wherein the poiypeptide is designated in the present application as "PR0703".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0703 polypegtide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0703 polypeptide having amino acid residues I to 730 of Figure 39 (SEQ ID N0:102); or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0703 polypeptide having amino acid residues from about 43 to 730 of Figure 39 (SEQ ID N0:102), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA509I3-1287 vector deposited on March 31, 1998 as ATCC~209716 which includes the nucleotide sequence encoding PR0703.
In another embodiment, the invention provides isolated PR0703 polypeptide. In particular, the invention provides isolated native sequence PR0703 polypeptide, which in one embodimem, includes an amino acid sequence comprising residues 1 to 730 of Figure 39 (SEQ ID NO:I02). In another embodiment, the invention provides an isolated PR0703 polypeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about 43 to 730 of Figure 30 (SEQ ID N0:102). Optionally, the PR0730 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA50913-1287 vector deposited on March 31, 1998 as ATCC 209716.

16. P__R,_~70 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to K-glypican, wherein the polypeptide is. designated in the present application as "PR0705".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0705 poiypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0705 polypeptide having amino acid residues 1 to 555 of Figure 41 (SEQ ID N0:109), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PRO705 polypeptide having amino acid residues about 24 to 555 of Figure 41 {SEQ ID N0:109), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50914-1289 vector deposited on March 31, 1998 as ATCC 209722 which includes the nucleotide sequence encoding PR0705.
In another embodiment, the invention provides isolated PR0705 polypeptide. In particular, the invention provides isolated native sequence PR0705 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 555 of Figure 41 (SEQ ID NO:109). An additional embodiment of the present invention is directed to an isolated PR0705 polypeptide comprising amino acid residues about 24 to 555 of Figure 41 (SEQ
ID N0:109). Optionally, the PR0705 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA50914-1289 vector deposited on March 31, 1998 as ATCC 209722.
17. 07 8 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the aryl sulfatases, wherein the polypeptide is designated in the present application as "PR0708".
In or>e embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO?08 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0708 polypeptide having amino acid residues 1 to 515 of Figure 43 (SEQ ID N0:114), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48296-1292 vector deposited on March 11, 1998 as ATCC 209668 which includes the nucleotide sequence encoding PR0708.
In another embodimem, the invention provides isolated PR0708 polypeptide. In particular, the invention provides isolated native sequence PR0708 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 5I5 of Figure 43 (SEQ ID N0:114). Another embodiment is directed to a PR0708 polypeptide comprising residues 38-515 of the amino acid .sequence shown in Figure 43 (SEQ ID N0:114).
Optionally, the PR0708 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA48296-1292 vector deposited on March 11, 1998 as ATCC 209668.
18. P_R0320 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to fibulin, wherein the polypeptide is designated in the present application as "PR0320" .
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0320 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0320 polypeptide having amino acid residues 1 to 338 of Figure 45 (SEQ ID N0:119), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucaeic acid sequence may comprise the cDNA insert of the vector deposited on March 11, 1998 as ATCC 209670 which includes the nucleotide sequence encoding PR0320.
In another embodiment, the invention provides isolated PR0320 polypeptide. In particular, the invention provides isolated native sequence PR0320 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 338 of Figure 45 (SEQ ID N0:119). Optionally, the PR0320 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 11, 1998 as ATCC 209670.
19. PR 324 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to oxidoreductases, wherein the polypeptide is designated in the present application as "PR0324".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0324 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0324 poiypeptide IS having amino acid residues 1 to 289 of Figure 47 (SEQ ID NO:i24), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at Least moderate, and optionally, under high suingency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0324 polypeptide having amino acid residues 1 or about 32 to X of Figure 47 (SEQ ID N0:124), where X
is any amino acid from i31 to I40, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA36343-1310 vector deposited on March 30, I998 as ATCC 209718 which includes the nucleotide sequence encoding PR0324.
In another embodiment, the invention provides isolated PR0324 polypeptide, In particular, the invention provides isolated native sequence PR0324 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 289 of Figure 4? (SEQ ID N0:124). The invention also provides isolated PR0324 polypeptide comprising residues 1 or about 32 to X of Figure 47 (SEQ ID
N0:124), wherein X is any amino acid from about 13I-140. Optionally, the PR0324 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the eDNA insert of the DNA36343-1310 vector deposited on March 30, 1998 as ATCC 209718.
20. PR0351 Applicants have identified a eDNA clone that encodes a novel polypeptide having sequence similarity to prostasin, wherein the polypeptide is designated in the present application as "PR0351".
In one embodiment, the invention provides an 'aolated nucleic acid molecule comprising DNA encoding a PR0351 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0351 polypeptide having amino acid residues 1 to 571 of Figure 49 (SEQ ID NO:I32), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0351 polypeptide having amino acid residues about 16 to S7I of Figure 49 (SEQ 1D N0:132), or is complementary to such encoding nucleic acid sequence. and remains stably bound to it under at least moderate, and optionally, under high suingency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA40571-1315 vector deposited on April 21, 1998 as ATCC 209784 which includes the nucleotide sequence encoding PR0351.
In another embodiment, the invention provides isolated PR0351 polypeptide. In particular, the invention provides isolated native sequence PR0351 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 571 of Figure 49 (SEQ ID N0:132). In another embodiment, the invention provides an isolated PR0351 polypeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about 16 to 571 of Figure 49 (SEQ ID N0:132). Optionally, the PR0351 polypegtide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA40571-1315 vector deposited on April 21, 1998 as ATCC 209784.
21. PR 2 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to butyrophilin, wherein the polypeptide is designated in the present application as "PR0352".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0352 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0352 polypeptide having amino acid residues 1 to 316 of Figure 51 (SEQ ID N0:137), or is complementary to such encoding nucleic acid. sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0352 polypeptide having amino acid residues of about 29 to 316 of Figure 51 (SEQ ID NO:I37), or 1 or about 29 to X of Figure 51, where X is any amino acid from 246 to 255, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA4I386-1316 vector deposited on March 26, 1998 as ATCC
209703 which includes the nucleotide sequence encoding PR0352.
In another embodiment, the invention provides isolated PRO352 polypeptide. 1n particular, the invention provides isolated native sequence PR0352 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 316 of Figure 51 (SEQ 1D N0:137). In other embodiments, the invention provides isolated PRO352 polypeptide comprising residues about 29 to 316 of Figure 51 (SEQ ID
N0:137) and 1 or about 29 to X of Figtue 51 (SEQ ID N0:137), wherein X is any amino acid from 246 to 255.
Optionally, the PR0352 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA41386-1316 vector deposited on March 26, 1998 as ATCC 209703.
22. gR0381 Applicants have identified a cDNA clone that et~odes a novel polypeptide having homology to imtttunophilin proteins, wherein the polypeptide is designated in the present application as "PR038I ".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0381 polypeptide: In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0381 polypeptide having amino acid residues 1 to 211 of Figure 53 (SEQ ID N0:145), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. 1n another aspect, the isolated nucleic acid comprises DNA
encoding the PR0381 polypeptide having amino acid residues about 21 to 211 of Figure 53 (SEQ ID N0:145), or is complementary to such encoding ttucleic WO 99146281 PCT/IjS99105028 acid sequence, and remains stably bound to it under at lease moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44194-1317 vectoz deposited on April 28, 1998 as ATCC 209808 which includes the nucleotide sequence encoding PR0381.
In another embodiment, the invention provides isolated PR0381 polypeptide. In particular, the invention provides isolated native sequence PR0381 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 2II of Figure 53 (SEQ ID N0:14S). Another embodiment is directed to a PR0381 plypeptide comprising amino acids about 21 to 211 of Figure S3 (SEQ ID
N0:145). Optionally, the PR0381 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA44194-1317 vector deposited on April 28, 1998 as ATCC 209808.
23. PR 6 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the beta-2 subunit of a sodium channel, wherein the polypeptide is designated in the present application as "PR0386".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0386 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0386 polypeptide IS having amino acid residues 1 to 21S of Figure SS (SEQ ID NO:1S0), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0386 polypeptide having amino acid residues about 21 to 215 of Figure 55 {SEQ ID NO:ISO) or I or about 21 to X, where X is any amino acid from 1S6 to 165 of Figure SS (SEQ ID NO:1S0), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45415-1318 vector deposited on April 28, 1998 as ATCC 209810 which includes the nucleotide sequence encoding PR0386.
In another embodiment, the invention provides isolated PR0386 polypeptide. In particular, the invention provides isolated native sequence PR0386 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 215 of Figure SS (SEQ ID NO:1S0). Other embodiments of the present invention are directed to PR0386 polypeptides comprising amino acids about 21 to ZIS of Figure SS (SEQ ID N0:150) and 1 or about 21 to X of Figure SS (SEQ ID NO:I50), wherein X is any amino acid from 156 to 165 of Figure SS (SEQ ID
NO:1S0). Optionally, the PR0386 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA4S415-1318 vector deposited on April 28, 1998 as ATCC 209810.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO:1S1 which corrsponds to an EST designated herein as DNA23350.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ 1D NO: iS2 which corrsponds to an EST designated herein as DNA23S36.
24. PR054o Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to LCAT, wherein the polypeptide is designated in the present application as "PR0540" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROS40 polypeptide. In one aspect, tl~ isolated nucleic acid comprises DNA
encoding the PROS40 polypeptide r WO 99/46281 PCTIUS9910~028 having amino acid residues 1 to 412 of Figure 59 (SEQ ID N0:157), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0540 poiypeptide having amino acid residues about 29 to 412 of Figure 59 (SEQ ID N0:157), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44189-1322 vector deposited on March 26, 1998 as ATCC 209b99 which includes the nucleotide sequence encoding PR0540.
In another embodiment, the invention provides isolated PR0540 polypeptide. In particular, the invention provides isolated native sequence PR0540 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 412 of Figure 59 (SEQ ID NO:15?). The invention also provides isolated PR0540 : polypeptide, which in one embodiment, includes an amino acid sequence comprising residues about 29 to 412 of Figure 59 (SEQ ID N0:157). Optionally, the PR0540 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA44189-1322 vector deposited on March 26, 1998 as ATCC
209699.
25. PR0615 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to synaptogyrin, wherein the polypeptide is designated in the present application as "PR0615".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR06I5 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0615 polypeptide having amino acid residues 1 to 224 of Figure 61 (SEQ ID N0:162), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0615 polypeptide having amino acid residues X to 224 of Figure 61 (SEQ ID N0:162), where X is any amino acid from 157 to 166, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48304-1323 vector deposited on April 28, 1998 as ATCC 209811 which includes the nucleotide sequence encoding PR0615.
In another embodiment, the invention provides isolated PR0615 polypeptide, In particular, the invention provides isolated native sequence PR0615 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 224 of Figure 61 (SEQ ID N0:162). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0615 polypeptide which comprises amino acid residues X to 224 of Figure 61 (SEQ ID N0:162), where X is any amino acid from 157 to 166 of Figure 61 (SEQ ID NOa62).
Optionally, the PR0615 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA48304-1323 vector deposited on April 28, 1998 as ATCC 209811.
26. ~t0~18 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to enteropeptidase, wherein the polypeptide is designated in the present application as "PRO618".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a WO 99!46281 PCT/US99105U28 PR06I8 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0618 polypeptide having amino acid residues 1 to 802 of Figure 63 (SEQ ID N0:169), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding an isolated extracellular domain of a PR0618 polypeptide having amino acid residues X to 802 of Figure 63 (SEQ
ID N0:169), where X is any amino acid from 63 to 72 of Figure 63 (SEQ ID N0:169), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions, The isolated nucleic acid sequence tray comprise the cDNA insert of the DNA49152-1324 vector deposited on April 28, 1998 as ATCC 209813 which includes the nucleotide sequence encoding P80618.
In another embodiment, the invention provides isolated PR0618 polypeptide. In particular, the invention provides isolated native sequence PR0618 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues l to 802 of Figure 63 (SEQ ID N0:169). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PR0618 polypeptide comprising amino acid X to 802 where X
is any amino acid from 63 to 72 of Figure 63 (SEQ ID N0:169). Optionally, the PR0618 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA insert of the DNA49152-1324 vector deposited I S on April 28, 1998 as ATCC 209813.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID N0:170, designated herein as DNA35597 (see Figure 64).
27. gR0719 Applicants have identified a cDNA clone that encodes a novel poIypeptide having homology to lipoprotein lipase H, wherein the polypeptide is designated in the present application as "PR0719".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0719 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0719 polypeptide having amino acid residues 1 to 354 of Figure 66 (SEQ ID N0:178), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0719 polypeptide having amid acid residues about 17 to 354 of Figure 66 (SEQ ID N0:178), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA49646-1327 vector deposited on March 26, 1998 as ATCC 209705 which includes the nucleotide sequence encoding PRO719.
In another embodiment, the invention provides isolated PR0719 polypeptide. In particular, the invention provides isolated native sequence PR0719 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 354 of Figure 66 (SEQ ID N0:178). In another embodiment, the invention provides isolated PR07I9 palypeptide which comprises residues about 17 to 354 of Figure 66 (SEQ
ID N0:178). Optionally, the PR0719 poiypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA49646-1327 vector deposited on March 26, 1998 as ATCC 209705.

WO 99146281 PCTlUS99/05028 28. PR0724 Applicants have identified a eDNA clone that encodes a novel polypeptide having homology to the LDL
receptor, wherein the polypeptide is designated in the present application as "PR0724".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0724 poiypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0724 polypeptide having amino acid residues 1 to 713 of Figure 68 (SEQ ID N0:183), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding a soluble PR0724 poiypeptide having amino acid residues 1 to X of Figure 68 (SEQ ID N0:183) where X is any amino acid from amino acid 437 to 446, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The above two polypeptides may either possess or not possess the signal peptide. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA49631-1328 vector deposited on April 28, 1998 as ATCC 209806 which includes the nucleotide sequence encoding PR0724.
In another embodiment, the invention provides isolated PR~0724 polypeptide. In particular, the invention provides isolated native sequence PR0724 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 713 of Figure 68 (SEQ ID N0:183). In another embodiment, the invention provides isolated soluble PR0724 polypeptide. In particular, the invention provides isolated soluble PR0724 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to X of Figure 68 (SEQ ID N0:183), where X is any amino acid from 437 to 446 of the sequence shown in Figure 68 (SEQ ID
N0:183). Optionally, the PR0724 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA49631-1328 vector deposited on April 28, 1998 as ATCC 209806.
29. PR0772 Applicants have identified a eDNA clone that encodes a novel polypeptide having homology to A4 protein, wherein the polypeptide is designated in the present application as "PR0772" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0772 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO772 polypeptide having amino acid residues 1 to 152 of Figure 70 (SEQ ID N0:190), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0772 polypeptide having amino acid residues 1 to X of Figure 70 (SEQ ID N0:190), where X is any amino acid from 21 to 30 of Figure 70 (SEQ ID N0:190), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNA49645-1347 vector deposited on April 28, 1998 as ATCC 209809 which includes the nucleotide sequence encoding PR0772.
In another embodiment, the invention provides isolated PR0772 polypeptide. In particular, the invention provides isolated native sequence PR0772 polypeptide, which in one embodiment, includes an amino acid seque~e comprising residues 1 to 152 of Figure 70 (SEQ ID N0:190). Additional embodiments of the present invention are directed to PR0772 polypeptides comprising amino acids t to X of Figure 70 (SEQ ID N0:190), where X is any amino acid from 21 to 30 of Figure 70 (SEQ ID N0:190). Optionally, the PR0772 polypeptide is obtained or is WO 99!46281 PCT/US99IOS028 obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA49645-1347 vector deposited on April 28, 1998 as ATCC 209809.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA43509 comprising the nucleotide sequence of SEQ ID N0:191 (Figure 71).
30. PR0852 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to various protease enzymes, wherein the poiypeptide is designated izf the present application as "PRO852".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0852 poiypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0852 polypeptide having amino acid residues 1 to 518 of Figure 73 (SEQ ID NO: l 96), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0852 polypeptide having amino acid residues about 21 to SI8 of Figure 73 (SEQ ID N0:196) or 1 or about 21 to X of Figure 73 (SEQ ID
N0:196) where X is any amino acid from amino acid 461 to amino acid 470 of Figure 73 (SEQ ID N0:196), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45493-1349 vector deposited on April 28, 1998 as ATCC 209805 which includes the nucleotide sequence encoding PR0852.
In another embodiment, the invention provides isolated PR0852 polypeptide. In particular, the invention provides isolated native sequence PR0852 polypeptide; which in one embodiment, includes an amino acid sequence comprising residues 1 to 518 of Figure 73 (SEQ ID N0:196). In other embodiments, the PR0852 comprises amino acids about 21 to amino acid 518 of Figure 73 (SEQ ID N0:196) or amino acids 1 or about 21 to X of Figure 73 (SEQ ID N0:196), where X is any amino acid from amino acid 461 to amino acid 470 of Figure 73 (SEQ ID
N0:196). Optionally; the PR0852 polypepude is obtained ar is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA45493-1349 vector deposited on April 28, 1998 as ATGC 209805.
31. ~Q~3 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to reductase, wherein the polypeptide is designated in the present application as "PR08S3".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0853 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO853 polypeptide having amino acid residues 1 to 377 of Figure ?S (SEQ ID N0:206), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0853 polypepdde having amino acid residues about 17 to 377 of Figure 75 (SEQ ID N0:206), or is complementary t0 Such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48227-1350 vector deposited on April 28, 1998 as ATCC 209812 which includes the nucleotide sequence encoding PR0853.
In another embodiment, the invention provides isolated PR0853 polypeptide. In particular, the invention WO 99!46281 PCT/US99/05028 provides isolated native sequence PR0853 poIypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 377 of Figure 75 (SEQ 1D N0:206). In another embodiment, the invention provides an isolated PR0853 polypeptide_ absent the signal sequence, which includes an amino acid sequence comprising residues from about 17 to 3?7 of Figure 75 (SEQ ID N0;206). Optionally, the PR0853 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA48227-1350 vector deposited on April 28, 1998 as ATCC 209812.
32. PR0860 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to neurofascin, wherein the polypeptide is designated in the presem application as "PR0860".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0860 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0860 poiypeptide having amino acid residues 1 to 985 of Figure 77 (SEQ ID N0:211), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0860 polypeptide having amino acid residues 1 to X of Figure 77 (SEQ 1D N0:211), where X is any amino acid from 443-452 of Figure 77 (SEQ ID N0:211), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency cotxlitions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA41404-1352 vector deposited on May 6, 1998 as ATCC
209844 which includes the nucleotide sequence encoding PR0860.
In another embodiment, the invention provides isolated PR0860 pulypeptide. In particular, the invention provides isolated native sequence PR0860 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 985 of Figure 77 (SEQ ID N0:21I). In another embodiment, the invention provides an isolated PR0860 polypeptide which includes an amino acid sequence comprising residues 1 to X of Figure 77 (SEQ
ID N0:211), where X is any amino acid residue from 443 to 452 of Figure 77 (SEQ ID N0:211). Optionally, the PR08b0 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA41404-1352 vector deposited on May 6, 1998 as ATCC 209844.
33. R 4 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to CMRF35, wherein the polypeptide is designated in the present application as "PR0846".
Iri one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0846 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0846 polypeptide having amino acid residues 1 to 332 of Figure 79 (SEQ ID N0:216), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under ivgh stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0846 polypeptide having amino acid residues about 18 to 332 of Figure 79 (SEQ ID N0:216) or 1 or about 18 to X of SEQ ID N0:216, where X is any amino acid from 243 to 252 of Figure 79 (SEQ ID N0:216), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44196-1353 vector WO 99!4628I PCT/US99l05028 deposited on May 6, 1998 as ATCC 209847 which includes the nucleotide sequence encoding PR0846.
In another embodiment, the invention provides isolated PR0846 polypeptide. In particular, the invention provides isolated native sequence PR0846 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 332 of Figure 79 (SEQ ID N0:216). In other embodiments, the invention provides an isolated PR0846 polypeptide absem the signal sequence, which includes an amino acid sequence comprising residues from about 18 to 332 of Figure 79 (SEQ ID N0:2I6). Additional embodiments of the present invention are directed to an isolated PR0846 polypeptide comprising amino acid I or about 18 to X of Figure 79 (SEQ ID N0:216); where X is any amino acid from 243 to 252 of Figure ?9 (SEQ 1D N0:2I6). Optionally, the PR0846 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA44196-1353 vector deposited on May 6, 1998 as ATCC 209847.
34. PR0862 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to lysozyme, wherein the poIypeptide is designated in the present application as "PR0862".
In one embodiment, the invention provides an isoiated nucleic acid molecule comprising DNA encoding a PR0862 potypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0862 polypeptide having amino acid residues 1 to 146 of Figure 81 (SEQ ID N0:221), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0862 polypeptide having amino acid residues about 19 to 146 of Figure 81 (SEQ ID N0:221), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at Least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA52187-1354 vector deposited on May 6, 1998 as ATCC 209845 which includes the nucleotide sequence encoding PR0862.
In another embodiment, the invention provides isolated PR0862 polypeptide. In particular, the invention provides isolated native sequence PR0862 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 146 of Figure 81 (SEQ ID N0:221). In another embodiment, the invention provides an isolated PRO862 polypeptide absent the sigttat sequence, which inchtdes an amino acid sequence comprising residues from about 19 to i46 of Figure 81 (SEQ 1D N0:221). Optionally, the PR0862 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA5218?-1354 vector deposited on May 6, 1998 as ATCC 209845.
3S. PR0864 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence similarity to Wnt-4, wherein the polypeptide is designated in the present application as "PR0864".
in one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0864 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0864 polypeptide having amino mid residues 1 to 351 of Figure 83 (SEQ 1D N0:226), or is complementary to such encoding nucleic acid sequence, and remains stabiy bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0864 polypeptide having amino acid rrsidues about 23 to 351 of Figure 83 (SEQ ID NO:226), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA48328-1355 vector deposited on May 6, 1998 as ATCC 209843 which includes the nucleotide sequence encoding PR0864.
In another embodiment, the invention provides isolated PR0864 polypeptide. In particular, the invention provides isolated native sequence PR0864 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 351 of Figure 83 (SEQ ID N0:226). In another embodiment, the invention provides an isolated PR0864 polypeptide absent the signal sequence, which includes an amino acid sequence comprising residues from about 23 to 351 of Figure 83 (SEQ ID N0:226). Optionally, the PR0864 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA48328-1355 vector deposited on May 6, 1998 as ATCC 209843 36. P80792 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD23, wherein the polypeptide is designated in the present application as "~PRO792".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0792 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0792 polypeptide having amino acid residues 1 to 293 of Figure 85 (SEQ ID N0:231), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0792 polypeptide having amino acid residues X to 293 of Figure 85 (SEQ ID N0:231) where X is any amino acid from 50 to 59 of Figure 85 (SEQ ID N0:231), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA56352-1358 vector deposited on May 6, 1998 as ATCC
209846 which includes the nucleotide sequence encoding PRO792.
In another embodiment, the invention provides isolated PR0792 polypeptide. In particular, the invention provides isolated native sequence PR0792 polypeptide,1 which in one embodiment, includes an amino acid sequence comprising residues 1 to 293 of Figure 85 (SEQ ID N0:231). An additional embodiment of the present invention is directed to PR0792 polypeptide comprising amino acids X to 293 of Figure 85 (SEQ ID N0:231), where X is any amino acid from SO to 59 of Figure 85 (SEQ ID N0:231). Optionally, the PR0792 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA56352-1358 vector deposited on May b, 1998 as ATCC 209846.
37. P_ 80866 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to mindin and spondin proteins, wherein the polypeptide is designated in the present application as "P80866" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0866 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0866 polypeptide having amino acid residues 1 to 331 of Figure 87 (SEQ ID N0:236), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA
encoding the PR0866 polypeptide having s8 amino acid residues about 27 to 229 of Figure 87 (SEQ ID N0:236), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA53971-1359 vector deposited on April 7, 1998 as ATCC 209750 which includes the nucleotide sequence encoding PR0866.
In another emlwdiment, the invention provides isolated PR0866 polypeptide. In particular, the invention provides isolated native sequence PR0866 polypeptide; which in one embodiment, includes an amino acid sequence comprising residues 1 to 331 of Figure 87 (SEQ ID N0:236). Another embodiment of the present invention is directed to PR0866 polypeptides comprising amino acids about 27 to 331 of Figure 87 (SEQ ID N0:236).
Optionally, the PR0866 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA53971-1359 vector deposited on April 7, 1998 as ATCC 209750.
38. PRO 7 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CyP-60, wherein the polypeptide is designated in the present application as "PR0871".
In one embodimem, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0871 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0871 polypeptide having amino acid residues 1 to 472 of Figure 89 (SEQ ID N0:245), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. in other aspects, the isolated nucleic acid comprises DNA encoding the PR0871 polypeptide having amino acid residues about 22 to 472 of Figure 89 (SEQ ID N0:245), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA50919-1361 vector deposited on May 6, /998 as ATCC 209848 which includes the nucleotide sequence encoding PR0871.
In another embodiment, the invention provides isolated PRO87I polypeptide. In particular, the invention provides isolated native sequence PR0871 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 472 of Figure 89 (SEQ ID N0:245). An additional embodiment of the present invention is directed to PR0871 polypeptides comprising amino acids about 22 to 472 of Figure 89 (SEQ ID N0:245).
Optionally, the PR087I polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA50919-1361 vector deposited on May 6, /998 as ATCC 209848.
39. PR0873 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to carboxylesterase, wherein the polypeptide is designated in the present application as "PR0873".
In ors embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0873 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0873 polypeptide having amino acid residues 1 to 545 of Figure 91 (SEQ ID NO:254), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0873 polypeptide having amino acid residues about 30 to about 545 of Figure 91 (SEQ ID N0:254), or is complementary to such encoding rnicleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA44179-1362 vector deposited on May 6, 1998 as ATCC 209851 which includes the nucleotide sequence encoding PR0873.
In another embodiment, the invention provides isolated FR0873 polypeptide. In particular, the invention provides isolated native sequence PR0873 polypeptide, which in one embodiment>
includes an amino acid sequence comprising residues 1 to 545 of Figure 91 (SEQ ID N0:254). Additional embodiments of the present invention are directed to PR0873 polypeptides comprising amino acids about 30 to about 545 of Figure 91 {SEQ ID N0:254).
Optionally, the PR0873 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA44179-1362 vector deposited on May 6, 1998 as ATCC 209851.
40. PRO 4 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD33 and OB binding protein-2, wherein the polypeptide is designated in the present application as "PR0940".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0940 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0940 polypeptide having amino acid residues 1 to 544 of Figure 93 (SEQ ID N0:259), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0940 polypeptide having amino acid residues about 16 to 544 of Figure 93 (SEQ ID N0:259) or 1 or about 16 to X of Figure 93 (SEQ ID
N0:259), where X is any amino acid from 394 to 403 of Figure 93 (SEQ ID
NO:259), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA54002-1367 vector deposited on April 7, 1998 as ATCC 209754 which includes the nucleotide sequence encoding PR0944.
In another embodiment, the invention provides isolated PR0940 polypeptide. In particular, the invention provides isolated native sequence PR0940 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 544 of Figure 93 (SEQ ID N0:259). Other embodiments of the present invention are directed to PR0940 polypeptides comprising amino acids about 16 to 544 of Figure 93 (SEQ 1D N0:259) or I or about 16 to X of Figure 93 (SEQ ID N0:259), where X is any amino acid from 394 to 403 of Figure 93 (SEQ ID
N0:259). Optionally, the PR0940 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA54002-1367 vector deposited on April 7, 1998 as ATCC 209754.
41. PR
Applicarus have identified a cDNA clone that encodes a novel polypeptide having homology to a cadherin protein, wherein the polypeptide is designated in the present application as "PR0941 ".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0941 polygeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0941 polypeptide having amino acid residues 1 to 772 of Figure 95 (SEQ ID N0:254), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optianalIy, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0941 polypeptide having amino acid residues about 22 to 772 of Figure 95 (SEQ ID NO:264) or 1 or about 22 to X of Figure 95 (SEQ ID
N0:264), where X is any amino acid from 592 to 601 of Figure 95 (SEQ ID
N0:264), or is complementary to such 't encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA53906-1368 vector deposited on Apri17, 1998 as ATCC 209747 which includes the nucleotide sequence encoding PR0941.
In another embodiment, the invention provides isolated PR0941 pvlypeptide. In particular, the invention provides isolated native sequence PR0941 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues t to 772 of Figure 95 (SEQ ID N0:264). Additional embodiments of the present invention are directed to PRQ941 polypeptides which comprise amino acid about 21 to 772 of Figure 95 (SEQ ID N0:264) or 1 or about 22 to X of Figure 95 (SEQ ID N0:264), where X is any amino acid from 592 to 601 of Figure 95 (SEQ ID
N0:264). Optionally, the PR0941 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNAS3906-1368 vector deposited on Apri17, 1998 as ATCC 209747.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA6415 comprising the nucleotide sequence of Figure 96 {SEQ ID N0:265).
42. 944 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to Clostridium perfringens enterotoxin receptor (CPE-R), wherein the polypeptide is designated in the present application as "PR0944".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0944 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRU944 polypeptide having amino acid residues I to 211 of Figure 98 (SEQ 1D N0:270), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0944 polypeptide having amino acid residues about 22 to 229 of Figure 98 (SEQ ID N0:270) or amino acid 1 or about 22 to X of Figure 98 (SEQ ID N0:270) where X is any amino acid from 77 to 80 of Figure 98 (SEQ ID
N0:270), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally; under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA52185 1370 vector deposited on May 14, 1998 as ATCC 209861 which includes the nucleotide sequence encoding PR0944.
In another embodiment, the invention provides isolated PR0944 polypeptide. In particular, the invention provides isolated native sequence PR0944 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 21 I of Figure 98 (SEQ ID N0:270). Additional embodiments of the present invention are directed to PR0944 polypeptides comprising amino acids about 22 to 211 of Figure 98 (SEQ ID N0:270) or amino arid 1 or about 22 to X of Figure 98 (SEQ ID N0:270j, where X is any amino acid from 77 to 86 of Figure 98 (SEQ
ID N0:270). Optionally, the PR0944 polypeptide is obtained yr is obtainable by expressing the pvlypeptide encoded by the cDNA insert of the DNA52i85-1370 vector deposited on May 14, 199$ as ATCC 209861.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA14007 comprising the nucleotide sequence of Figure 99 (SEQ ID N0:271).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12733 comprising the nucleotide sequence of Figure 1:00 {SEQ ID N0:272).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12746 comprising the nucleotide sequence of Figure 101 (SEQ ID N0:273).

WO 99/46281 PCTlUS99105028 In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12834 comprising the nucleotide sequence of Figure 102 (SEQ ID N0:274).
1n another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA12846 comprising the nucleotide sequence of Fiugure 103 (SEQ ID N0:275).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13104 comprising the nucleotide sequence of Figure 104 (SEQ ID N0:276).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13259 comprising the nucleotide sequence of Figure 105 (SEQ ID N0:277).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNAI3959 comprising the nucleotide sequence of Figure 106 {SEQ ID N0:278).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13961 comprising the nucleotide sequence of Figure 107 (SEQ ID N0:279).
43. PR0983 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a vesicle IS associated protein, VAP-33, wherein the polypeptide is designated in the present application as "PR0983".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0983 polypeptide, In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0983 polypeptide having amino acid residues 1 to 243 of Figure 109 (SEQ iD N0:284), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0983 polypeptide having amino acid residue 1 to X of Figure 109 (SEQ ID N0:284) where X is any amino acid from 219 to 228 of Figure 109 (SEQ 1D N0:284), or is complementary to such encoding nucleic acid sequence, and remains stately bound to it under at least moderate, and optionally, under high stringency conditions.
The isolated nucleic acid sequence may comprise the cDNA insert of the DNA53977-1371 vector deposited on May 14, 1998 as ATCC 209862 which includes the nucleotide sequence encoding PR0983.
In another embodiment, the invention provides isolated PR0983 polypeptide. In particular, the invention provides isolated native sequence PR0983 polypeptide, which in one embodiment, includes an amino acid sequence c~tnprising residues I to 243 of Figure 109 (SEQ ID N0:284). Additional embodiments of the present invention are directed to PR0983 poiypeptides comprising amino acid 1 to X of Figure 109 (SEQ ID N0:284), where X is any amino acid from 219 to 228 of Figure 109 (SEQ ID N0:284). Optionally, the PR0983 polypegtide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA53977-1371 vector deposited on May 14, 1998 as ATCC 209862.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA17130 comprising the nucleotide sequence of Figure 110 (SEQ ID N0:285).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA23466 comprising the nucleotide sequence of Figure 111 (SEQ ID N0:286).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA26818 comprising the nucleotide sequence of Figure 112 (SEQ ID N0:287).
In another embodiment, the invention provides an expressed sequence tag {EST) designated herein as WO 99!46281 PCT/US99/05028 DNA37618 comprising the nucleotide sequence of Figure I 13 (SEQ ID N0:288).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA41732 comprising the, nucleotide sequence of Figure I 14 {SEQ ID N0:289).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA45980 comprising the nucleotide sequence of Figure 115 {SEQ ID NO:290).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA46372 comprising the nucleotide sequence of Figure 116 (SEQ ID N0:291).
44. RP 01057 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to proteases, wherein the polypeptide is designated in the present application as "PR01057".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01057 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01057 polypeptide having amino acid residues 1 to 413 of Figure 118 (SEQ ID N0:296), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency .
i5 conditions. In other aspects, the isolated nucleic acid comprises DNA
encoding the PROI057 polypeptide having amino acid residues about 17 to 413 of Figure 118 (SEQ ID NO:296), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA57253-1382 vector deposited on May I4, 1998 as ATCC 209867 which includes the nucleotide sequence encoding PR01057.
In another embodiment, the invention provides isolated PROi057 polypeptide. In particular, the invention provides isolated native sequence PRO105? polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 413 of Figure 118 (SEQ ID N0:296). Additional embodiments of the present invention are directed to PR01057 polypeptides comprising amino acids about 17 to 413 of Figure 118 (SEQ ID N0:296).
Optionally, the PR01057 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA57253-1382 vector deposited on May i4, 1998 as ATCC 209867.
45. PROI071 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to thrombospondin, wherein the polypeptide is designated in the present application as "PROI071".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROI071 poIypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01071 polypeptide having amino acid residues 1 to 525 of Figure 120 (SEQ ID N0:301), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions, In other aspects, the isolated nucleic acid comprises DNA encoding the PR01071 polypeptide having amino acid residues about 26 to 525 of Figure 120' (SEQ ID N0:301 ), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the DNA58847-1383 vector deposited on May 20, 1998 as ATCC 209879 which includes the nucleotide sequence encoding PR01071.
in another embodiment, the invention provides isolated PROI071 polypeptide. In particular, the invention provides isolated native sequence PR01071 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 525 of Figure 120 (SEQ ID N0:301). Additional embodiments of the present invention are directed to PR01071 polypeptides comprising amino acids about 26 to 525 of Figure 120 (SEQ ID NO:301).
Optionally, the PR01071 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA58847-1383 vector deposited on May 20, 1998 as ATCC 209879.
46. PR01072 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to reductase proteins, wherein the polypeptide is designated in the present application as "PR01072".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01072 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01072 polypeptide having amino acid residues 1 to 336 of Figure 122 (SEQ ID N0:303), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PRO10?2 polypeptide having amino acid residues about 22 to 336 of Figure 122 (SEQ ID N0:303), or is complementary to such encoding nucleic IS acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence tnay comprise the cDNA insert of the DNA58747-1384 vector deposited on May 14, 1998 as ATCC 209868 which includes the nucleotide sequence encoding PR01072.
In another embodiment, the invention provides isolated PR01072 polypeptide. In particular, the invention provides isolated native sequence PR01072 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 336 of Figure 122 (SEQ 1D N0:303). Additional embodiments of the present invention are directed to PR01072 polypeptides comprising amino acids about 22 to 336 of Figure 122 (SEQ ID N0:303).
Optionally, the PR01072 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA58747-1384 vector deposited on May 14, 1998 as ATCC 209868.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA40210 comprising the nucleotide sequence of Figure 123 (SEQ ID N0:304).
47. PR 107 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to protein disulfide isomerase, wherein the polypeptide is designated in the present application as "PR01075".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01075 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01075 polypeptide having atnitto acid residues 1 to 406 of Figure 125 (SEQ ID N0:309), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR01075 polypeptide having amino acid residues about 30 to 406 of Figure 125 (SEQ iD N0:309), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence tray comprise the cDNA insert of the DNA57689-1385 vector deposited on May 14, 1998 as ATCC 209869 which includes the nucleotide sequence encoding PRO1075 In another etnbodimern, the invention provides isolated PR01075 polypeptide.
In particular, the invention ?4 provides isolated native sequence PR01075 poIypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 406 of Figure I25 (SEQ ID N0:309). Additional embodiments of the present invention are directed to PROI075 polypeptides comprising amino acids about 30 to 406 of Figure 125 (SEQ ID N0:309).
Optionally, the PR01075 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA57689-1385 vector deposited on May i4, 1998 as ATCC 209869.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA23059 comprising the nucleotide sequence of Figure 126 (SEQ ID N0:310).
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA19463 comprising the nucleotide sequence of Figure 12? (SEQ ID N0:311).
48. R0 1 Applicarns have identified a cDNA clone that encodes a xtovel polypeptide having homology to the cornichon protein, wherein the polypeptide is designated in the present application as "PRQ181":
In ors embodiment; the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0181 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0181 polypeptide having amino acid residues 1 to 144 of Figure 129 (SEQ ID N0:322), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high suingency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PRO18I polypeptide having amino acid residues about 21 to 144 of Figure 129 (SEQ ID N0:322) or amino acid I or about 21 to X of Figure I29 (SEQ ID N0:322) where X is any amino acid from 52 to 6I of Figure 129 (SEQ ID
N0:322), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA23330-I390 vector deposited on April 14, 1998 as ATCC 209775 which includes the nucleotide sequence encoding PR0181.
In another embodiment, the invention provides isolated PR0181 polypeptide. In particular, the invention provides isolated native sequence PR0181 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 144 of Figure i29 (SEQ ID N0:322). Additional embodiments of the present invention are directed to PR0181 polypeptides comprising amino acids about 21 to 144 of Figure 129 (SEQ ID N0:322) or amino acid I or about 21 to X of Figure 129 (SEQ ID N0:322), where X is any amino acid from 52 to 61 of Figure 129 (SEQ ID N0:322). Optionally, the PR0181 poiypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA23330-1390 vector deposited on April 14, 1998 as ATCC 209775.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA13242 comprising the nucleotide sequence of Figure I30 (SEQ ID N0:323).
49. PR0195 Applicants have identified a cDNA clone that encodes a novel transmembrane polypeptide, wherein the polypeptide is designated in the present application as "PR0195".
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROI95 polypeptide. 1n one aspect, the isolated nucleic acid comprises DNA
encoding the PROI95 polypeptide having amino acid residues 1 to 323 of Figure I32 (SEQ ID N0:330), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0195 polypeptide having amino acid residues about 32 to 323 of Figure I32 (SEQ ID N0:330) or amino acid 1 or about 32 to X of Figure 132 (SEQ ID N0:330) where X is any amino acid from 236 to 245 of Figure I32 (SEQ
1D N0:330), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA26847-1395 vector deposited on April 14, 1998 as ATCC 209772 which includes the nucleotide sequence encoding PR0195 In another embodiment, the invention provides isolated PR0195 polypeptide. In particular, the invention provides isolated native sequence PR0195 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 323 of Figure 132 (SEQ ID N0:330). Additional embodiments of the present invention are directed to PR0195 polypeptides comprising amino acids about 32 to 323 of Figure 132 (SEQ ID N0:330) or amino 10: acid I or about 32 to X of Figure i32 (SEQ ID N0:330), where X is any amino acid from 236 to 245 of Figure 132 (5EQ ID N0:330). Optionally, the PROI95 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA26847-1395 vector deposited on April 14, 1998 as ATCC 209772.
In another embodiment, the invention provides an expressed sequence tag (FST) comprising the nucleotide sequence of Figure I33 (SEQ ID N0:331), herein designated DNA15062.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of Figure 134 (SEQ ID N0:332), herein designated DNA13199.
50. 80865 Applicants have identified a cDNA clone that encodes a novel secreted polypeptide, wherein the polypeptide is designated in the present application as "P80865".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0865 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0865 polypeptide having anvno acid residues 1 to 468 of Figure 136 (SEQ ID N0:337), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0865 polypeptide having amino acid residues about 24 to 229 of Figure 136 (SEQ ID N0:337), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA53974-1401 vector deposited on April 14, 1998 as ATCC 209774 which includes the nucleotide sequence encoding PR0865.
In another embodiment, the invention provides isolated PR0865 polypeptide. In particular, the invention provides isolated native sequence PR0865 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 468 of Figure I36 (SEQ ID N0:337). An additional embodiment of the present invention is directed to a PR0865 polypeptide comprising amino acids about 24 to 468 of Figure 136 (SEQ JD N0:337).
Optionally, the PR0865 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA53974-1401 vector deposited on April 14, 1998 as ATCC 209774.
In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of Figure 137 (SEQ ID N0:338), herein designated as DNA37b42.
?6 SI. RP 0827 Applicants have identified a cDNA clone that encodes a novel poiypeptide having homology to integrin proteins, wherein the polypeptide is designated in the present application as "PRO827".
1n one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0827 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0827 polypeptide having amino acid residues 1 to 124 of Figure 139 (SEQ ID N0:346), or is complemenrary to such encoding nucleic acid sequence, and remains stabiy bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0827 polypeptide having amino acid residues about 23 to 124 of Figure 139 (SEQ ID N0:346), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA57039-1402 vector deposited on April 14, 1998 as ATCC 209777 which includes the nucleotide sequence encoding PR0827.
In another embodiment, the invention provides isolated PR0827 polypeptide. In particular, the invention provides isolated native sequence PR0827 polypeptide, which in one embodiment,: includes an amino acid sequence comprising residues 1 to 324 of Figure 139 (SEQ ID N0:346). An additional embodiment of the present invention is directed to a PR0827 poiypeptide comprising amino acids about 23 to 124 of Figure 139 (S$Q ID N0:346).
Optionally, the PR0827 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the DNA57039-1402 vector deposited on April 14, 1998 as ATCC 209777.
S2. PROIiI4 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to cytolcine receptor family-4 proteins, wherein the polypeptide is designated in the present application as "PROI I14".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROll I4 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01114 polypeptide having amino acid residues 1 to 311 of Figure 142 (SEQ ID N0:352), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR01114 polypeptide having amino acid residues about 30 to 311 of Figure 142 (SEQ ID N0:352) or amino acid I or about 30 to X of Figure 142 (SEQ ID N0:352), where, X is arty amino acid from 225 to 234 of Figure I42 (SEQ ID N0:352), or is comple~ntary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA57033-1403 vector deposited on May 27, 1998 as ATCC 209905 which includes the nucleotide sequence encoding PR01114.
3n another embodiment, the invention provides isolated PR01114 polypeptide. In particular, the invention provides isolaoed native sequerxe PROs 114 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 311 of Figure 142 (SEQ ID N0:352). Additional embodiments of the present invention are directed to PROl l I4 polypeptides comprising amino acids about 30 lo 31 I of Figure 142 (SEQ ID N0:352) or amino acid 1 or about 30 to X of Figure 142 (SEQ ID N0:352), where X is any amino acid from 225 to 234 of Figure 142 (SEQ ID N0:352). Optionally, the PROI 114 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA57033-1403 vector deposited on May 27, 1998 as ATCC 209905.

WO 99I4b281 PCTIUS99/05028 In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA48466 comprising the nucleotide sequence of Figure 143 (SEQ ID N0:353).
A cDNA clone (DNA57033-1403) has been identified that encodes a novel interferon receptor polypeptide, designated in the present application as "PROl I 14 interferon receptor".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01114 interferon receptor polypeptide.
In one aspect, the isolated nucleic acid comprises DNA having at least about 80% sequence identity, preferably at least about 85% sequence identity, more preferably at least about 90% sequence identity, most preferably at least about 95 %a sequence identity to (a) a DNA molecule encoding a PR01114 interferon receptor polypeptide having the sequence of amino acid residues from about 1 or about 30 to about 311, inclusive of Figure 142 (SEQ ID N0:352), or (b) the complement of the DNA molecule of (a).
In another aspect, the invention concerns an isolated nucleic acid molecule encoding a PR01114 interferon receptor polypeptide comprising DNA hybridizing to the complement of the nucleic acid between about nucleotides 250 or about 337 and about 1182, inclusive, of Figure 141 (SEQ ID N0:351).
Preferably, hybridization occurs under stringent hybridization and wash conditions.
IS In a further aspect, the invention concerns an isolated nucleic acid molecule comprising DNA having at least about 80 % sequence identity, preferably at least about 85 % sequence identity, more preferably at least about 90 sequence identity, most preferably at least about 95% sequence identity to (a) a DNA molecule encoding the same mature polypeptide encoded by the human protein cDNA in ATCC Deposit No.
209905 (DNA57033-1403) or (b) the complement of the nucleic acid molecule of (a). In a preferred embodiment, the nucleic acid comprises a DNA
encoding the same mature polypepude encoded by the human protein cDNA in ATCC
Deposit No. 209905 (DNA57033-1403).
In still a further aspect, the invention concerns an isolated nucleic acid molecule comprising (a) DNA
ea polypeptide having at least about 80 % sequence identity, preferably at (east about 85 % sequence identity, more preferably at least about 90% sequence identity, most preferably at least about 95 % sequence identity to the sequence of amino acid residues 1 or about 30 to about 3I1, inclusive of Figure 142 (SEQ ID N0:352), or (b) the complement of the DNA of (a).
In a further aspect, the invention concerns an isolated nucleic acid molecule having at least 10 nucleotides and produced by hybridizing,a test DNA molecule under stringent conditions with (a) a DNA molecule encoding a PR01114 interferon receptor polypeptide having the sequence of amino acid residues from 1 or about 30 to about 311, inclusive of Figure 142 (SEQ ID N0:352), or (b) the complement of the DNA
molecule of (a), and, if the DNA
molecule has at least about an 80 % sequence identity, prefereably at least about an 85% sequence identity, more preferably at least about a 90% sequence identity, most preferably at least about a 95% sequence identity to (a) or (b), isolating the test DNA molecule.
In a specific aspect, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01114 interferon receptor polypeptide, with or without the N-terminal signal sequence andlor the initiating a~thionine, and its soluble, i.e., transmembrane domain deleted or inactivated variants, or is complementary to such encoding nucleic acid molecule: The signal peptide has been tentatively identified as extending from about amino acid position 1 to about amino acid position 29 in the sequence of Figure 142 (SEQ ID N0:352). The transmembrane dUmalD has been tentatively identified as extending from about amino acid position 230 to about amino acid position WO 99I46Z8I PCTlUS99/OS028 255 in the PR01 I14 iruerferon receptor amino acid sequence (Figure I42, SEQ
ID N0:352).
in another aspect, the invention concerns an isolated nucleic acid molecule comprising (a) DNA encoding a polypeptide scoring at least about 80~ positives, preferably at least about 85 % positives, more preferably at least about 90% positives, most preferably at least about 95% positives when compared with the amino acid sequence of residues 1 or about 30 to about 311, inclusive of Figure 142 (SEQ ID N0:352), or (b) the complement of the DNA
of (a).
Another embodiment is directed to fragments of a PR01114 interferon receptor polypeptide coding sequence that may find use as hybridization probes. Such nucleic acid fragments are from about 20 to about 80 nucleotides in length, preferably from about 20 to about 60 nucleotides in Length, more preferably from about 20 to about 50 nucleotides in length and most preferably from about 20 to about 40 nucleotides in length and may be derived from the nucleotide sequence shown in Figure 141 (SEQ ID N0:351).
In another embodiment, the invention provides a vector comprising DNA encoding PROI114 interferon receptor or its variants. The vector may comprise airy of the isolated nucleic acid molecules hereinabove identified.
A host cell comprising such a vector is also provided. $y way of example, the host cells may be CHO cells, E. colt, or yeast. A process for producing PR01114 interferon receptor polypeptides is further provided and comprises culturing host ceps under conditions suitable for expression of PR01114 interferon receptor and recovering PROl I I4 interferon receptor from the cell culture.
In another embodiment, the invention provides isolated PR01114 interferon receptor polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
In a specific aspect, the invention provides isolated native sequence PROI114 interferon receptor palypeptide, which in certain embodiments, includes an amino acid sequence comprising residues 1 or about 30 to about 3I I of Figure 142 (SEQ ID N0:352}.
In another aspect, the invention concerns an isolated PROl 114 interferon receptor polypeptide, comprising an amino acid sequence having at least about 80 % sequence identity, preferably at least about 85 % sequence identity, more preferably at least about 90~ sequence identity; most preferably at least about 95 % sequence identity to the sequence of amino acid residues 1 or about 30 to about 311, inclusive of Figure 142 (SEQ ID N0:352).
In a further aspect, the invention concerns an isolated PR01114 interferon receptor pviypeptide, compt~ising an amino acid sequence scoring at least about 80% positives, preferably at least about 85 % positives, more preferably at least about 909b positives, most preferably at least about 95% positives when compared with the amino acid sequence of residues I or about 30 to about 311, inclusive of Figure 142 (SEQ
ID N0:352).
In yet another aspect, the invention concerns an isolated PROI114 interferon receptor polypeptide, comprising the sequence of amino acid residues t or about 30 to about 311, inclusive of Figure 142 (SEQ ID
N0:352), or a fragmetu thereof sufficient to provide a binding site for an anti-PROl 114 interferon receptor antibody.
Preferably, the PR01114 interferon receptor fragment retains a qualitative biological activity of a native PR01114 interferon receptor polypeptide.
In a still further aspect, the invention provides a polypeptide produced by (t) hybridizing a test DNA
molecule under stringent conditions with (a) a DNA molecule encoding a PRO1214 interferon receptor polypeptide having tip sequence of amitm acid residues from about 1 or about 30 to about 311, inclusive of Figure 142 {SEQ ID
N0:352), or (b) the corriplement of the DNA molecule of (a), and if the test DNA molecule has at least about an 80 ~
sequence identity, preferably at least about an 85°~ sequence identity, more preferably at least about a 90~ sequence identity, most preferably at least about a 95 %a sequence identity to (a) or (b), (ii) culturing a host cell comprising the test DNA molecule under conditions suitable for expression of the polypeptide, and (iii) recovering the polypeptide from the cell culture.
In another embodiment, the invention provides chimeric molecules comprising a PR01114 interferon receptor polypeptide fused to a heterologous polypeptide or amino acid sequence. An example of such a chimeric molecule comprises a PR01114 interferon receptor polypeptide fused to an epitope tag sequence or a Fc region of an itnmunoglobulin.
In another embodiment, the invention provides an antibody which specifically binds to a PROl I 14 interferon receptor poiypeptide. Optionally, the antibody is a monoclonal antibody.
In yet another embodiment, the invention concerns agonists and antagonists of a native PR01114 interferon receptor polypepude. In a particular embodiment, the agonist or antagonist is an anti-PR01114 interferon receptor antibody.
In a further embodiment, the invention concerns a method of identifying agonists or antagonists of a native PR01114 interferon receptor polypeptide by contacting the native PROI l 14 interferon receptor polypeptide with a candidate molecule and monitoring a biological activity mediated by said polypeptide.
IS In a still further embodiment, the invention concerns a composition comprising a PRO11I4 interferon receptor polypeptide, or an agonist or antagonist as hereinabove defined, in combination with a pharmaceutically acceptable carrier.
53. R02 7 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to carbonic anhydrase, wherein the polypeptide is designated in the present application as "PR0237".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0237 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0237 polypeptide having amino acid residues 1 to 328 of Figure 145 (SEQ ID N0:358), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0237 polypeptide having amino acid residues about 24 to 328 of Figure 145 (SEQ ID N0:358) or amino acid 1 or about 24 to X of Figure 145 (SEQ ID N0:.358), where X is any amino acid from 172 to 181 of Figure 145 (SEQ
ID N0:358), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA34353-1428 vector deposited on May 12, 1998 as ATCC 209855 which includes the nucleotide sequence encoding PR0237.
In another embodiment, the invention provides isolated PR0237 polypeptide. In particular, the invention provides isolated native. sequence PR0237 polypeptide, which in one embodiment, includes an amino acid sequence comprising residt~s 1 to 328 of Figure 145 (SEQ 1D N0:358). Additional embodiments of the present invention are directed to PR0237 polypeptides comprising amino acids about 24 to 328 of Figure 145 (SEQ ID N0:358) or amino acid 1 or about 24 to X of Figure 145 (SEQ ID N0:358), where X is any amino acid from in to 181 of Figure 145 (SEQ ID N0:358). Optionally, the PRO237 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA34353-1428 vector deposited on May 12, 1998 as ATCC 209855.

54. PR0541 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a trypsin inhibitor protein, wherein the potypeptide is designated in the present application as "PR0541 ".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0541 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROS41 polypeptide having amino acid residues 1 to S00 of Figure 147 (SEQ ID N0:363), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0541 polypeptide having amino acid residues about 21 to 500 of Figure 147 (SEQ ID N0:363), or is complementary to sucb encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency IO conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA45417-1432 vector deposited on May 27, 1998 as ATCC 209910 which includes the nucleotide sequence encoding PR0541.
In another embodiment, the invention provides isolated PRO541 polypeptide. In particular, the invention provides isolated native sequence PR0541 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues l to SOO of Figure 147 (SEQ ID N0:363). Additional embodiments of the present invention are directed to PR0541 polypeptides comprising amino acids about 21 to 500 of Figure 147 (SEQ ID N0:363).
Optionally, the PROS41 polypeptide is obtained or is obtainable by expressing the poiypeptide encoded by the cDNA
insert of the DNA45417-1432 vector deposited on May 27, 1998 as ATCC 209910.
SS. PRQ273 Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as "PR0273".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0273 poiypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0273 polypeptide having amino acid residues 1 through 1I I of Figure 149 (SEQ ID N0:370), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
In another embodiment, the invention provides isolated PR0273 polypeptide. In particular, the invention provides isolated native sequence PR02T3 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I through 111 of.Figure 149 (SEQ 1D NO:370).
36. PR0701 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to neuroligins 1, 2, and 3, wherein the polypeptide is designated in the present application as "PR0701".
In ors embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR070I poiypepcide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0701 polypeptide having amino acid residues 1 through 816 of Figure 151 (SEQ ID N0:375), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited with the ATCC
on March 31, 1998 which includes the nucleotide sequence encoding PR070I.
$I

In another embodiment, the invention provides isolated PR0701 polypeptide. In particular, the invention provides isolated native sequence PRO?O1 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 816 of Figure 151 (SEQ ID N0:375). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PR0701 polypeptide. Optionally, the PR070I
polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector $ deposited with the ATCC on March 31, 1998.
57. PR0704 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with VIP36, wherein the polypeptide is designated in the present application as "PR0704".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0704 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0704 polypeptide having amino acid residues 1 through 348 of Figure 153 (SEQ ID N0:380), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate>
and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 31, 1998 with the ATCC as DNA50911-1288, which includes the nucleotide sequence encoding PR0704.
In another embodiment, the invention provides isolated PR0704 polypeptide. In particular, the invention provides isolated native sequence PR0704 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 348 of Figure 153 (SEQ ID N0:380). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0704 polypeptide. Optionally, the PR0704 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 31, 1998 with the ATCC as DNA50911-1288.
58. PR0706 Applicanas have identified a cDNA clone that encodes a novel polypeptide having homology to prostatic. acid phosphatase precursor and lysosomai acid phosphatase precursor, wherein the polypeptide is designated in the present application as "PR0706" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0706 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0706 polypeptide having amino acid residues 1 through 480 of Figure 155 (SEQ ID N0:385), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the vector deposited on April 21 >
1998 with the ATCC as DNA48329-1290 which includes the nucleotide sequence encoding PR0706.
In another embodiment, the invention provides isolated PR0706 polypeptide. In particular, the invention provides isolated native sequence PR0706 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 480 of Figure 155 (SEQ ID N0:385), or comprising residues 19 through 480 of Figure I55 (SEQ ID N0:385). Optionally, the PRO706 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 21, 1998 with the ATCC as DNA48329-1290.

WO 99146281 PCTIUS99lOS028 59. RP 0703 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to cadherins, particularly cadherin FIBS, wherein the polypeptide is designated in the presern application as "PR0707".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0707 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding . the PR0707, polypeptide S having amino acid residues 1 to 916 of Figure 157 (SEQ ID N0:390), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 27, 1998 with the ATCC as DNA48306-1291 which includes the nucleotide sequence encoding PR0707.
In another embodiment, the invention provides isolated PR0707 polypeptide. In particular, the invention provides isolated native sequence PR0707 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues l to 916 of Figure 1s7 (SEQ ID N0:390). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0707 polypeptide.
Optionally, the PR0707 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 27,.1998 with the ATCC as DNA48306-1291.
is 60. P 3 Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to neuropsin, wherein the polypeptide is designated in the present application as "PR0322"
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0322 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0322 polypeptide having amino acid residues I or 24 through 260 of Figure 159 (SEQ ID N0:395), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 11, 1998 as ATCC no. 209b69 which includes the nucleotide sequence encoding PR0322.
In another embodiment, the invention provides isolated PR0322 polypeptide. In particular, the invention provides isolated native sequence PR0322 polypeptide, which in one embodiment, iacludes an amino acid sequence comprising residues 1 or 24 through 260 of Figuxe 159 (SEQ ID N0:395). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0322 polypeptide. Optionally, the PR0322 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 11, 1998 as ATCC no. 209669.
61. ~'R0526 Applicants have identified a eDNA clone that encodes a novel polypeptide having sequence identity with ALS, wherein the polypeptide is designated in the present application as "PRO526".
3s In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0526 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0526 polypeptide having amino acid residues 1 to 473 of Figure 161 (SEQ ID N0:400), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated ttucieic acid sequence may comprise the cDNA insert of the vector deposited on March 26, 1998 with the ATCC as DNA44184-1319 which includes the nucleotide sequence encoding PR0526.
In another embodiment, the invention provides isolated PROS26 polypeptide. In particular, the invention provides isolated native sequence PROS26 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 473 of Figure 161 {SEQ ID N0:400). Optionally, the PROS26 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 26, 1998 S with the ATCC as DNA44184-1319 which includes the nucleotide sequence encoding PR0526.
62. gR0531 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with protocadherins, wherein the polypeptide is designated in the present application as "PROS31".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROS31 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROS31 polypeptide having amino acid residues 1 to ?89 of Figure 163 (SEQ 1D N0:40S), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 26, 1 S 1998 as DNA48314-1320 which includes the nucleotide sequence encoding PR0531.
In another embodiment, the invention provides isolated PROS31 polypeptide. In particular, the invention provides isolated native sequence PROS31 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 789 of Figure 163 (SEQ ID N0:40S). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0531 polypeptide.
Optionally, the PROS31 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on March 25, 1998 as DNA48314-1320.
63. P 4 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with 2S disulfide isomerase (sometimes referred to herein as protein disulfide isomerase), wherein the polypeptide is designated in the present application as "PR0534".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0534 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROS34 polypeptide having amino acid residues 1 to 360 of Figure 16S (SEQ ID N0:410), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 26, 1998 as DNA48333-1321 which includes the nucleotide sequence encoding PROS34.
In another embodiment, the invention provides isolated PR0534 polypeptide. In particular, the invention provides isolated native sequence PR0534 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 360 of Figure 165 (SEQ ID N0:410). An additional embodiment of the present invention is directed to an isolated exuacellular domain of a PROS34 polypeptide.
Optionally, the PROS34 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on March 26, 1998 as DNA48333-1321.

WO 99146281 PC"T/US99/05028 64. PR069:7 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with sFRPs, wherein the polypeptide is designated in the present application as "PR0697".
In one embodiment, the invention provides an isoiated nucleic acid molecule comprising DNA encoding a PR0697 polypeptideIn one aspect, the isolated nucleic acid comprises DNA
encoding the PR0697 polypeptide having amino acid residues 1 through 295 of Figure I67 (SEQ ID N0:415), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the eDNA insert of the vector deposited with the ATCC
on March 26, 1998 as DNA50920-1325 which includes the nucleotide sequence encoding PR0697.
1n another embodiment, the invention provides isolated PR0697 polypeptide. In particular, the invention provides isolated native sequence PR0697 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I through 295 of Figure 167 (SEQ ID N0:415). Optionally, the PR0697 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited with the ATCC
on March 26, 1998 as DNA50920-1325.
65. P 7 7 Applicants have identified a cDNA clone that encodes a novel I2 transmembrane polypeptide, wherein the polypeptide is designated in the present application as "PR0717".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0717 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR07I7 polypeptide having amino acid residues 1 through 560 of Figure 169 (SEQ ID N0:420), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 28', 1998 with the ATCC as DNA50988-1326 which includes the nucleotide sequence encoding PR0717.
In another embodiment, the invention provides isolated PR0717 polypeptide. In particular, the invention provides isolated native sequence PR07I7 polypeptide, which in one embodimenx, includes an amino acid sequence comprising residues 1 through 560 of Figure 169 (SEQ ID N0:420). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0717 polypeptide. Optionally, the PR07I7 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 28, 1998 with the ATCC as DNA50988-1326.
66. PR0731 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with protocadherin 4, wherein the polypeptide is designated in the present application as "PRp731".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0731 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0731 polypeptide having amino acid residues 1 through 1184 of Figure 171 (SEQ ID N0:425), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on March 3I , 1998 with the ATCC as DNA48331-1329 which includes the nucleotide sequence encoding PR0731.

WO 99/46281 ' PCTlUS99/OS028 In another embodiment, the invention provides isolated PR0731 polypeptide. In particular, the invention provides isolated native sequence PR0731 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 1184 of Figure 171 (SEQ ID N0:425). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0731 polypeptide. Optionally, the PR0731 golypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on March 31, 1998 with the ATCC as DNA48331-1329.
67. PR0218 Applicants have identified a cDNA clone that encodes a novel mufti-transmembrane protein having sequence identity with membrane regulator proteins, wherein the polypeptide is designated in the present application as "PR0218".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0218 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0218 polypeptide having amino acid residues I through 455 of Figure 173 (SEQ ID N0:430), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 28, 1998 with the ATCC as DNA30867-1335 which includes the nucleotide sequence encoding PR0218.
In another embodiment, the invention provides isolated PR0218 polypeptide. In particular, the invention provides isolated native sequence PR0218 polypeptide, which in one embodiment, includes an anl;no acid sequence comprising residues 1 through 455 of Figure 173 (SEQ ID N0:430). Optionally, the PR0218 polypeptide is obtained or is obtainable by expressing the polypepdde encoded by the cDNA insert of the vector deposited on April 28, 1998 with the ATCC as DNA30867-1335.
In another embodiment, the invention provides an expressed sequence tag (EST) sequence comprising the nucleotide sequence of Figure 1?4 {SEQ ID N0:431), designated herein as DNA14472.
In another embodiment, the invention provides an expressed sequence tag (EST) sequence comprising the nucleotide sequence of Figure 175 (SEQ ID N0:432), designated herein as DNA15846.
68. PR0768 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with integrins, wherein the polypeptide is designated in the present application as "PR0768".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0768 polypeptide, 1n one aspect, the isolated nucleic acid comprises DNA
encoding the PR0768 polypeptide having amino acid residues I through 1141 of Figure 177 {SEQ ID N0:437), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 6, 1998 as DNA55737-1345 which includes the nucleotide sequence encoding PR0768.
1n another embodiment, the invention provides isolated PR0768 polypeptide. In particular, the invention provides isolated native sequence PR0768 polypeptide, which in one.
embodiment, includes an amino acid sequence comprising residues 1 through 1141 of Figure 177 (SEQ 1D N0:437). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR0768 polypeptide. Optionally , the PR0768 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 6, 1998 as DNA55737-1345.
69. PR0771 Applicants have identified a eDNA clone that encodes a novel polypeptide having sequence identity with testican, wherein the polypeptide is designated in the present application as "PR0771 ".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0771 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0771 polypeptide having amino acid residues 1 through 436 of Figure 179 (SEQ ID N0:442), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency l0 conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April 7, 1998 with the ATCC as DNA49829-1346 which includes the nucleotide sequence encoding PR0771.
In another embodiment, the invention provides isolated PR0771 polypeptide. In particular, he invention provides isolated native sequence PR0771 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 436 of Figure 179 (SEQ ID N0:442). Optionally, the PR0771 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on April 7, 1998 with the ATCC as DNA49829-1346 70. PR0733 Applicants have identified a cDNA clone that encodes a novel poiypeptide having sequence identity with the T11ST2 receptor binding protein, wherein the polypeptide is designated in the present application as "PR0733".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0733 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PRO?33 polypeptide having amino acid residues 1 through 229 of Figure 18I (SEQ ID N0:447); or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on April. 7, 1998 with the ATCC as DNA52196-1348 which includes the nucleotide sequence encoding PR0733.
In another embodiment, the invention provides isolated PR0733 polypeptide. In particular, the invention provides isolated t~ttive sequence PR0733 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 229 of Figure 181 (SEQ ID N0:447). An additional embodiment of the present invention is directed to an isolated extraceIlular domain of a PR0733 polypeptide. Optionally; the PR0733 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on Apri17, 1998 as DNA52196-1348.

71. PROlø~
Applicants have identified a cDNA clone that encodes a novel polypeptide having seguence identity with pancreatitis-associated protein, wherein the polypeptide is designated in the present application as "PR0162".
In one er~odiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0162 polypeptide. In one aspect, .the isolated nucleic acid comprises DNA
encoding the PR0162 polypeptide having amino acid residues 1 through 175 of Figure 183 (SEQ ID NO:452), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56965-1356 which includes the nucleotide sequence encoding PROI62.
In another embodiment, the invention provides isolated PR0162 polypeptide. In particular, the invention provides isolated native sequence PR0162 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues l through 175 of Figure 183 (SEQ ID N0:452). Optionally, the PR0162 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56965-1356.

72. PR0788 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with anti-neoplastic urinary protein, wherein the polypeptide is designated in the present application as "PR0788".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0788 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0788 polypeptide having amino acid residues I through 125 of Figure 185 {SEQ ID N0:454), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56405-1357 which includes the nucleotide sequence encoding PR0788.
In another embodiment, the invention provides isolated PR0788 polypeptide. In particular, the invention provides isolated native sequence PR0788 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 125 of Figure 185 (SEQ ID N0:454). An additional embodimem of the present invention is directed to an isolated exuaceIlular domain of a PR0788 polypeptide. Optionally, the PR0788 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 6, 1998 with the ATCC as DNA56405-1357.
'13. PR01d08 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with diclckopf 1 (dklc-1), wherein the polypepiide is designated in the present application as "PR01008".
In one embodiment,. the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01008 polypepti~. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROI008 polypeptide having amino acid residues 1 through 266 of Figure 187 (SEQ ID N0:456), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 20, 1998 with the ATCC as DNA57530-1375 which includes the nucleotide sequence encoding PR01008.
In another embodiment, the invention provides isolated PR01008 polypeptide. In particular, the invention provides isolated native sequence PR01008 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 266 of Figure 187 (SEQ ID N0:456). Optionally, the PR01008 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 20, 1998 with the ATCC as DNAS?530-1375.

In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA16508 comprising the nucleotide sequence of Figure 188 (SEQ ID N0:457).
74. P 0 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with disulfide isomerase and phospholipase C, wherein the polypeptide is designated in the present application as "P801012" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01012 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01012 polypeptide having amino acid residues 1 through 747 of Figure 190 (SEQ ID N0:459), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA56439-1376, which includes the nucleotide sequence encoding PR01012.
In another embodiment, the invention provides isolated PR01012 polypeptide. In particular, the invention provides isolated native sequence PROI012 polypeptic3e, which in one embodiment. includes an amino acid sequence comprising residues 1 through 747 of Figure 190 (SEQ ID N0:459). Optionally, the PROl0I2 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert oT the vector deposited on May 14, 1998 with the ATCC as DNA56439-1376.
75. R l Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with reductase, wherein the polypeptide is designated in he present application as "P801014".
In one embodiment, the invention provides, an isolated nucleic acid molecule comprising DNA encoding a FR01014 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01014 polypeptide having amino acid residues I through 300 of Figure 192 (SEQ ID N0:464), or is complementary to such encoding nucleic acid sequence, and remains stably bound to is under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 20, 1998 as DNA56409-1377 with the ATCC which includes the nucleotide sequence encoding PR01014.
In another embodiment, the invention provides isolated PROlOI4 polypeptide. in particular, the invention provides isolated native sequence PROI014 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 300 of Figure 192 (SEQ ID N0:464). Optionally, the PROlUI4 polypeptide is obtained or is obtainable by expressing the polypeptide encoded. by the cDNA
insert of the vector deposited on May 20, 1998 as DNA56409-1377 with the ATCC.
76. P_ 801017 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with HNK-I sulfotransferase, wherein the polypeptide is designated in the present application as "PR010I7".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PROI017 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROIOI7 polypeptide having amino acid residues I through 414 of Figure 194 (SEQ ID NO:466), or is complementary to such encoding WO 99!46281 PCT/US99I05028 nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 20, I998 with the ATCC as DNA56112-1379 which includes the nucleotide sequence encoding PR01017.
In another embodiment, the invention provides isolated PR01017 polypeptide. In particular, the invention provides isolated native sequence PR01017 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 414 of Figure 194 (SEQ ID N0:466). Optionally, the PR01017 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 20, 1998 with the ATCC as DNA56I12-1379.
77. PR0474 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with dehydrogenase, wherein the polypeptide is designated in the present application as "PR0474", In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0474 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0474 polypeptide having amino acid residues 1 through 270 of Figure 196 (SEQ ID N0:468), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA56045-1380 which includes the nucleotide sequence encoding PR0474.
In another embodiment, the invention provides isolated PR0474 polypeptide. In particular, the invention provides isolated native sequence PR0474 polypepiide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 270 of Figure 196 (SEQ m N0:468). Optionally, the PR0474 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA56045-1380.
78. P Ol Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with IL-17, wherein the polypeptide is designated in the present application as "PR01031".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01031 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01031 polypeptide having amino acid residues 1 through 180 of Figure 198 (SEQ ID N0:470), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA59294-1381 which includes the nucleotide sequence encoding PR01031.
In another embodiment, the invention provides isolated PROI031 polypeptide. In particular, the invention provides isolated native sequence PR01031 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 180 of Figure 198 (SEQ ID N0:470). Optionally, the PR01031 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 14, 1998 with the ATCC as DNA59294-1381.

79. P 093 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity to protein disulfide isomerase,. wherein the polypeptide is designated in the present application as "PR0938".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR0938 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR0938 polypeptide having amino acid residues 1 to 349 of Figure 200 (SEQ ID N0:472), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In other aspects, the isolated nucleic acid comprises DNA encoding the PR0938 polypeptide having amino acid residues about 23 to 349 of Figure 200 (SEQ ID N0:472) or amino acid 1 or about 23 to X of Figure 200 (SEQ ID N0:472), where X is any amino acid from 186 to 195 of Figure 200 (SEQ
ID N0:472), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the DNA56433-1406 vector deposited on May 12, 1998, as ATCC Accession No.
209857 which includes the nucleotide sequence encoding PR0938.
In another embodiment, the invention provides isolated PR0938 polypeptide. In particular, the invention provides isolated native sequence PR0938 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 349 of Figure 200 (SEQ ID N0:472). Additional embodiments of the present invention are directed to PR0938 polypeptides comprising amino acids about 23 to 349 of Figure 200 (SEQ ID N0:472) or amino acid 1 or about Z3 to X of Figure 200 (SEQ ID N0:472), where X is any amino acid from 186 to 195 of Figure 200 (SEQ 1D N0:472). Optionally, the PR0938 polypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA56433-1406 vector deposited on May 12, 1998, as ATCC Accession No:
209857.
80. PR01,Q~,2 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with a lectin-like oxidized LDL receptor, wherein the polypeptide is designated in the present application as "PR01082" .
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01082 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PROI082 polypeptide having amino acid residues l,through 201 of Figure 202 (SEQ ID N0:477), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions: The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 14, 1998 with the ATCC as DNA53912-1457 which includes the nucleotide sequence encoding PR01082.
In anger embodiment, the invention provides isolated PROIU82 polypeptide. In particular, the invention provides isolated native sequence PR01082 polypeptide, which in one embodiment, includes an amino acid seque~e comprising residues 1 through 201 of Figure 202 (SEQ ID N0:477). An additional embodiment of the present invention is directed to an isolated domain of a PR01082 poIypeptide, excluding the transmembrane domain.
Optionally, the PR01082 polypeptide is obtait~d or is obtainable by expressing the polypeptide encoded by the cDNA
insert of the vector deposited on May 14, 1998 with the ATCC as DNA53912-1457.

81. PR01483 Applicants have identified a cDNA clone that encodes a novel polypeptide having sequence identity with a 7TM receptor, latrophilin-related protein 1, and a macrophage restricted cell surface glycoprotein, wherein the polypeptide is designated in the present application as "PR01083".
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PR01083 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the PR01083 polypeptide having amino acid residues 1 through 693 of Figure 204 (SEQ ID N0:483), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at feast moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector deposited on May 12, 1998 with the ATCC as DNA50921-1458 which includes the nucleotide sequence encoding PR01083.
In another embodiment, the invention provides isolated PR01083 polypeptide. In particular, the invention provides isolated native sequence PR01083 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 693 of Figure 204 (SEQ ID N0:483). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PR01083 polypeptide. Optionally, the PR01083 poIypeptide is obtained or is obtainable by expressing the polypeptide encoded by the cDNA insert of the vector deposited on May 12, 1998 with the ATCC as DNA50921-1458.
In another embodiment, the invention provides an expressed sequence tag (EST) designated herein as DNA24256 which comprises the nucleotide sequence of Figure 205 (SEQ ID
N0:484).
82. PR0200_ The objects of this invention, as defined generally supra, are achieved at least in part by the provision of a novel polypeptide, VEGF-E also herein designated PR0200, (SEQ ID N0:488) and the nucleic acid encoding therefor, SEQ ID N0:487, residues 259 through 1293.
In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a VEGF-E polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encoding the VEGF-E polypeptide having amino acid residues 1 through 345 of Figure 207 (SEQ ID N0:488), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under low stringency conditions. In another embodiment, variants are provided wherein the VEGF-E nucleic acid has single or multiple deletions, substitutions, insertions, truncations or combinations thereof.
In another embodiment, the invention provides isolated VEGF-E polypeptide. In particular, the invention provides an isolated native sequence VEGF-E polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 345 of Figure 207 (SEQ ID N0:488). In another embodiment, variants are provided wherein the VEGF-E polypeptide has single or multiple deletions, substitutions, insertions, truncations or combinations thereof.
In yet further embodiments, the present invention is directed to compositions useful for treating indications where proliferation, survival and/or differentiation of cells is desired, comprising a therapeutically effective amount of a VEGF-E polypeptide hereof in admixture with a pharmaceutically acceptable carrier.
The invention further includes associated embodiments of VEGF-E such as modified VEGF-E polypeptides and modified variants which have the same biological applications as VEGF-E, and pharmaceutical compositions incorporating same. Inhibitors of VEGF-E are also provided.

WO 99146281 ~ PC"T/US99105028 83. PR0285 and PR0286 Applicants have identified two novel cDNA clones that encode novel human Toll polypeptides, designated in the present application as PR0285 (encoded by DNA4002I-1154) and PR0286 (encoded by DNA42663-1154).
In one embodiment, the invention provides an isolated nucleic acid molecule comprising a DNA encoding a polypeptide having at least about 80% sequence identity, preferably at least about 85~ sequence identity, more preferably at least about 90% sequence identity, most preferably at least about 959b sequence identity to (a) a DNA
molecule encoding a PR0285 polypeptide having amino acid residues 27 to 839 of Figure 209 (SEQ ID N0:496);
or (b) to a DNA molecule encoding a PRO286 polypeptide having amino acid residues 27 to 825 of Figure 211 (SEQ
ID N0:498) or (c) the complement of the DNA molecule of (a) or (b). The complementary DNA molecule preferably remains stably bound to such encoding nucleic acid sequence under at least moderate, and optionally, under high stringency conditions.
In a further embodiment, the isolated nucleic acid molecule comprises a polynucleotide that has at least about 90%, preferably at least about 95% sequence identity with a polynucleotide encoding a polypeptide comprising the sequence of amino acids 1 to 839 of Figure 209 (SEQ ID N0:496); or at least about 90% , preferably at least about 95 % sequence identity with a polynucleotide encoding a polypeptide comprising the sequence of amino acids 1 to 1041 of Figure 211 (SEQ ID N0:498).
In a specific embodiment, the invention provides an isolated nucleic acid molecule comprising DNA
encoding native or variant PR0285 and PR0286 polypeptides, with or without the N-terminal signal sequence, and with or without the transmembrane regions of the respective full-length sequences. In one aspect, the isolated nucleic acid comprises DNA encoding a mature, full-length native PR0285 or PR0286 polypeptide having amino acid residues 1 to 1049 of Figure 209 (SEQ ID N0:496) and 1 to 1041 of Figure 211 (SEQ ID NO: 498), or is complementary to such encoding nucleic acid sequence. In another aspect, the invention concerns an isolated nucleic acid molecule that comprises DNA encoding a native PR0285 or PR0286 polypeptide without an N-terminal signal sequence, or is complementary to such encoding nucleic acid sequence. In yet another embodiment, the invention concerns nucleic acid encoding transmembrar>e-domain deleted or inactivated forms of the full-length native PR0285 or PR0286 proteins.
In another embodiment, the invention the isolated nucleic acid molecule comprises the clone (DNA40021-i 154) deposited on October 17, 1997, under ATCC number 209389; or the clone (DNA42663-1154) deposited on October 17, 1997, under ATCC number 209386.
In yet another embodiment, the invention provides a vector comprising DNA
encoding PR0285 and PR0286 polypeptides, or their variatus. Thus, the vector may comprise any of the isolated nucleic acid molecules hereinabove defined.
In another embodiimer>t, the invention provides isolated PR0285 and PR0286 polypeptides. In particular, the invention provides isolated native sequence PR0285 arid PR0286 polypeptides, which in one embodiment, include the amino acid sequences comprising residues 1 to 1049 and 1 to 1041 of Figures 209 and 211 (SEQ ID NOS:496 and 498), respectively. The invention also provides for variants of the PR0285 and PR0286 polypeptides which are encoded by any of the isolated nucleic acid molecules hereinabove defined.
Specific variants include, but are not limited to, deletion (truncated) variants of the full-length native sequence PRO285 and PR0286 polypeptides which lack the respective N-terminal signal sequences and/or have their respective transmembrane and/or cytoplasmic domains deleted or inactivated.

The invention also specifically includes antibodies with dual specificities, e.g., bispecific antibodies binding more than one Toll polypeptide.
In yet another embodiment, the invention concerns agonists and antagonists of the native PR0285 and PR0286 polypeptides. In a particular embodiment, the agonist or antagonist is an anti-PR0285 or anti-PR0286 antibody. .
In a further embodiment, the invention concerns screening assays to identify agonists or antagonists of the native PR0285 and PR0286 polypeptides.
In a still further embodiment, the invention concerns a composition comprising a PR0285 or PR0286 polypeptide, or an agonist or antagonist as hereinabove defined, in combination with a pharmaceutically acceptable carrier.
The invention further concerns a composition comprising an antibody specifically binding a PR0285 or PR0286 polypeptide, in combination with a pharmaceutically acceptable carrier.
The invention also concerns a method of treating septic shock comprising administering to a patient an effective amount of an antagonist of a PR0285 or PR0286 polypeptide. In a specific embodiment, the antagonist is a blocking antibody specifically binding a native PR0285 or PR0286 polypeptide.
84. PR0213-1. PR01330 and PR01449 The present invention concerns compositions and methods for the diagnosis and treatment of neoplastic cell growth and proliferation in mammals, including humans. The present invention is based on the identification of genes that are amplified in the genome of tumor cells. Such gene amplification is expected to he associated with the overexpression of the gene product and contribute to tumorigenesis.
Accordingly, the proteins encoded by the amplified genes are believed to be useful targets for the diagnosis andlor treatment (including prevention) of certain cancers, and may act as predictors of the prognosis of tumor treatment.
In one embodiment, the present invention provides an isolated nucleic acid molecule comprising. DNA encoding a PR0213-1, PR01330 and/or PR01449 polypeptide. In one aspect, the isolated nucleic acid comprises DNA
encodit>g the PR0213-1, PR01330 andlor PR01449 polypeptide having amino acid residues 1 to 295 of Figure 213 (SEQ ID N0:506), 20 to 273 of Figure 215 (SEQ ID N0:508) and 20 to 273 of Figure 217 (SEQ ID NO:510), respectively, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. The isolated nucleic acid sequence may comprise the cDNA insert of the vector designated as DNA30943-1163 (ATCC 209791) deposited on April 21, 1998;
DNA6490?-1163-1 (ATCC 203242) deposited on September 9, 1998 and/or DNA64908-1163-1 (ATCC 203243) deposited on September 9, 1998.
In another embodiment, the present invention comprises an isolated nucleic acid molecule having at least about 80% sequence identity, preferably at least about 85% sequence identity, more preferably at least about 90%
sequerxe identity, most preferably at least about 95 % sequence identity to (a) a DNA molecule encoding a PR0213-1, PR01330 and/or PR01449 polypeptide having amino acid residues 1 to 295 of Figure 213 (SEQ ID N0:506), 20 to 273 of Figure 2I5 (SEQ ID N0:508) and 20 to 273 of Figure 217 (SEQ ID
NO:510), respectively; or (b) the complement of the DNA molecule of (a).
In another embodiment, the invention provides an isolated PR0213-1, PROI330 and/or PR01449 polypeptide. In particular, the invention provides isolated native sequence PR0213-I , PR01330 and/or PR01449 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 295 of Figure 213 (SEQ ID N0:506), 20 to 273 of Figure 215 (SEQ ID N0:508) or 20 to 273 of Figure 217 (SEQ ID N0:510), respectively. Optionally, the PR0213-1, PR01330 and/or PR01449 polypeptide is obtained or obtainable by expressing the polypeptide encoded by the cDNA insert of the DNA30943-1163 (ATCC 209791), DNA64907-1163-1 (ATCC 203242) or DNAb4908-1163-1 {ATCC 203243).
In another aspect, the invention provides an isolated PR0213-i, PR01330, andlor PR01449 polypeptide, comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 85%
sequence identity, more preferably at least about 95 % sequence identity to amino acid residues 1 to 295 of Figure 213 {SEQ ID N0:506), 20 to 273 of Figure 215 (SEQ ID N0:508) or 20 to 273 of Figure 217 (SEQ 1D N0:510), inclusive.
In yet another embodiment, the invention provides an isolated PR0213-1, PR01330, and/or PR01449 polypeptide, comprising the amino acid residues 1 to 295 of Figure 213 (SBQ 1D
N0:506), 20 to 273 of Figure 215 (SEQ ID N0:508) or 20 to 273 of Figure 217 (SEQ ID N0:510), or a fragment thereof sufficient to provide a binding site for an anti-PR0213-.1, anti-PR01330 andlor anti-PR01449 anribody.
Preferably, the PR02i3-i, PR01330, andlor PR01449 fragment retains a qualitative biological activity of a native PR0213-1, PROi330, andlor PR01449 polypeptide.
In a filrttter aspect, the invention concerns an isolated PR0213-1, PR01330, and/or PR01449 polypeptide, comprising an amino acid sequence scoring at least about 80 % positives, preferably at least about 85 % positives, more preferably at least about 90% positives, most preferably at least about 95% positives when compared with the amino acid sequence of residues 1 to 295 of Figure 213 (SEQ ID N0:506), 20 to 273 of Figure 215 {SEQ 1D
N0:508) and 20 to 273 of Figure 217 (SEQ ID NO:510), respectively.
In still a further aspect, the invention provides a polypeptide produced by (i) hybridizing a test DNA
molecule under stringent conditions with: (a) a DNA molecule encoding a PR0213-1, PR01330, andlor PR01449 polypeptide having the amino acid residues from 1 to 295 of Figure 213 (SEQ ID
N0:506), 20 to 273 of Figure 215 (SEQ ID N0:508) and 20 to 273 of Figure 217 (SEQ ID N0:510), respectively; or the complement of the DNA
molecule of (a), and if said test DNA molecule has at least about an 80%
sequence identity to (a) or (b), (ii) culturing a host cell comprising said test DNA molecule under conditions suitable for the expression of said polypeptide, and (iii) recovering said polypeptide from the cell culture.
In ot~ embodiment, the present invention concerns an isolated antibody which binds a PR0213-1, PR01330 andlor PR01449 polypeptide. In one aspect, the,' antibody induces death of a cell overexpressing a PR0213-1, PR01330 andlor PR01449 polypeptide. In another aspect; the antibody is a monoclonal antibody, which preferably has nonhuman complementarity determining region (CDR) residues and human framework region (FR) residues.
The antibody may be labeled and may be immobilized on a solid support. In a further aspect, the antibody is an antibody fragment, a single-chain antibody, or an anti-idiotypic antibody.
In another embodiment, the invention concerns a composition comprising an antibody which binds a PR0213-I, PROi330 and/or PR01449 poiypeptide in admixture with a pharmaceutically acceptable carrier. In one aspect, the composition comprises a therapeutically effective amount of the antibody. In another aspect, the composition comprises a further active ingredient; which may, for example, be a further antibody or a cytotoxic or chemotherapeutic agent. Preferably, the composition is sterile.

In a further embodiment, the invention concerns nucleic acid encoding an anti-PR02I3-1, anti-PR01330 andlor anti-PR01449 antibody, and vectors and recombinant host cells comprising such nucleic acid.
The invention further concerns antagonists and agonists of a PR0213-1, PR01330 and/or PR01449 polypeptide that inhibit one or more of the functions or activities of the PR0213-7 , PR01330 and/or PR01449 polypeptide.
In a further embodiment, the invention concerns isolated nucleic acid molecules that hybridize to the complement of the nucleic acid molecules encoding the PR0213-1, PR01330 and/or PR01449 polypeptides. The nucleic acid preferably is DNA, and hybridization preferably occurs under stringent conditions. Such nucleic acid molecules can act as antisense molecules of the amplified genes identified herein, which, in turn, can fmd use in the modulation of the respective amplified genes, or as antisense primers in amplification reactions. Furthermore, such sequences can be used as part of ribozyme andlor triple helix sequence which, in turn, may be used in regulation of the amplified genes.
In another embodiment, the invention concerns a method for determining the presence of a PR02I3-1, PROI330 and/or PR01449 polypeptide comprising exposing a cell suspected of containing the PR0213-1, PR01330 andlor PR01449 polypeptide to an anti-PR02I3-1, PR01330 andlor PR01449 antibody and determining binding of the antibody to the cell.
In yet another embodiment, the present invention concerns a method of diagnosing tumor in a mammal, comprising detecting the level of expression of a gene encoding a PR0213-1, PR01330 and/or PR01449 polypeptide (a) in a test sample of tissue cells obtained from the martunal, and (b) in a control sample of known normal tissue cells of the same cell type, wherein a higher expression level in the test sample indicates the presence of tumor in the mammal from which the test tissue cells were obtained.
In another embodiment, the present invention concerns a method of diagnosing tumor in a mammal, comprising (a) contacting an anti-PR0213-1, anti-PR01330 and/or anti-PR01449 antibody with a test sample of tissue cells obtained from the mammal, and (b) detecting the formation of a complex between the anti-PR0213-1, anti-PR01330 and/or anti-PR01449 antibody and the PR0213-1, PR01330 andlor PR01449 polypeptide in the test sample. The detection may be qualitative or quantitative, and may be performed in comparison with monitoring the complex formation in a control sample of known normal tissue cells of the same cell type. A larger quantity of complexes formed in the test sample indicates the presence of tumor in the mammal from which the test tissue cells were obtained. The antibody preferably carries a detectable label. Complex formation can be monitored, for example, by light microscopy, flow cytometry, fluorimeay, or other techniques known in the art. The test sample is usually obtained from an individual suspected to have neoplastic cell growth or proliferation (e.g. cancerous cells).
In another embodiment, the present invention concetvs a cancer diagnostic kit, comprising an anti-PR0213-1, anti-PR01330 and/or anti-PR01449 antibody and a carrier (e.g. a buffer) in suitable packaging. The kit preferably contains instructions for using the antibody to detect the PR0213-1, PR01330 andlor PR01449 polypeptide.
In yet another embodiment, the invention concerns a method for inhibiting the growth of tumor cells comprising exposing a cell which overexpresses a PRO213-1, PR01330 and/or PR01449 polypeptide to an effective amount of an agent inhibiting the expression andlor activity of the PR0213-1, PR01330 andlor PR01449 polypeptide. The agent preferably is an anti-PR0213-1, anti-PR01330 andlor anti-PR01449 antibody, a small organic and inorganic molecule, peptide, phosphopeptide, antisense or ribozyme molecule, or a triple helix molecule.
In a specific aspect, the agent, e.g. anti-PR0213-1, anti-PR01330 andlor anti-PR01449 antibody induces cell death.

In a further aspect, the tumor cells are further exposed to radiation treatment and/or a cytotoxic or chemotherapeutic agent.
In a further embodiment, the invention concerns an article of manufacture, comprising:
a) a container;
b) a label on the container; and c) a composition comprising an active agent contained within the container;
wherein the composition is effective for inhibiting the growth of tumor cells, the label on the container indicates that the composition can be used for treating conditions characterized by overexpression of a PR0213-1, PR01330 and/or PR01449 polypeptide, and the active agent in the composition is an agent inhibiting the expression andlor activity of the PR02i3-1, PR01330 atullor PROI449 polypeptide. In a preferred aspect, the active agent is an anti-PR0213-1, anti-PR01330 and/or anti PR01449 antibody.
In yet a further embodiment, the invention provides a method for identifying a compound capable of inhibiting the expression andlor activity of a PR0213-1, PR01330 and/or PR01449 polypeptide, comprising contacting a candidate compound with a PR0213-1, PROI330 andlor PR01449 polypeptide under conditions and for a time sufficient to allow these two components to interact. . In a specific aspect, either the candidate compound or the PR0213-l, PR01330 atxllor PR01449 polypeptide is immobilized on a solid support. In another aspect, the non-immobilized component carries a detectable label.
85. ~R0298 Applicants have identified a cDNA clone that encodes a novel polypeptide. The DNA is designated in the present application as "DNA39975-1210", encoding a novel mufti-transmembrane protein, referred to as "PR0298" .
In one embodiment, the itrvendon provides an isolated nucleic acid molecule cotttprising DNA having at least about 80%, preferably at least about 85%, more preferably at least about 90%, most preferably at least about 95%
sequence identity to (a) a DNA molecule encoding PR0298, comprising the sequence of amino acids 1 to 3b4 of Figure 219 (SEQ ID NO:515), or (b) the complement of the DNA molecule of (a}.
In one aspect, the isolated nucleic acid comprises DNA encoding a PR0298 polypeptide having amino acid residues 1 to 364 of Figure 219 (SEQ ID
NO:515), or is comgletrtetttary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.
1n a further embodiment, the invention concerns an isolated nucleic acid molecule comprising DNA having at least an 80% sequence identity to (a) a DNA molecule encoding the same mature polypeptide encoded by the human protein cDNA in ATCC Deposit No. 209783 (DNA39975-1210); or (b) the complement of the DNA molecule of (a).
In a still further embodiment, the invention concerns nucleic acid which comprises a DNA molecule encoding the same mature polypeptide encoded by the human protein cDNA in ATCC
Deposit No. 209783 (DNA39975-1210).
In another embodiment, the invention provides isolated PR0298 polypeptide. ht particular, the invention provides isolated native sequence PR0298 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues I to 364 of Figure 219 (SEQ ID NO:515).
In another embodiment, the invention provides an expressed sequence tag (EST) designated DNA26832 comprising the nucleotide sequence of Figure 220 (SEQ ID N0:516).

86. PR0337 Applicants have identified a cDNA clone (DNA433ib-1237) that encodes a novel polypeptide, designated in the present application as. "PR0337".
In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 80%
sequence identity to (a) a DNA molecule encoding a PR0337 polypeptide comprising the sequence of amino acids 1 to 344 of Figure ?22, (SEQ ID N0:523), or (b) the complement of the DNA
molecule of (a). The sequence identity preferably is about 85%, more preferably about 90%, most preferably about 95%.
In one aspect, the isolated nucleic acid has at least about 80%, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95 (including 96, 97, 98 and 99 % } sequence identity with a polypeptide having amino acid residues 1 to 344 of Figure 222 (SEQ ID NO:523). Preferably, the highest degree of sequence identity occurs within the immunoglobuiin and major histocompatibiliry domains (amino acids 113 to 130 of Figure 222, SEQ ID N0:523).
In a further embodiment, the isolated nucleic acid molecule comprises DNA
encoding a neurotrimin polypeptide having amino acid residues 1 to 344 of Figure 222 (SEQ ID N0:523), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA4331b-1237, deposited with the ATCC under accession number ATCC 209487, alternatively the coding sequence of clone DNA43316-1237, deposited under accession number ATCC 209487.
In yet another embodiment, the invention provides isolated PR0337 polypeptide.
In particular, the invention provides isolated native sequence PR0337 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 344 of Figure 222 (SEQ ID NO:523). Native PR0337 polypeptides with or without the native signal sequence (amino acids 1 to about 28 in Figure 222 (SEQ ID
N0:523), and with or without the initiating methionine are specifically included. Alternatively, the invention provides a PR0337 polypeptide encoded by the rnicleic acid deposited under accession number ATCC 209487.
In yet another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequences identified in Figure 223 as DNA42301 (SEQ 1D N0:524).
87. PR0403 Applicants have identified a cDNA clone (DNA55800-1263) that encodes a novel polypeptide, designated in the present application as "PR0403".
In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 80%
sequence identity to (a) a DNA molecule encoding a PR0403 polypeptide comprising the sequence of amino acids 1 to 736 of Figure 225 {SEQ >D N0:526), or {b) the complement of the DNA
molecule of (a). The sequence identity preferably is about 85 % , more preferably about 90 %, most preferably about 95 % . In one aspect, the isolated nucleic acid has at least about 80~, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95% sequence identity with a polypeptide having amino acid residues 1 to 736 of Figure 225 (SEQ ID
N0:526). Preferably, the highest degree of sequence identity occurs within:
(1) the putative N-glycosylatation sites (amino acid residues 132, 136, 177, 237, 282, 349, 505, 598 and 60b; (2) Cys residues conserved with the Kell blood group protein family (amino acid residues 65, 70, 88 and 96) and the putative zinc binding motif (amino acid residues 570-579}.

In a further embodiment, the isolated nucleic acid molecule comprises DNA
encoding a PR0403 polypeptide having amino acid residues 1 to 736 of Figure 225 (SEQ ID N0:52b), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under ai least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA55800-1263, deposited with the ATCC under accession number ATCC 209b80, alternatively the coding sequence of clone DNA55800-1263, deposited under accession number ATCC 209680.
In yet another embodiment, the invention provides isolated PR0403 polypeptide.
In particular, the invention provides isolated native sequence PR0403 poIypeptide, which in one embodiment, includes an amino acid sequence corr~rising residues 1 to 736 of Figure 225 (SEQ ID N0:526). Native PR0403 polypeptides with or the initiating methionine are specifically included. Alter atively, the invention provides a PR0403 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209680.
In yet another embodiment, the invention provides an expressed sequence tag (ES'I~~and other sequence frxgtnertis comprising the nucleotide sequences identified herein as DNA34415 (Figures 226A-B; SEQ ID N0:527);
DNA49830 (Figure 227 ; SEQ ID N0:528) and DNA49831 (Figure 228; SEQ ID
N0:529).
88. Additional Embodiments In other embodiments of the present invention; the invention provides vectors comprising DNA encoding any of the above or below described polypeptides. A host cell comprising any such vector is also provided. By way of example, the host cells may be CHO cells, E. coli; or yeast. A process for producing any of the above or below described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypepcide from the cell culture.
In other embodiments, the invention provides chimeric molecules comprising any of the above or below described polypeptides fused to a heterologous polypeptide or amino acid sequence. An example of such a chimeric molecule comprises atry of the above or below described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.
In another embodiment, the invention provides an antibody which specifically binds to any of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody.
In yet other embodiments, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences, wherein those probes may be derived from any of the above or below described nucleotide sequences.
BRIEF DESCRIPT~QN OF THE D_~~tAWINGS_ Figure 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequence PR0213 cDNA, wherein SEQ
ID NO:1 is a clone designated herein as "UNQ187" and/or "DNA30943-1163".
Figure 2 shows the amino acid sequence (SEQ B7 N02) rived from the coding sequence of 5EQ ID NO;1 shown in Figure 1.
Figure 3 shows a nucleotide sequence (SEQ ID N0:6) of a native sequence PR0274 cDNA, wherein SEQ
ID N0:6 is a clone designated herein as °UNQ241" andJor "DNA39987-11$4".
Figure 4 shows the amino acid sequence (SEQ >D N0:7) derived from the coding sequence of SEQ ID N0:6 shown in Figure 3.

Figure 5 shows an EST nucleotide sequence designated herein as DNA17873 (SEQ
1D N0:8).
Figure 6 shows an EST nucleotide sequence designated herein as DNA36157 (SEQ
iD N0:9).
Figure 7 shows an EST nucleotide sequence designated herein as DNA28929 (SEQ
ID NO:10).
Figure 8 shows a nucleotide sequence (SEQ ID N0:18) of a native sequence PR0300 cDNA, wherein SEQ
ID NO:I8 is a clone designated herein as "UNQ263" and/or "DNA40625-1189".
Figure 9 shows the amino acid sequence (SEQ ID N0:19) derived from the coding sequence of SEQ ID
N0:18 shown in Figure 8.
Figure 10 shows a nucleotide sequence (SEQ ID N0:27) of a native sequence PR0284 cDNA, wherein SEQ
ID N0:27 is a clone designated herein as "UNQ247" andlor "DNA23318-1211 ".
Figure 11 shows the amino acid sequence (SEQ ID N0:28) derived from the coding sequence of SEQ ID
N0:27 shown in Figure 10.
Figure 12 shows an EST nucleotide sequence designated herein as DNA12982 (SEQ
ID N0:29).
Figure 13 shows an EST nucleotide sequence designated herein as DNAI5886 (SEQ
ID N0:30).
Figure 14 shows a nucleotide sequence (SEQ ID N0:35) of a native sequence PR0296 cDNA, wherein SEQ
ID N0:35 is a clone designated herein as "UNQ260" andlor "DNA39979-1213".
Figure 15 shows the amino acid sequence (SEQ ID N0:36) derived from the coding sequence of SEQ ID
N0:35 shown in Figure 14.
Figure 16 shows an EST nucleotide sequence designated herein as DNA23020 (SEQ
ID N0:3?).
Figure 17 shows an EST nucleotide sequence designated herein as DNA2197I (SEQ
ID N0:38).
Figure 18 shows an EST nucleotide sequence designated herein as DNA29037 (SEQ
ID N0:39).
Figure 19 shows a nucleotide sequence (SEQ ID N0:44) of a native sequence PR0329 cDNA, wherein SEQ
ID N0:44 is a clone designated herein as "UNQ291" and/or "DNA40594-1233".
Figure 20 shows the amino acid sequence (SEQ 1D N0:45) derived from the coding sequence of SEQ ID
N0:44 shown in Figure 19.
Figure 21 shows a nucleotide sequence (SEQ ID N0:51) of a native sequence PR0362 cDNA, wherein SEQ
ID N0:51 is a clone designated herein as "UNQ317" andlor "DNA45416-1251".
Figure 22 shows the amino acid sequence (SEQ ID N0:52) derived from the coding sequence of SEQ ID
N0:51 shown in Figure 21.
Figure 23 shows a nucleotide sequence (SEQ D7 N0:58) of a native sequence PR0363 cDNA, wherein SEQ
ID N0:58 is a clone designated herein as "UNQ318" and/or "DNA45419-1252".
Figure 24 shows the amino acid .sequence (SEQ ID N0:59) derived from the coding sequence of SEQ 1D
N0:58 shown in Figure 23.
Figure 25 shows a nucleotide sequence (SEQ ID N0:63) of a native sequence PR0868 cDNA, wherein SEQ
ID N0:63 is a clone designated herein as "UNQ437" and/or "DNA52594-1270".
Figure 26 shows the amino acid sequence (SEQ ID N0:64) derived from the coding sequence of SEQ ID
N0:63 shown in Figure 25.
Figure 27 shows a nucleotide sequence (SEQ 1D N0:68) of a native sequence PR0382 cDNA, wherein SEQ
ID N0:68 is a clone designated herein as "UNQ323" and/or "DNA45234-1277".
Figure 28 shows the amino acid sequence (SEQ ID N0:69) derived from the coding sequence of SEQ ID
N0:68 shown in Figure 27.

Figure 29 shows a nucleotide sequence (SEQ ID N0:73) of a native sequence PR0545 cDNA, wherein SEQ
ID N0:73 is a clone designated herein as "UNQ346" andlor "DNA49624-1279".
Figure 30 shows the, amino acid sequence (SEQ ID N0:74) derived from the coding sequence of SEQ ID
N0:73 shown in Figure 29.
Figure 31 shows an EST nucleotide sequence designated herein as DNA13217 {SEQ
ID N0:75).
Figure 32 shows a nucleotide sequence (SEQ 1D N0:84) of a native sequence PR0617 cDNA, wherein SEQ
ID N0:84 is a clone designated herein as "UNQ353" andlor "DNA48309-1280".
Figure 33 shows the amino acid sequence (SEQ ID N0:85) derived from the coding sequence of SEQ ID
N0:84 shown in Figure 32:
Figure 34 shows a nucleotide sequence (SEQ ID N0:89) of a native sequence PR0700 cDNA, wherein SEQ
ID N0:89 is a clone designated herein as "UNQ364" andlor "DNA46776-1284".
Figure 35 shows the amino acid sequence {SEQ ID N0:90) derived from the coding sequence of SEQ ID
N0:89 shown in Figure 34:
Figure 36 shows a nucleotide sequence (SEQ B7 N0:96) of a native sequence PR0702 cDNA, wherein SEQ
ID N0:96 is a clone designated herein as "UNQ366",and/or "DNA50980-1286".
Figure 37 shows the amino acid sequence (SEQ ID N0:97) derived from the coding sequence of SEQ ID
N0:96 shown in Figure 36.
Figure 38 shows a nucleotide sequence (SEQ ID NO:101) of a native sequence PR0703 cDNA, wherein SEQ ID NO:101 is a clone designated herein as "UNQ367" and/or "DNA50913-1287".
Figure 39 shows the amino acid sequence (SEQ ID N0:102) derived from the coding sequence of SEQ ID
NO:lOI shown in Figure 38.
Figure 40 shows a nucleotide sequence (SEQ ID N0:108) of a native sequence PR0705 cDNA; wherein SEQ ID N0:108 is a clone designated herein as "UNQ369" and/or "DNA50914-1289".
Figure 41 shows the amino acid sequence (SEQ 1D N0:109) derived from the coding sequence of SEQ ID
N0:108 shown in Figure 40.
Figures 42A-B show a nucleotide sequence (SEQ )D N0:113) of a native sequence PR0708 cDNA, wherein SEQ ID N0:113 is a clone designated herein as "UNQ372" and/or "DNA48296-1292".
Figure 43 shows the amino acid sequence (SEQ ID N0:114) derived from the coding sequence of SEQ ID
N0:113 shown in Figures 42A-B.
Figure 44 shows a nucleotide sequence (SEQ ID NO:118) of a native sequence PR0320 cDNA; wherein SEQ ID NO:118 is a clone designated herein as "UNQ281" andlor "DNA32284-1307".
Figure 45 shows the amino acid sequence (SEQ ID N0:119) derived from the coding sequence of SEQ ID
N0:118 shown in Figure 44.
Figure 46 shows a nucleotide sequence (SEQ ID N0:123) of a native sequence PR0324 cDNA, wherein SEQ ID N0:123 is a clone designated herein as "UNQ285" and/or "DNA36343-1310".
Figure 47 shows the amino acid sequence (S$Q ID NO:I24) derived from the coding sequence of SEQ ID
NOa23 shown in Figure 46.
Figure 48 shows a nucleotide sequence (SEQ ID N0:131) of a native sequence PR035I cDNA, wherein SEQ ID N0:131 is a clone designated herein as "UNQ308" and/or "DNA40571-1315".

WO 99/46281 PCT/lJS99I05028 Figure 49 shows the amino acid sequence {SEQ ID N0:132) derived from the coding sequence of SEQ ID
N0:131 shown in Figure 48.
Figure 50 shows a nucleotide sequence (SEQ ID N0:136) of a native sequence PR0352 cDNA, wherein SEQ ID NO:136 is a clone designated herein as "UNQ309" and/or "DNA41386-1316".
Figure 51 shows the amino acid sequence {SEQ ID N0:137) derived from the coding sequence of SEQ ID
NO:I36 shown in Figure 50.
Figure S2 shows a nucleotide sequence (SEQ ID N0:144) of a native sequence PR0381 cDNA, wherein SEQ ID N0:144 is a clone designated herein as "UNQ322" and/or "DNA44194-1317".
Figure 53 shows the amino acid sequence (SEQ ID N0:145) derived from the coding sequence of SEQ ID
N0:144 shown in Figure 52 Figure 54 shows a nucleotide sequence (SEQ 1D N0:149) of a native sequence PR0386 cDNA, wherein SEQ ID N0:149 is a clone designated herein as "UNQ326" andlor "DNA45415-1318".
Figure 55 shows the amino acid sequence (SEQ ID NO:150) derived from the coding sequence of SEQ ID
N0:149 shown in Figure 54.
Figure 56 shows an EST nucleotide sequence designated herein as DNA23350 (SEQ
ID NO:151).
Figure 57 shows an EST nucleotide sequence designated herein as DNA23536 (SEQ
ID NO:1S2).
Figure 58 shows a nucleotide sequence (SEQ ID N0:156) of a native sequence PR0540 cDNA, wherein SEQ ID N0:156 is a clone designated herein as "UNQ341" andlor "DNA44189-1322".
Figure 59 shows the amino acid sequence (SEQ ID N0:157) derived from the coding sequence of SEQ ID
N0:156 shown in Figure 58.
Figure 60 shows a nucleotide sequence (SEQ ID N0:161) of a native sequence PR0615 cDNA, wherein SEQ ID N0:161 is a clone designated herein as "UNQ352" andlor "DNA48304-1323".
Figure 61 shows the amino acid sequence (SEQ ID NO:I62) derived from the coding sequence of SEQ ID
N0:161 shown in Figure 60.
Figure 62 shows a nucleotide sequence (SEQ ID N0:168) of a native sequence PR0618 cDNA, wherein SEQ ID N0:168 is a clone designated herein as "UNQ354" and/or "DNA49152-1324".
Figure 63 shows the amino acid sequence (SEQ ID N0:169} derived from the coding sequence of SEQ ID
N0:168 shown in Figure 62.
Figure 64 shows an EST nucleotide sequence designated herein as DNA35597 (SEQ
1D N0:170).
Figure 65 shows a nucleotide sequence (SEQ ID N0:177) of a native sequence PR0719 cDNA, wherein SEQ ID N0:177 is a clone designated herein as "UNQ387" andlor "DNA49646-1327".
Figure 66 shows the amino acid sequence (SEQ ID N0:178) derived from the coding sequence of SEQ ID
N0:177 shown in Figure 65.
Figure 67 shows a nucleotide sequence (SEQ ID N0:182) of a native sequence PRO724 cDNA, wherein SEQ ID N0:182 is a clone designated herein as "UNQ389" and/or "DNA49631-1328".
Figure 68 shows the amino acid sequence (SEQ ID N0:183) derived from the coding sequence of SEQ ID
N0:182 shown in Figure 67.
Figure 69 shows a nucleotide sequence (SEQ ID N0:189) of a native sequence PR0772 cDNA, wherein SEQ ID N0:189 is a clone designated herein as "UNQ410" and/or "DNA49645-1347".

Figure 70 shows the amino acid sequence (SEQ ID N0:190) derived from the coding sequence of SEQ ID
N0:189 shown in Figure 69.
Figure 71 shows an EST nucleotide sequence designated herein as DNA43509 (SEQ
ID N0:191).
Figure 72 shows a nucleotide sequence (SEQ 1D N0:195) of a native sequence PR0852 cDNA, wherein SEQ ID N0:195 is a clone designated herein as "UNQ418" and/or "DNA45493-1349".
Figure 73 shows the amino acid sequence (SEQ ID N0:19b) derived from the coding sequence of SEQ ID
N0:195 shown in Figure 72.
Figure 74 shows a nucleotide sequence (SEQ ID N0:205) of a native sequence PR0853 cDNA, wherein SEQ ID N0:205 is a clone designated herein as "UNQ419" andlor "DNA48227-1350".
Figure 75 shows the amino acid sequence (SEQ ID N0:206) derived from the coding sequence of SEQ ID
N0:205 shown in Figure 74.
Figures 76A-B show a nucleotide sequence (SEQ ID N0:210) of a native sequence PR0860 cDNA, wherein SEQ 1D N0:210 is a clone designated herein as "UNQ421" and/or "DNA41404-1352".
Figure 77 shows the amino acid sequence {SEQ ID N0:211) derived from the coding sequence of SEQ ID
N0:210 shown in Figures 76A-B.
Figure 78 shows a nucleotide sequence (SEQ ID N0:2i5) of a native sequence PR0846 cDNA, wherein SEQ ID N0:215 is a clone designated herein as "UNQ422" andlor "DNA44196-1353".
Figure 79 shows the amino acid sequence (SEQ ID N0:216) derived from the coding sequence of SEQ ID
N0:215 shown in Figure 78.
Figure 80 shows a nucleotide sequence (SEQ ID N0:220) of a native sequence PR0862 cDNA, wherein SEQ ID N0:220 is a clone designated herein as "UNQ424" andlor "DNA52187-1354".
Figure 81 shows the amino acid sequence (SEQ ID N0:221) derived from the coding sequence of SEQ ID
N0:220 shown in Figure 80.
Figure 82 shows a nucleotide sequence (SEQ ID N0:225) of a native sequence PR0864 cDNA, wherein SEQ ID N0:225 is a clone designated herein as "UNQ426" and/or "DNA48328-1355".
Figure 83 shows the amino acid sequence {SEQ ID N0:226) derived from the coding sequence of SEQ ID
N0:225 shown in Figure 82.
Figure 84 shows a nucleotide sequence (SEQ ID N0:230) of a native sequence PR0792 cDNA, wherein SEQ ID N0:230 is a clone designated herein as "UNQ431" andlor "DNA56352-1358".
Figure 85 shows the amino acid sequence {SEQ ID N0:231) derived from the coding sequence of SEQ ID
N0:230 shown in Figure 84.
Figure 86 shows a nucleotide sequence (SEQ ID N0:235) of a native sequence PR0866 cDNA, wherein SEQ ID N0:235 is a clone designated herein as "UNQ435" andlor "DNA53971-1359".
Figure 87 shows the amino acid sequence (SEQ ID N0:236) derived from the coding sequence of SEQ ID
N0:235 shown in Figure 86.
Figure 88 shows a nucleotide sequence (SEQ ID N0:244) of a native sequence PR0871 cDNA, wherein SEQ ID N0:244 is a clone designated herein as "UNQ438" andlor "DNA50919-1361 ".
Figure 89 shows the amino acid sequence (SEQ ID N0:245) derived from the coding sequence of SEQ ID
N0:244 shown in Figure 88.

Figure 90 shows a nucleotide sequence (SEQ ID N0:253) of a native sequence PR0873 cDNA, wherein SEQ ID N0:253 is a clone designated herein as "UNQ440" and/or "DNA44179-1362".
Figure 91 shows the amino acid sequence (SEQ ID N0:254) derived from the coding sequence of SEQ ID
N0:253 shown in Figure 90.
Figure 92 shows a nucleotide sequence (SEQ ID N0:258) of a native sequence PR0940 cDNA, wherein SEQ ID N0:258 is a clone designated herein as "UNQ477" and/or "DNA54002-1367".
Figure 93 shows the amino acid sequence (SEQ ID N0:259) derived from the coding sequence of SEQ ID
N0:258 shown in Figure 92.
Figure 94 shows a nucleotide sequence (SEQ ID N0:263) of a native sequence PR0941 cDNA, wherein SEQ ID N0:263 is a clone designated herein as "UNQ478" andlor "DNA53906-1368".
Figwe 95 shows the amino acid sequence (SEQ ID N0:264) derived from the coding sequence of SEQ ID
N0:263 shown in Figure 94.
Figure 96 shows an EST nucleotide sequence designated herein as DNA6415 (SEQ
ID N0:265).
Figure 97 shows a nucleotide sequence (SEQ ID N0:269) of a native sequence PR0944 cDNA, wherein SEQ ID N0:269 is a clone designated herein as "UNQ481" andlor "DNA52185-1370".
Figure 98 shows the amino acid sequence (SEQ ID N0:270) derived from the coding sequence of SEQ ID
N0:269 shown in Figure 97.
Figure 99 shows an EST nucleotide sequence designated herein as DNA14007 (SEQ
ID N0:271).
Figure 100 shows an EST nucleotide sequence designated herein as DNA12773 (SEQ
ID N0:272).
Figure 101 shows an EST nucleotide sequence designated herein as DNA12746 (SEQ
ID N0:273).
Figure 102 shows an EST nucleotide sequence designated herein as DNA12834 (SEQ
ID N0:274).
Figure 103 shows an EST nucleotide sequence designated herein as DNA12846 (SEQ
ID N0:275).
Figure 104 shows an EST nucleotide sequence designated herein as DNA13104 (SEQ
ID N0:276).
Figure 105 shows an EST nucleotide sequence designated herein as DNA13259 (SEQ
ID N0:277).
Figure 106 shows an EST nucleotide sequence designated herein as DNA13959 {SEQ
ID N0:278).
Figure 107 shows an EST nucieotide sequence designated herein as DNA13961 (SEQ
ID N0:279).
Figure 108 shows a nucleotide sequence (SEQ ID N0:283) of a native sequence PR0983 cDNA, wherein SEQ ID N0:283 is a clone designated herein as "UNQ484" andlor "DNA53977-1371".
Figure 109 shows the amino acid sequence (SEQ ID N0:284) derived from the coding sequence of SEQ ID
N0:283 shown in Figure 108.
Figure 110 shows an EST nucleotide sequence designated herein as DNA17130 (SEQ
ID N0:285).
Figure 11 i shows an EST nucleotide sequence designated herein as DNA23466 (SEQ ID N0:286).
Figure 112 shows an EST nucleotide sequence designated herein as DNA26818 (SEQ
ID N0:287).
Figure 113 shows an EST nucleotide sequence designated herein as DNA37618 (SEQ
ID N0:288).
Figure 114 shows an EST nucleotide sequence designated herein as DNA41732 (SEQ
ID N0:289).
Figure 115 shows an EST nucleotide sequence designated herein as DNA45980 (SEQ
ID N0:290).
Figure lib shows an EST nucleotide sequence designated herein as DNA46372 (SEQ
1D N0:291).
Figure 1i7 shows a rntcleotide sequence (SEQ ID N0:295) of a native sequence PR01057 cDNA, wherein SEQ ID N0:295 is a clone designated herein as "UNQ522" and/or "DNA57253-1382".

Figure 118 shows the amino acid sequence (SEQ ID N0:296) derived from the coding sequence of SEQ ID
NO:295 shown in Figure I 17.
Figure 119 shows a nucleotide sequence (SEQ ID N0:300) of a native sequence PR01071 cDNA, wherein SEQ ID NO:300 is a clone designated herein as "UNQ528" andlor "DNA58847-1383".
Figure 120 shows the amino acid sequence (SEQ ID N0:301) derived from the coding sequence of SEQ TD
N0:300 shown in Figure 119.
Figure I21 shows a nucleotide sequence (SEQ ID N0:30Z) of a native sequence PR01072 cDNA, wherein SEQ ID N0:302 is a clone designated herein as "UNQ529" and/or "DNA58747-1384".
Figure 122 shows the amino acid sequence (SEQ ID N0:303) derived from the coding sequence of SEQ ID
N0:302 shown in Figure 121.
Figure 123 shows an EST nucleotide sequence designated herein as DNA40210 (SEQ
ID N0:304).
Figure 124 shows a nucleotide sequence (SEQ ID N0:308) of a native sequence PR01075 cDNA, wherein SEQ ID N0:308 is a clone designated herein as "UNQ532" andlor "DNAS?689-1385".
Figure 125 shows the amino acid sequence (SEQ ID N0:309) derived from the coding sequence of SEQ ID
N0:308 shown in Figure I24.
Figure 126 shows an EST nucleotide sequence designated herein as DNA13059 (SEQ
ID N0:310).
Figure 127 shows an EST nucleotide sequence designated herein as DNA19463 (SEQ
ID N0:311).
Figure 128 shows a nucleotide sequence (SEQ ID N0:32i) of a native sequence PR0181 cDNA, wherein SEQ ID N0:321 is a clone designated herein as "UNQ155" andlor "DNA23330-1390".
Figure 129 shows the amino acid sequence ($EQ ID N0:322) derived from the coding sequence of SEQ ID
N0:321 shown in Figure i28.
Figure 130 shows an EST nucleotide sequence designated herein as DNA13242 (SEQ
ID N0:323).
Figure 131 shows a nucleotide sequence (SEQ ID N0:329) of a native sequence PR0195 cDNA, wherein SEQ ID N0:329 is a clone designated herein as "UNQ169" and/or "DNA26847-1395".
Figure 132 shows the amino acid sequence (SEQ ID N0:330) derived from the coding sequence of SEQ ID
N0:329 shown in Figure 131.
Figure 133 shows an EST nucleotide sequence designated herein as DNA15062 (SEQ
ID N0:331).
Figure i34 shows an EST nucleotide sequence designated herein as DNAi3I99 (SEQ
ID N0:332).
Figure 135 shows a nucleotide sequence (SEQ ID N0;336) of a native sequence PR0865 cDNA, wherein SEQ ID N0:336 is a clone designated herein as "UNQ434' and/or "DNA53974-1401".
Figure 136 shows the amino acid sequence (SEQ ID N0:337) derived from the coding sequence of SEQ ID
N0:336 shown in Figure 135.
Figure 137 shows an EST nucleotide sequence designated herein as DNA37642 (SEQ
ID N0:338).
Figure 138 shows a nucleotide sequence (SEQ ID N0:345) of a native sequence PR0827 cDNA, wherein SEQ ID N0:345 is a clone designated herein as "UNQ468" andlor "DNA57039-1402".
Figure 139 shows the amino acid sequence (SEQ 1D N0:346) derived from the coding sequence of SEQ ID
N0:345 shown in Figure 138. .
Figure 140 shows an EST nucleotide sequence designated herein as DNA47?51 (SEQ
ID N0:347).
Figure 141 shows a rntcleotide sequence (SEQ ID N0;351) of a native sequence PR01114 cDNA, wherein SEQ ID N0:35I is a clone designated herein as "UNQ557" and/or "DNA57033-1403".
ios r WO 99/46281 PCTlUS99/05028 Figure 142 shows the amino acid sequence (SEQ ID N0:352) derived from the coding sequence of SEQ ID
N0:351 shown in Figure 141.
Figure 143 shows an EST nucleotide sequence designated herein as DNA48466 (SEQ
1D N0:353).
Figure 144 shows a nucleotide sequence {SEQ ID N0:357) of a native sequence PR023? cDNA, wherein SEQ ID N0:357 is a clone designated herein as "UNQ211 " and/or °DNA34353-1428" .
Figure I45 shows the amino acid sequence (SEQ ID N0:358) derived from the coding sequence of SEQ ID
N0:357 shown in Figure 144.
Figure 146 shows a nucleotide sequence (SEQ ID N0:362) of a native sequence PR0541 cDNA, wherein SEQ ID N0:362 is a clone designated herein as "UNQ342" andlor "DNA45417-1432"
Figure 147 shows the amino acid sequence (SEQ ID N0:363) derived from the coding sequence of SEQ ID
N0:362 shown in Figure 146.
Figure 148 shows a nucleotide sequence (SEQ ID N0:369) of a native sequence PR0273 cDNA, wherein SEQ ID N0:369 is a clone designated herein as "UNQ240" andlor "DNA39523-1192".
Figure 149 shows the amino acid sequence (SEQ ID N0:370) derived from the coding sequence of SEQ ID
N0:369 shown in Figure 148.
Figure 150 shows a nucleotide sequence (SEQ ID N0:374) of a native sequence PR0701 cDNA, wherein SEQ ID N0:374 is a clone designated herein as "UNQ365" and/or "DNA44205-1285".
Figure 151 shows the amino acid sequence (SEQ ID N0:375) derived from the coding sequence of SEQ ID
N0:374 shown in Figure 150.
Figure 152 shows a nucleotide sequence (SEQ ID N0:379) of a native sequence PR0704 cDNA, wherein SEQ ID N0:379 is a clone designated herein as "UNQ368" and/or "DNA5091I-1288".
Figure 153 shows the amino acid sequence (SEQ ID N0:380) derived from the coding sequence of SEQ ID
N0:379 shown in Figure 152.
Figure 154 shows a nucleotide sequence (SEQ ID N0:384) of a native sequence PRO?06 cDNA, wherein SEQ ID N0:384 is a clone designated herein as "UNQ370" and/or "DNA48329-1290".
Figure 155 shows the amino acid sequence (SEQ ID N0:385) derived from the coding sequence of SEQ ID
N0:384 shown in Figure 154.
Figure 156 shows a nucleotide sequence (SEQ ID N0:389) of a native sequence PR0707 cDNA, wherein SEQ ID N0:389 is a clone designated herein as "UNQ371" and/or "DNA48306-1291".
Figure 157 shows the amino acid sequence (SEQ ID N0:390) derived from the coding sequence of SEQ ID
N0:389 shown in Figure I56.
Figure 158 shows a nucleotide sequence (SEQ ID N0:394) of a native sequence PR0322 cDNA, wherein SEQ ID N0:394 is a clone designated herein as "UNQ283" andlor "DNA48336-1309".
Figure 159 shows the amino acid sequence (SEQ ID N0:395) derived from the coding sequence of SEQ ID
N0:394 shown in Figure 158.
Figure 160 shows a nucleotide sequence (SEQ ID N0:399) of a native sequence PR0526 cDNA, wherein SEQ ID N0:399 is a clone designated herein as "UNQ330" and/or °DNA44184-1319".
Figure 161 shows the amino acid sequence (SEQ ID N0:400) derived from the coding sequence of SEQ ID
N0:399 shown in Figure 160.

Figure 162 shows a nucleotide seqticncc (SEQ ID N0:404) of a native sequence PR0531 eDNA, wherein SEQ ID N0:404 is a clone designated herein as "UNQ332' and/or "DNA48314-1320".
Figure 153 shows the amino acid sequence (SEQ 1D N0:44S) derived from the coding sequence of SEQ ID
N0:404 shown in Figure 162.
Figure 164 shows a nucleotide sequence (SEQ ID N0:4139) of a native sequence FROS34 cDNA, wherein S SEQ ID N0:409 is a clone designated herein as "UNQ335" andlor "DNA48333-1321".
Figure 1b5 shows the amigo acid sequence {SEQ 1D N0:410) derived from the coding sequence of SEQ ID
N0:409 shown in Figure 164.
Figure I66 shows a nucleotide sequence (SEQ ID N0:414) of a native sequence PR0697 eDNA, wherein SEQ 1D N0:414 is a clone designated herein as "UNQ36l" and/or "DNA50920-1325".
Figure i67 shows the amino acid sequence (SEQ ID N0:415) derived from the coding sequence of SEQ ID
N0:414 shown in Figure 166_ ,_ Figure 168 shows a nucleotide sequence (SEQ ID N0:4i9) of a native sequence PR0717 cDNA, wherein SEQ ID N0:419 is a clone designated herein as "UNQ385" andlor "DNA50988-1326".
Figure 169 shows the amino acid sequence (SEQ ID N0:420) derived from the coding sequence of SEQ ID
1 S N0:419 shown in Figure l 68.
Figures 170A-B show a nucleotide sequence (SEQ ID N0:424) of a native sequence PR0731 cDNA, wherein SEQ ID N0:424 is a clone designated herein as "UNQ395' andlor "DNA48331-1329".
Fgure 171 shows the amino acid sequence (SEQ ID N0:425) derived from the coding sequence of SEQ ID
N0:424 shown in Figures 170A-B.
Figure 172 shows a nucleotide sequence (SEQ ID N0:429) of a native sequence PR0218 eDNA, wherein SEQ ID N0:429 is a clone designated herein as "UNQ192" andlor "DNA30867-1335".
Figure 173 SNOWS the amino acid sequence (SEQ ID N0:430) derived from the coding sequence of SEQ 1D
N0:429 shown in Figure I?2.
Figure I?4 shows an EST nucleotide sequence designated herein as DNA14472 (SEQ
ID N0:431)_ Figure 175 shows an EST nucleotide sequence designated herein as DNA15846 {SEQ
ID N0:432).
Figures I76A-B show a nucleotide sequence (SEQ ID N0:436) of a native sequence PR0768 cDNA, wherein SEQ ID N0:436 is a clone designated herein as "UNQ406" andlor "DNASS737-1345".
Figure 177 shows the amino acid sequence (SEQ ID N0:437) derived from the coding sequence of SEQ ID
N0:436 shown in Figures i76A-B.
Figure 178 shows a nucleotide, sequenex (SEQ ID N0:441) of a native sequence PR0771 eDNA, wherein SEQ ID N0:441 is a clone designated herein as "UNQ409" andlor "DNA49829-I346".
Figure 179 shows the amino acid sequence (SEQ ID N0:442) derived froth the coding sequence of SEQ ID
N0:441 shown in Figure 178.
Figures 180A-B show a nucleotide sequence (SEQ iD N0:446) of a native sequence PR0733 cDNA, 3S wherein SEQ ID N0:446 is a clone designated herein as "UNQ411 " andlor "DNA52196-1348".
Figure 181 shows the arrtino acid sequence (SEQ ID N0:447) derived from the coding sequence of SEQ ID
N0:446 shown in Figures 180A-B.
Figure 182 shows a nucleotide sequence (SEQ ID N0:451) of a native seauenex PR0162 eDNA, wherein SEQ ID N0:451 is a clone designated herein as "UNQ429" and/or "DNAS6965-1356".

Figure 183 shows the amino acid sequence (SEQ ID N0:452) derived from the coding sequence of SEQ ID
N0:451 shown in Figwe 182.
Figure 184 shows a nucleotide sequence (SEQ ID N0:453) of a native sequence PRO?88 cDNA, wherein SEQ ID N0:453 is a clone designated herein as "UNQ430" andlor "DNA56405-135?".
Figure 185 shows the amino acid sequence (SEQ ID N0:454) derived from the coding sequence of SEQ ID
N0:453 shown in Figure 184.
Figure 18b shows a nucleotide sequence (SEQ ID N0:455) of a native sequence PR01008 cDNA, wherein SEQ ID N0:455 is a clone designated herein as "UNQ492" and/or "DNA57530-1375".
Figure 187 shows the amino acid sequence (SEQ 1D N0:456) derived from the coding sequence of SEQ ID
N0:455 shown in Figure 186.
Figure 188 shows an EST nucleotide sequence designated herein as DNA16508 (SEQ
ID N0:45?).
Figures 189A-B show a nucleotide sequence (SEQ TD N0:458) of a native sequence PR01012 cDNA, wherein SEQ ID N0:458 is a clone designated herein as "UNQ495" and/or "DNA56439-1376".
Figure 190 shows the amino acid sequence (SEQ ID N0:459) derived from the coding sequence of SEQ ID
N0:458 shown in Figures 189A-B.
Figure 191 shows a nucleotide sequence (SEQ ID N0:463) of a native sequence PR01014 cDNA, wherein SEQ ID N0:463 is a clone designated herein as "UNQ497" and/or "DNA56409-1377".
Figure 192 shows the amino acid sequence (SEQ ID N0:464) derived from the coding sequence of SEQ ID
NO:463 shown in Figure 191.
Figure .193 shows a nucleotide sequence (SEQ ID N0:465) of a native sequence PR01017 cDNA, wherein SEQ ID N0:4b5 is a clone designated herein as "UNQ500" andlor "DNA56112-1379".
Figure 194 shows the amino acid sequence (SEQ ID N0:466) derived from the coding sequence of SEQ ID
N0:465 shown in Figure 193.
Figure 195 shows a nucleotide sequence (SEQ ID N0:467) of a native sequence PR0474 cDNA, wherein SEQ ID N0:467 is a clone designated herein as "UNQ502" andlor "DNA56045-1380", Figure 196 shows the amino acid sequence (SEQ ID N0:468) derived from the coding sequence of SEQ ID
N0:467 shown in Figure 195.
Figure 197 shows a nucleotide sequence (SEQ ID N0:469) of a native sequence PR01031 cDNA, wherein SEQ ID N0:469 is a clone designated herein as "UNQ516" and/or "DNA59294-1381".
Figure 198 shows the amino acid sequence (SEQ ID N0:470) derived from the coding sequence of SEQ ID
N0:469 shown in Figure 197.
Figure 199 shows a nucleotide sequence (SEQ ID N0:471) of a native sequence PR0938 cDNA, wherein SEQ 1D N0:471 is a cione designated herein as "UNQ475" and/or "DNA56433-1406".
Figure 200 shows the amino acid sequence (SEQ ID N0:4?2) derived from the coding sequence of SEQ ID
N0:471 shown in Figure 199.
Figure 201 shows a nucleatide sequence (SEQ ID N0:476) of a native sequence PR01082 cDNA, wherein SEQ ID N0:476 is a clone designated herein as "UNQ539" andlor "DNA53912-1457".
Figure 202 shows the amino acid sequetux (SEQ ID N0:477) derived from the coding scquence of SEQ ID
N0:4?6 shown in Figure 201.

WO 99146281 PCTlUS99/05028 Figure 203 shows a nucleotide sequence (SEQ ID N(0:482) of a native sequence PR01083 cDNA, wherein SEQ ID N0:482 is a clone designated herein as "UNQ540" andlor "DNA50921-14$8".
Figure 204 shows the amino acid sequence (SEQ ID N0:483) derived from the coding sequence of SEQ ID
N0:482 shown in Figure 203.
Figure 205 shows an EST nucleotide sequence designated herein as DNA24256 (SEQ
ID N0:484).
Figure 206 shows a nucleotide sequence {SEQ ID N0:487) of a native sequence PR0200 cDNA, wherein SEQ ID N0:487 is a clone designated herein as "UNQ174" and/or °DNA29101-1122".
Figure 207 shows the amino acid sequence (SEQ ID N0:488) derived from the coding sequence of SEQ ID
N0:487 shown in Figure 206.
Figure 208 shows a nucleotide sequence {SEQ ID N0:495) of a native sequence PR0285 cDNA, wherein SEQ ID N0:495 is a clone designated herein as "DNA4002I-l I54".
Figure 209 shows the amino acid sequence (SEQ ID N0:496) derived from the coding sequence of SEQ ID
N0:495 shown in Figure 208.
Figures 210A-B show a nucleotide sequence (SEQ ID N0:497) of a native sequence PR0286 cDNA, wherein SEQ ID N0:497 is a clone designated herein as "DNA42663-1154~.
Figure 211 shows the amino acid sequence (SEQ ID N0:498) derived from the coding sequence of SEQ ID
N0:497 shown in Figures 210A-B.
Figure 212 shows a nucleotide sequence (SEQ ID N0:505) of a native sequence PR0213-1 cDNA, wherein SEQ ID N0:505 is a clone designated herein as "DNA30943-1-I 163-1 ".
Figure 213 shows the amino acid sequetxe (SEQ ID N0:506} derived from the coding sequence of SEQ 3D
N0:505 shown in Figure 212.
Figure 214 shows a nucleotide sequence (SEQ ID N0:507) of a native sequence PR01330 cDNA, wherein SEQ ID N0:507 is a clone designated herein as "DNA6490?-1163-1".
Figure 215 shows the amid acid sequer~e (SEQ ID N0:508) derived from the coding sequence of SEQ ID
N0:507 shown in Figure 214.
Figure 216 shows a rntcleotide sequence (SEQ ID N0:509) of a native sequence PR01449 cDNA, wherein SEQ ID N0:509 is a clone designated herein as "DNA64908-1163-1".
Figure 217 shows the amino acid sequence (SEQ ID N0:510) derived from the coding sequence of SEQ ID
N0:509 shown in Figure 216.
Figure 218 shows a nucleotide sequence (SEQ ID N0:514) of a native sequence PR0298 cDNA, wherein SEQ ID N0:514 is a clone designated herein as °UNQ261 " and/or "DNA3997S-1210".
Figure 219 shows the amid acid sequence (SEQ ID N0:515) derived from the coding sequence of SEQ ID
N0:514 shown in Figure 218.
Figure 220 shows an EST nucleotide sequence designated herein as DNA26832 (SEQ
ID NO:516).
Figure 221 shows a nucleotide sequence (SEQ ID N0:522) of a native sequence PR0337 cDNA, wherein SEQ ID NO:522 is a clone designated herein as "DNA43316-1237".
Figure 222 shows the amino acid sequence (SEQ ID N0:523) derived from the coding sequence of SEQ ID
N0:522 shown in Figure 221.
Figure 223 shows an EST nucleotide sequence designated herein as DNA42301 (SEQ
ID N0:524).

Figure 224 shows a nucleotide sequence (SEQ ID N0:525) of a native sequence PR0403 cDNA, wherein SEQ ID N0:525 is a clone designated herein as "DNA55800-1263" .
Figure 225 shows the amino acid sequence (SEQ ID N0:526) derived from the coding sequence of SEQ ID
N0:525 shown in Figure 224.
Figures 226A-B show an EST nucleotide sequence designated herein as DNA34415 (SEQ ID N0:527).
Figure 227 shows an EST nucleotide sequence designated herein as DNA49830 (SEQ
ID N0:528).
Figure 228 shows an EST nucleotide sequence designated herein as DNA49831 (SEQ
1D N0:529).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Definitions The terms "PRO polypeptide" and "PRO" as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PROlnumber) refers to specific polypeptide sequences as described herein. The terms "PROlrnunber polypeptide"
and "PROlnumber" as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein). The PRO
polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
A "native sequence PRO polypeptide" comprises a polypeptide having the same amino acid sequence as the corresponding PRO polypeptide derived from nature. Such native sequence PRO
poiypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The term "native sequence PRO polypeptide"
specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms {e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. In various embodiments of the invention, the native sequence PR0213 polypeptide is a mature or full-length native sequence PR0213 polypeptide comprising amino acids 1 to 295 of Figure 2 (SEQ ID N0:2), the native sequence PR0274 polypeptide is a mature or full-length native sequence PR0274 polypeptide comprising amino acids 1 to 492 of Figure 4 (SEQ ID N0:7), the native sequence PR0300 polypeptide is a mature or full-length native sequence PR0300 polypeptide comprising amino acids 1 to 457 of Figtue 9 (SEQ
1D N0:19), the native sequetxe PR0284 polypeptide is a mature or full-length native sequence PR0284 palypeptide comprising amino acids 1 to 285 of Figure 11 (SEQ ID N0:28), the native sequence PR0296 polypeptide is a mature or full-length native sequence PR0296 polypeptide comprising amino acids 1 to 204 of Figure 15 (SEQ 1D N0:36), the native sequence PR0329 polypeptide is a mature or full-length native sequence PR0329 polypeptide comprising amino acids 1 to 359 of Figure 20 (SEQ ID NO:45), the native sequence PRO362 polypeptide is a mature or full-length native sequence PR0362 polypeptide comprising amino acids 1 to 321 of Figure 22 (SEQ ID N0:52), the native sequence PR0363 polypeptide is a mature or full-length native sequence PR0363 polypeptide comprising amino acids 1 to 373 of Figure 24 (SEQ ID N0;59)> the native sequence PRO868 polypeptide is a mature or full-length native sequence PR0868 polypeptide comprising amino acids 1 to 655 of Figure 26 (SEQ ID N0:64), the native sequence PR0382 polypeptide is a mature or full-length native sequence PR0382 polypeptide comprising amino acids 1 to 453 of Figure 28 (SEQ ID N0:69), the native sequence PR0545 polypeptide is a mature or full-length native sequence PR0545 polypeptide comprising amino acids l to 735 of Figure 30 (SEQ ID N0:74), the native sequence PR0617 polypeptide is a mature or full-length native sequence PR0617 polypeptide comprising amino acids 1 to 67 of Figwe 33 (SEQ 1D N0:85), the native sequence PRO?00 polypeptide is a mature or full-length native sequence PR0700 polypeptide comprising amino acids 1 to 432 of Figure 35 (SEQ ID N0:90), the native sequence PR0702 pol~peptide is a mature or full-length native sequence PR0702 poIypeptide comprising amino acids 1 to 277 of Figure 37 (SEQ ID N0:97), the native sequence PR0703 polypeptide is a mature or full-length native sequence PR0703 polypeptide comprising amino acids I to 730 of Figure 39 (SEQ
ID N0:102), the native sequence PR0705 polypeptide is a mature or full-length native sequence PR0705 polypeptide comprising amino acids 1 to 555 of Figure 41 (SEQ ID N0:109), the native sequence PR0708 polypeptide is a mature or full-length native sequence PR0708 poiypeptide comprising amino acids 1 to 515 of Figure 43 (SEQ ID
N0:114), the native sequence PR0320 polypeptide is a mature or full-length native sequence PR0320 polypeptide comprising amino acids 1 to 338 of Figure 45 (5EQ ID N0:119), the native sequence PR0324 polypeptide is a mature or full-length native sequence PR0324 poiypeptide comprising amino acids t to 289 of Figure 47 (SEQ ID N0:124), the native sequence PR0351 polypeptide is a mature or full-length native sequence PR0351 polypeptide comprising amino acids 1 to 571 of Figure 49 (SEQ ID N0:132), the native sequence PR0352 polypeptidc is a mature or full-Length native sequence PR0352 polypeptide comprising amino acids 1 to 316 of Figure 51 (SEQ ID N0:137), the native sequence PR0381 polypeptide is a mature or full-Length native sequence PR038I polypeptide comprising amino acids 1 to 211 of Figure 53 {SEQ ID N0:145), the native equence PR0386 polypeptide is a mature or full-Length native sequence PR0386 I5 polypeptide comprising amino acids 1 to 215 of Figure 55 (SEQ ID N0:150), the native sequence PR0540 polypeptide is a mauue or full-length native sequence PR0540 polypeptide comprising amino acids t to 412 of Figure 59 (SEQ ID N0:157), the native sequence PR0615 polypeptide is a mature or full-length native sequence PR06I5 polypeptide comprising amino acids t to 224 of Figure 61 (SEQ ID N0:162), the native sequence PR0618 polypeptide is a mature or full-length native sequence PR0618 polypeptide comprising amino acids t to 802 of Figure 63 (SEQ ID N0:169), the native sequence PR0719 polypeptide is a mature or full-length native sequence PR0719 polypeptide comprising amino acids 1 to 354 of Figure 66 (SEQ ID N0:178), the native sequence PR0724 polypeptide is a mature or full-length native sequence PR0724 polypeptide comprising amino acids I to 7i3 of Figure 68 (SEQ ID NO:I83), the native sequence PR0772 polypeptide is a mature or full-length native sequence PR0772 polypeptide comprising amino acids 1 to 152 of Figure 70 (SEQ ID N0:190), the native sequence PR0852 polypepdde is a mature or full-length native sequence PR0852 poiypeptide comprising amino acids 1 to 518 of Figure 73 (SEQ 1D N0:196), the native sequence PR0853 polypeptide is a mantre or full-length native sequence PR0853 polypeptide comprising amino acids 1 to 37? of Figure 75 (SEQ iD N0:206), the native sequence PR0860 polypeptide is a mature or full-Length native sequence PR0860 polypeptide comprising amino acids I to 985 of Figure 77 (SEQ ID N0:211), the native sequence PR0846 polypeptide is a mature or full-length native sequence PR0846 polypeptide comprising amino acids 1- to 332 of Figure 79 (SEQ ID N0:216), the native sequence PR0862 polypeptide is a mature or full-length native sequence PR0862 polypeptide comprising ainino acids 1 to 146 of Figure 81 (SEQ ID N0:221), the native sequence PR0864 polypeptide is a mature or full-length native sequence PR0864 polypeptide comprising amino acids 1 to 351 of Figure 83 (SEQ ID N0:226), the native sequence PR0792 polypeptide is a rnautre or full-length native sequence PR0792 poiypeptidc comprising amino acids 1 to 293 of Figure 85 (SEQ ID N0:23i), the native sequence PR0866 polypeptide is a mature or full-length native sequence PR0866 polypeptide comprising amino acids t to 331 of Figure 87 (SEQ ID NO:236), the native sequence PR0871 polypeptide is a manue or full-length native sequence PR0871 polypeptide comprising amino acids 1 to 472 of Figure 89 (SEQ lD N0:245), the native sequence PR0873 polypeptide is a mature or full-length native sequence PR0873 polypeptide comprising amino acids 1 to 545 of Figure 91 (SEQ ID N0:254), the native sequence PR0940 polypeptide is a mature or full-length native sequence PR0940 polypeptide comprising amino acids 1 to 544 of Figure 93 (SEQ ID N0:259}, the native sequence PR094I polypeptide is a mature or full-length native sequence PR0941 polypeptide comprising amino acids 1 to 772 of Figure 95 (SEQ ID N0:264), the native sequence PR0944 polypeptide is a mature or full length native sequence PR0944 polypeptide comprising amino acids 1 to 21 lof Figure 98 (SEQ ID N0:270}, the native sequence PR0983 polypeptide is a mature or full-length native sequence PR0983 polypeptide comprising amino acids 1 to 243 of Figure 109 (SEQ ID N0:284), the native sequence PR01057 poiypeptide is a mature or full-length native sequence PR01057 polypeptide comprising amino acids 1 to 413 of Figure 118 (SEQ ID N0:296), the native sequence PR01071 polypeptide is a mature or full-length native sequence PR01071 polypeptide comprising amino acids 1 to 525 of Figure 120 (SEQ ID
N0:301), the native sequence PR01072 polypeptide is a mature or full-length native sequence PR01072 polypeptide comprising amino acids 1 to 336 of Figure 122 (SEQ ID N0:303), the native sequence PR01075 polypeptide is a mature or full-length native sequence PR01075 polypeptide comprising amino acids 1 to 406 of Figure 125 (SEQ ID N0:309), the native sequence PROI81 polypeptide is a mature or full-length native sequence PR018I
polypeptide comprising amino acids 1 to 144 of Figure 129 (SEQ ID N0:322), the native sequence PR0195 polypeptide is a mature or full-length native sequence PR0195 polypeptide comprising amino acids 1 to 323 of Figure 132 (SEQ
ID N0:330), the native sequence PR0865 polypeptide is a mature or full-length native sequence PR0865 polypeptide comprising amino acids 1 to 468 of Figure 136 (SEQ )D N0:337}, the native sequence PR0827 polypeptide is a mature or full-length native sequence PR0827 polypeptide comprising amino acids 1 to 124 of Figure 39 (SEQ ID
N0:346), the native sequence PR01114 polypeptide is a mature or full-length native sequence PR01114 polypeptide comprising amino acids I to 311 of Figure 142 (SEQ ID N0:352), the native sequence PR0237 polypeptide is a mature or full-length native sequence PR0237 polypeptide comprising amino acids 1 to 328 of Figure 145 (SEQ ID
N0:358), the native sequence PR0541 polypeptide is a mature or full-length native sequence PR0541 polypeptide comprising amino acids 1 to 500 of Figure 147 (SEQ ID N0:363), the native sequence PR0273 polypeptide is a mature or full-length native sequence PR0273 polypeptide comprising amino acids 1 through 111 of Figure 149 (SEQ ID
N0:370), the native sequence PR0741 polypeptide is a mature or full-length native sequence PR0701 polypeptide comprising amino acids 1 to 816 of Figure I51 (SEQ ID N0:375}, the native sequence PR0704 polypeptide is a full-length or mature native sequence PR0704 polypeptide comprising amino acids 1 or 40 through 348 of Figure 153 (SEQ 1D
N0:380), the native sequence PR0706 polypeptide is a mature or full-length native sequence PR0706 polypeptide comprising amino acids 1 to 480 of Figure 155 (SEQ ID N0:385), the native sequence PR0707 polypeptide is a full-length or mature native sequence PR0707 polypeptide comprising amino acids 1 or 31 through 916 of Figure 157 (SEQ ID N0:390), the native sequence PR0322 polypeptide is a mature or full-length native sequence PR0322 polypeptide comprising amino acids 24 or 1 to 260 of Figure 159 (SEQ ID N0:395}, the native sequence PR0526 polypeptide is a full-length or mature native sequence PR0526 polypeptide comprising amino acids 1 or 27 through 473 of Figure 161 (SEQ ID N0:400), the native sequence PR0531 polypeptide is a mature PR0531 polypeptide comprising amino acids I to 789 of Figure 163 (SEQ ID N0:405), the native sequence PR0534 polypeptide is a mature or full-length native sequence PR0534 polypeptide comprising amino acids 1 to 360 of Figure 165 (SEQ ID N0:410), the native sequence PRO697 polypeptide is a full-length or mature native sequence PR0697 polypeptide comprising amino acids I or 21 through 295 of Figure 167 (SEQ ID N0:415), the native sequence PR0717 polypeptide is a mature or full-length native sequence PR0717 polypeptide comprising amino acids 1 through 560 of Figure 169 (SEQ ID N0:420}, the native sequence PR0731 polypeptide is a full-length or mature native sequence PR0731 polypeptide comprising amino acids WO 99146281 PCTlUS99105028 1 or I4 through I 184 of Figure 171 (SEQ ID N0:425), the native sequence PR0218 polypeptide is a foil-iengih or mature native sequence PR02I8 polypeptide comprising amino acids 1 or 24 through 455 of Figure 173 (SEQ ID
N0:430), the native sequence PRO768 poiypeptide is a full-length or mature native sequence PR0768 polypeptide comprising amino acids 1 or 34 through 1141 of Figure I77 (SEQ ID N0:437), the native sequence PR077I
polypeptide is a full-length or mantre native sequence PRO771 polypeptide comprising amino acids 1 or I7 through 436 of Figure 179 (SEQ ID N0:442), the native sequence PR0733 poiypeptide is a mature or full-length native sequence PR0733 polypeptide comprising amino acids 24 or I through 229 of Figure 181 (SEQ ID N0:447), the native sequence PR0162 poiypeptide is a full-length or mature native sequence PR0162 polypeptide comprising amino acids 1 or 27 through 175 of Figure 183 (SEQ ID N0:452), the native sequence PR0788 polypeptide is a full-length or mantre native sequence PR0788 polypeptide comprising amino acids 1 or 18 through 125 of Figure 185 (SEQ ID N0:454), the native sequence PR01008 polypeptide is a full-length or mature native sequence PR01008 polypeptide comprising amino acids 1 or 24 through 266 of Figure 187 (SEQ ID
N0:456), the native sequence PR01012 poIypeptide is a mature or full-length native sequence PR01012 polypeptide comprising amino acids 1 through 747 of Figure 190 (SEQ 1D N0:459), the native sequence PROI014 polypeptide is a full-length or mature native sequence PR01014 polypeptide comprising amino acids 1 ar 20 through 300 of Figure 192 (SEQ ID N0:464), the native sequence PR01017 polypeptide is a full-length or mature native sequence PR01017 polypeptide comprising amine acids 1 or 32 through 414 of Figure 194 (SEQ ID N0:466), the native sequence PR0474 polypeptide is a mature or full-length native sequence PR0474 polypeptidt; comprising amino acids 1 through 270 of Figure 196 (SEQ
ID N0:468), the native sequence PR0103I polypeptide is a full-length or mature native sequence PR01031 polypepiide comprising amino acids 1 or 21 through 180 of Figure 198 (SEQ ID
N0:470), the native sequence PR0938 polypeptide is a mature or full-length native sequence PR0938 polypeptide comprising amino acids 1 to 349 of Figure 200 (SEQ ID N0:472), the native sequence PR01082 polypeptide is a full-length or mature native sequence PR01082 polypeptide comprising amino acids 1 through 201 of Figure 202 (SEQ ID
N0:4?7), the native sequence PR01083 polypeptide is a full-length or mature native sequence PR01083 polypeptide comprising amino acids 1 or 26 through 693 of Figure 204 (SEQ ID N0:483), the native sequence VEGF-E
polypeptide is a mature or full-length native sequence VEGF-E polypeptide comprising amino acids 1 through 345 as depicted in Figure 207 (SEQ ID
N0:488), the native sequence PR0285 is a mature or full-length native sequence PR0285 polypeptide comprising amino acids 1 to 1049 of Figure 209 (SEQ ID N0:496), the native sequence PR0286 is a mature or full-length native sequence PR0286 polypeptide comprising amino acids 1 to 1041 of Figure 211 (SEQ ID N0:298), the native sequence PR0298 is a mature or full-length native sequence PR0298 comprising amino acids 1 to 364 of Figure 219 (SEQ ID NO:515), the native sequence PR0337 is a mature or full-length native sequence human neurouimin comprising amino acids 1 to 344 of Figure 222 (SEQ ID N0:523), with or without the N-terminal signal sequence (residues 1 to abet 28), and with or without the initiating methionine at position 1 and the native sequence PR0403 is a mature or full-length native sequence comprising amino acids 1 to 736 of Figure 225 (SEQ ID N0:526), with or without the initiating methionine at position 1.
The PRO polypeptide "extracellular domain° or "ECD" refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytopIasmic domains. Ordinarily, a PRO poiypeptide ECD will have less than 1 % of such transmembrane andlor cytoplasmic domains and preferably, will have less than 0.5 % of such domains. It will be understood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic WO 99/46281 PCTlUS99105028 domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified. Optionally, therefore, an extracellular domain of a PRO
polypeptide may contain from about 5 or fewer amino acids on either or the transmembrane domain as initially identified.
"PRO polypeptide variant" means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence iderniry with the full-length native sequence PRO
polypeptide sequence as disclosed herein.
Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a PRO
polypeptide variant will have at least about 80% amino acid sequence identity, more preferably at least about 8$~
amino acid sequence identity, and even more preferably at least about 90%
amino acid sequence identity, even more IU preferably at least about 91 % amino acid sequence identity, even more preferably at least about 92 % amino acid sequence identity, even more preferably at least about 93 % amino acid sequence identity, even more preferably at least about 94 % amino acid sequence identity, even more preferably at least about 95 % amino acid sequence identity;
yet more preferably at least about 96 % amino acid sequence identity, yet more preferably at least about 97 ~ amino acid sequence identity, yet more preferably at least about 98~ amino acid sequence identity and most preferably at least about 99 % amino acid sequence identity with the amino acid sequence of the full-length native amino acid sequence as disclosed herein.
"Percent (%) amino acid sequence identity" with respect to the PRO polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific PRO polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as pan of the sequence identity. Alignment for purposes of deterrninvtg percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. The preferred software alignment program is BLAST. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. 'The identity values used herein have been generated using the WU-BLAST-2 computer program (Altschul et al., Methods in Enzymology 2b6:460-480 (1996); http:/lblast.vwstlledu/blast/README.html).
Most of the WU-BLAST-2 search parameters were set to the default values. The adjustable parameters were set with the following values: overlap span = i, overlap fraction = 0.125, word threshold (T) = 11, and scoring matrix =
BLOSUM62. The HSP S and HSP
S2 parameters, which are dynamic values used by BLAST-2, are established by the program itself depending upon the composition of the sequence of interest and composition of the database against which the sequence is being searched. However, the values may be adjusted to increase sensitivity. A %
sequence identity value is determined by the fraction of matching identical residues divided by the total number of residues in the aligned region.
"Percent (%) nucleic acid sequence identity" with respect to PRO-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of detennining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megaiign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. The identity values used herein were generated by the- BLASTN module of VJU-BLAST-2 set to the default parameters, with overlap span and overlap fraction set to 1 and 0.125, respectively.
The term "positives", in the context of sequence comparison performed as described above, includes residues in the sequences compared that are not identical but have similar properties (e.g. as a result of conservative substitutions). The % value of positives is determined by the fraction of residues scoring a positive value in the BLOSUM 62 matrix divided by the total number of residues in the aligned region, as defined above.
The term "epitope tagged" where used herein refers to a chimeric polypeptide comprising a PRO
polypeptide, or domain sequence thereof; fused to a "tag polypeptide". The tag polypeptide has enough residues to provide an epitope against which an antibody may be made, or which can be identified by some other agent, yet is short enough such that it does not interfere with the activity of the PRO
golypeptide of interest. The tag polypeptide preferably is also fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 to about 50 amino acid residues (preferably, between about l0 to about 20 residues).
"Isolated," when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the poLypeptide, and may include enzymes, hormones, and other proteznaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least IS residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Cootnassie blue or, preferably, silver stain. Isolated polypeptide includes polypeptide in situ within recombinant cells, since at least one component of the PRO polypeptide natural environment will not be present. Ordinarily, however, isolated polypepride will be prepared by at least one purification step.
An "isolated" PRO polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the PRO polypeptide nucleic acid. An isolated PRO polypeptide nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated PRO polypeptide nucleic acid molecules therefore are distinguished from the specific PRO polypeptide nucleic acid molecule as it exists in natural cells. However, an isolated PRO polypeptide nucleic acid molecule includes PRO polypeptide nucleic acid molecules contained in cells that ordinarily express the PRO polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
The term "comrol seqtter>ces" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
Nucleic acid is "operably Linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DIVA for a presequence or secretory Leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that patvcipates in the secretion of the polypeptide; a promoter or enhancer is operabiy linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is WO 99146281 PCTlUS99/05028 operably linked to a coding sequence if it is positioned so as to facilitate uanslation. Generally, "operably linked"
means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance wish conventional practice.
The term "antibody" is used in the broadest sense and specifically covers single anti-PRO polypeptide monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies) and anri-PRO polypeptide antibody compositions with polyepitogic specificity. The terns "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts.
"Active" or "activity" for the purposes herein refers to fotm(s) of PRO
polypeptide which retain the biologic and/or itnmunologic activities of the specific native or naturally-occurring PRO polypeptide.
"Treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures.
Those in need of treatment include those already with the disorder as well as those prone to have the disorder of those in which the disorder is to be prevented.
"Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as sheep, dogs, horses, cats, cows, and the like.
Preferably, the mammal herein is a human.
"Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids;
antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or ittimunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, argirtine or lysine; tnanosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dexuins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; andlor nonionic surfactants such as TWEENT"", polyethylene glycol (PEG), and PLURONICST"".
The term "agonist" is used to refer to peptide and non-peptide analogs of the native PRO polypeptides (where native PRO polypeptide refers to pro-PRO polygeptide, pre-PRO
polypeptide, prepro-PRO polypeptide, or mature PRO polypeptide) of the present invention and to antibodies specifically binding such native PRO
polypeptides, provided that they retain at least one biological activity of a native PRO polypeptide. Preferably, the agonists of the present invention retain the qualitative binding recognition properties and receptor activation properties of the native PRO polypeptide.
The term "antagonist" is used to refer to a molecule inhibiting a biological activity of a native PRO
polypeptide of the present invention wherein native PRO polypeptide refers to pro-PRO polypeptide, pre-PRO
polypeptide, prepro-PRO polypeptide, or mature PRO polypeptide. Preferably, the antagonists herein inhibit the binding of a native PRO polypeptide of the present invention to a binding parater. A PRO polypeptide "antagonist"
is a molecule which prevents, or interferes with, a PRO antagonist effector function (e.g. a molecule which prevents or interfexes with binding andlor activation of a PRO polypeptide receptor by PRO polypeptide). Such molecules can be screened for their ability to competitively inhibit PRO polypeptide receptor activation by monitoring binding of native PRO polypeptide in the presence and absence of the test antagonist molecule, for example. An antagonist of the invention also encompasses an antisense polynucleotide against the PRO
polypeptide gene, which antisense polynucleotide blocks transcription or translation of the PRO polypeptide gene, thereby inhibiting its expression and biological activity.
"Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art; and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA
to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions; see Ausubel e1 al., Current Protocols in Molecular Biology, Wiiey Interscience Publishers, (1995).
"Stringent conditions" means (1) employing low ionic strength and high temperature for washing, for example, 0.015 sodium chloridel0.0015 M sodium citratel0.l h sodium dodecyl sulfate at 50°C, or (2) employing during hybridization a denaturing agent, such as formamide, for example, 50%
(vollvol) formamide with 0.1 % bovine serum albumin/0.1 ~ Fico3110.1 q6 polyvinylpyrrolidonel50 nM sodium phosphate buffer at pH 6.5 with 750 mM
sodium chloride, 75 mM sodium citrate at 42°C. Another example is use of 50% formamide, 5 x SSC (0.75 M
NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6I8), 0.1 % sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 ~cglml), 0.1 % SDS, and 10% dextran sulfate at 42°C, with washes at 42°C in 0.2 x SSC and 0:1 % SDS. Yet another example is hybridization using a buffer of 10~ dextran sulfate, 2 x SSC {sodium chloride/sodium citrate) and 50 % formamide at 55 °C;
followed by a high-stringency wash consisting of 0.1 x SSC containing EDTA at 55 °C.
"Moderately stringent conditions" are described in Sambrook et al., supra, and include the use of a washing solution and hybridization conditions (c.g., temperature, iottie strength, and ~SDS) less suingent than described above. An example of moderately stringent conditions is a condition such as overnight incubation at 37°C in a solution comprising: 20'~ forntamide, 5 x SSC (154 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10~ dextran sulfate, and 20 mglmL denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 37-50°C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc., as necessary to accommodate factors such as probe length and the like.
"Southern analysis" or "Southern blotting" is a method by which the presence of DNA sequences in a restriction endonucJease digest of DNA or a DNA-containing composition is confirmed by hybridization to a known, labeled oligonucleotide or DNA fragment. Southern analysis typically involves electrophoretic separation of DNA
digests on agarose gels, denaturation of the DNA after elecuophoretic separation, and transfer of the DNA to nitrocellulose, nylon, or another suitable membrane support for analysis with a radiolabeled, biotinylated, or enzyme-labeled probe as descn'bed in sections 9.37-9.52 of Sambrook er al. , Molecular Clonine: A Laboratory Meal (New York: Cold Spring Harbor Laboratory Press, 19$9).
"Northern analysis" or "Northern blotting" is a method used to identify RNA
sequences that hybridize to a imown probe such as an oligonucleotide, DNA fragttient, cDNA or fragment thereof, or RNA fragment. The probe is labeled with a radioisotope such as ~P, or by biotittylation, or with an enzyme. The RNA to be analyzed is usually electrophoretically separated on an agarose or polyacrylamide gel, transferred to nitrocellulose, nylon, or other suitable membrane, and hybridized with the probe, using standard techniques well known in the art such as those described in sections 7.39-7.52 of Sambrook et al., supra.
As used herein, the term "immunoadhesin" designates antibody-like molecules which combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of immunoglobulin constant domains.
Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody {i.e., is "heterologous"), and an itnmunoglobulin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-l and IgA-2), IgE, 1gD or IgM.
"Chronic" administration refers to administration of the agent{s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. "intermittent"
administration is ueatment that is not consecutively done without imerruption, but rather is cyclic in nature.
Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
As used herein, "vascular endothelial cell growth factor-E," or "VEGF-E,"
refers to a mammalian growth factor as described herein, including the human amino acid sequence of Figure 207, a sequence which has homology to VEGF and bone motphogenetic protein 1 and which includes complete conservation of all VEGF cysteine residues, which have been shown to be required for biological acuviry of VEGF. VEGF-E
expression includes expression in human fetal bone, thymus, and the gasuointestinal uact. The biological activity of native VEGF-E is shared by any analogue or variant thereof that is capable of promoting selective growth andlor survival of umbilical vein endothelial cells, induces proliferation of pluripotent fibroblast cells, induces immediate early gene c-fos in human endothelial cell lines and causes myocyte hypertrophy in cardiac cells, or which possesses an immune epitope that is immunologically cross-reactive with an antibody raised against at least one epitope of the corresponding native VEGF-E. The human VEGF-E herein is active on rat and mouse cells indicating conservation across species. Moreover, the VEGF-E herein is expressed at the growth plate region and has been shown to embrace fetal myocytes.
As used herein, "vascular endothelial cell growth factor," or "VEGF," refers to a mammalian growth factor as defined in U.S. Patent 5,332,671. The biological activity of native VEGF is shared by any analogue or variant thereof that is capable of promoting selective growth of vascular endothelial cells but not of bovine corneal endothelial cells, lens epithelial cells, adrenal cortex cells, BHK-21 fibroblasts, or keratinocytes, or that possesses an immune epitope that is immunologically cross-reactive with an antibody raised against at least one epitope of the corresponding native VEGF.
The terms "VEGF-E polypeptide" and "VEGF-E" when used herein encompass native sequence VEGF-E
poiygeptide and VEGF-E polypeptide variants (which are further defined herein). The VEGF-E polypeptides may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
Inhibitors of VEGF-E include those which reduce or inhibit the activity or expression of VEGF-E and includes antisense molecules.

WO 99/4628? PCT/US99/05028 The abbreviation "KDR" refers to the kinase domain region of the VEGF
molecule. VEGF-E has no homology with VEGF in this domain.
The abbreviation,"FLT-1 " refers to the FMS-like tyrosine kinase binding domain which is known to bind to the corresponding FLT-1 receptor. VEGF-E has no homology with VEGF in this domain.
"Toll receptor2", °TLR2" and "huTLR2" are used interchangeably, and refer to a human Toll receptor designated as "HuTLR2" by Rocket al., 'roc. Natl. Aca~Sci. USA, QS_, 588-593 (1998).
The term "expression vector" is used to define a vector, in which a nucleic acid encoding a PRO polypeptide herein is operably linked to control sequences capable of affecting its expression is a suitable host cells. Vectors ordinarily carry a replication site (although this is not necessary where chromosomal integration will occur).
Expression vectors also include marker sequences which are capable of providing phenotypic selection in transformed cells. For example, E. coli is typically transformed using pBR322, a plasmid derived from an E. toll species (Boiivar, et al., Gene ~: 95 [1977]). pBR322 contains genes for ampicillin and tetracycline resistance and thus provides easy means for identifying transformed cells, whether for purposes of cloning or expression. Expression vectors also optimally will contain sequences which are useful for the conuol of transcription and translation; e.g., promoters and Shine-Dalgamo sequences (for prokaryotes) or promoters and enhancers {for mammalian cells). The IS promoters may be, but need not be, inducible; even powerful constitutive promoters such as the CMV promoter for mammalian hosts have been found to produce the LHR without host cell toxicity.
While it is conceivable that expression vectors need not contain any expression control, replicative sequences or selection genes, their absence may hamper the identification of hybrid transfotmants and the achievement of high level hybrid immunoglobulin expression.
The term "lipopolysaccharide" or °LPS" is used herein as a synonym of "endotoxin." Lipopolysaccharides (LPS) are characteristic components of the outer membrane of Gram-negative bacteria, e.g., Escherichia toll. They consist of a polysaccharide part and a fat called lipid A. The polysaccharide, which varies from one bacterial species to another, is made up of the O-specific chain (built from repeating units of three to eight sugars) and the two-part core. Lipid A virtually always includes two glucosamine sugars modified by phosphate and a variable number of fatty 2S acids. For further information see, for example, Rietschel and Brade, scientific American August 1992, S4-6I.
The term "septic shock" is used herein in the broadest sense, including all definitions disclosed in Bone, ~
tern Med ,1~, 332-333 {I991). Specifically, septic shock starts with a systemic response to infection, a syndrome caDed sepsis. When this syndrome results in hypotension and organ dysfunction, it is caDed septic shock_ Septic shock may be initiated by gram-positive organisms and fungi, as well as endotoxin-containing Gram-negative organisms. Accordingly, the present definition is not limited to "endotoxin shock."
The phrases "gene amplification" and "gene duplication" are used interchangeably and refer to a process by which multiple copies of a gene or gene fragment are formed in a particular cell or cell line. The duplicated region (a stretch of amplified DNA) is often referred to as "amplicon". Usually, the amount of the messenger RNA
(mRNA) produced, i.e., the level of gene expression, also increases in the proportion of the number of copies made of the particular gene expressed.
"Tumor", as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, acrd all pre-cancerous and cancerous cells and tissues. The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples WO 99/4b281 PCT/US99I05028 of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, gliobIastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, wlval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer.
The term "cytotoxic agent" as used, herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g. I131, I125, Y90 and Re186), chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof.
A "chemotherageutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include adriamycin, doxorubicin, epirubicin, 5-fluorouracil, cytosine arabinoside ("Ara-C"), cyclophosphamide, thiotepa, busulfan, cytoxin, taxoids, e.g. paclitaxel (Taxol, Bristol-Myers Squibb Oncology, Princeton, NJ), and doxetaxcl (Taxotereu, Rhot>e-Poulenc Rorer, Antony, France), toxotere, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carmirtomycin, atninopterin, dactinomycin, mitomycins, esperamicins (see U.S.
Pat. No. 4,b75,187), melphalan and other related nitrogen mustards. Also included in this definition are hormonal agents that act to regulate or inhibit hormone action on tumors such as tamoxifen and onapristone.
A "growth inhibitory agent" when used herein refers to a compound or composition which inhibits growth of a cell, especially cancer cell overexpressing any of the genes identified herein, either in vitro or in vivo. Thus, the growth inhibitory agent is one which significantly reduces the percentage of cells overexpressing such genes in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), taxol, and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
Further information cart be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogens, and antineoplastic drugs "by Murakami et al.
(WB Saunders: Philadelphia, 1995), especially p.13.
"Doxorubicin" is an athracycline antibiodc.
The term "cytokine" is. a generic term for proteins released by one cell population which act on another cell as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and uaditional polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N-meihionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine;
insulin; proinsulin; relaxin;
prorelaxin; and the like. As used herein, the terns cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.
"Immunological cross-reactivity" as used herein means that the candidate polypeptide is capable of competitively inhibiting the qualitative biological activity of a PR0213-1, PR01330, or PR01449 polypeptide having this activity with poiyclonal antisera raised against the known active PR0213-1, PR01330, or PR01449 polypeptide.
Such antisera tray be prepared in comentional_ fashion by injecting goats or rabbits, for example, subcutaneously with the known active analogue in complete Freund's adjuvant, followed by booster intraperitoneal or subcutaneous injection in incomplete Freunds. The immunological cross-reactivity preferably is "specific", which means that the binding affinity of the immunological cross-reactive molecule (e:g., antibody) identified, to the corresponding FR0213-1, PR01330, or PR01449 polypeptide is significantly higher (preferably at least about 2-times, more preferably~at least about 4-times, even more preferably at least about 6-times, most preferably at least about 8-times higher} than the binding affinity of that molecule to any other known native polypeptide.
"Native antibodies" and "native immunoglobulins" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains aiid two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond; while the number of disulfide Linkages varies among the heavy chains of different immunoglobuLin isotypes. Each heavy and Light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH}
followed by a number of constant domains: Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant IO domain of the light chain is aligned with the first constant domain of the heavy chain, and the Light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.
The term "variable" refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarily-determining regions (CDRs) or hypervariable regions both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR
regions, largely adopting a ~-sheet configuration, connected by three CDRs;
which form loops connecting, and in sorts cases for>zting part of, the (i-sheet stmcture. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of ann'bodies (see Rabat et al., NIH Publ. No.91-3242, VoI. I; pages 647-669 (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.
"Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments;
diabodies; linear antibodies (Zapata et a1. , Protein Eng. 8(10): 1057-1062 [1995)); single-chain antibody molecules;
and multispecific antibodies formed from anu'body fragments.
Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fob" fragments, each with a single antigen-binding site, and a residual "Fe" fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab'}2 fragment that has two antigen..combining sites and is still capable of cross-linking antigen.
"Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site.
This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association.
h is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VI. dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.
However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

WO 99!46281 PCT/US99/OSQ28 The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments differ from Fab fragments by the addition of a few residues at the carboxy termitlus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH
is the designation herein for Fab' in which the cysteine residues) of the constant domains bear a free thiol group.
F(ab')2 ann'body fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned io different classes. There are five major classes of immunoglobulins; IgA, IgD, IgE, IgG, and IgM, and several of these may be funkier divided into subclasses (isorypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
"Single-chain Fv" or "sFv" antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).
The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH - VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097;
WO 93/I1161; and Hollinger et al., Proc. Nat!. Acad. Sci. USA, 90:6444-6448 (1993).
An "isolated" antibody is one which has been identified and separated andlor recovered from a component of its natural environment. Contanninant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. in preferred embodiments, the antibody will be purified (1) to gxeater than 959'o by weight of antibody as determined by the Lowry method, and most preferably more than 999e by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present.
Ordinarily, however, isolated antibody will be prepared by at least one purification step.
The word "label" when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a "labelled"
antibody. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.
By "solid phase" is meant a non-aqueous matrix to which tire antibody of the present invention can adhere.
Examples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In certain embodiments, depending on the context, the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Patent No, 4,275,149.
A "liposome" is a small vesicle composed of various types of lipids, phospholipids andlor surfactant which is useful for delivery of a drug (such as the and-ErbB2 antibodies disclosed herein and, optionally, a chemotherapeutic agent) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
II. Compositions and MethQc~ o~ the Invention 1. 'till-length PR021~ Polype~tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0213. In particular, Applicants have identified and isolated cDNA
encoding a PR0213 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that a portion of the PR02I3 polypeptide has significant homology with the human growth arrest-specific 6 (gash) protein. Accordingly, it is presently believed that PR0213 polypeptide disclosed in the present application may have the same or simular activity as does the gash protein.
is Full-len~h PR0274 Pol~pentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0274. In particular, Applicants have identified and isolated cDNA
encoding a PR0274 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PRO274 polypeptide have significant homology with the ? transmembrane segment receptor proteins and Fn54 protein. Accordingly, it is.
presently believed that PR0274 poiypeptide disclosed in the present application is a newly identified member of the 7 uansmembrane segment receptor protein andlor Fn54 protein family 3. Full-Length PR0300 Polype~tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0300. In particular, Applicants have identified and isolated cDNA
encoding a PR0300 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0300 polypeptide have significant homology with the human Diff 33 protein. Accordingly, it is presently believed that PR0300 polypeptide disclosed in the present application is a newly identified member of the Diff 33 family.
4. Full-length PP,~,t0284 Polv~e tp ides The present invention provides newly identified and isolated nucleotide sequences encoding poiypeptides referred to in the present application as PRO284. In particular, Applicants have identified and isolated cDNA
encoding a PR0284 polypepdde; as disclosed in further detail in the Examples below. To Applicants present lrnowledge, the UNQ24? (DNA23318-1211) nucleotide sequence encodes a novel factor; using BLAST and FastA
sequence alignment computer programs, no sequence identities to any irnown proteins were revealed.

WO 99!46281 PCT/US99l050Z8 Full-lenith PR0296 Poiypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0296. In particular, Applicants have identified and isolated cDNA
encoding a PR0296 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0296 polypeptide has significant similarity to the sarcoma-amplified SAS protein. Accordingly, it is presently believed that PR0296 polypeptide disclosed in the present application is a newly identified SAS protein homolog.
6. Full-length PR0329 Polype~tides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0329. In particular, Applicants have identified and isolated cDNA
encoding a PRO329 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0329 polypeptide has significant similarity to a high afFtnity immunoglobulin F~ receptor. Accordingly, it is presently believed that PR0329 poiypeptide disclosed in the present application is a newly identified F~ receptor homolog.
7. Full-length PR0362 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0362. In particular, Applicants have identified and isolated cDNA
encoding a PR0362 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0362 polypeptide has significant similarity to the A33 antigen protein as well as the HCAR protein and the NrCAM related cell adhesion molecule. Accordingly, it is presently believed that PR0362 polypeptide disclosed in the present application is a newly A33 antigen and HCAR protein homolog.
8. Full-length PR0363 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0363. In particular, Applicants have identified and isolated cDNA
encoding a PR0363 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0363 polypeptide has significant similarity to the cell surface protein HCAR. Accordingly, it is presently believed that FR0363 polypeptide disclosed in the present application is a newly HCAR homolog.
9. F tofu l-length PR0868 Polypeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides 3~ referred to in the present application as PR0868. In particular, Applicants have identified and isolated cDNA
encoding a PR0868 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligzmnetu computer programs, Applicants found that the PR0868 poIypeptide has significant similarity to the tumor necrosis factor receptor. Accordingly, it is presently believed that PR0868 polypeptide disclosed in the present application is a newly identified member of the tumor necrosis factor receptor family of proteins.

WO 99/46281 PC'f/US99/05028 10. ~nll-length PR0382~pegtiyes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present.application as PR0382. In particular, Applicants have idemified and isolated eDNA
encoding a PR0382 polypeptide, as disclosed in fiuther detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs> Applicants found that the native PR0382 polypeptide shares significant homology with various serine protease proteins. Applicants have also found that the DNA encoding the PR0382 polypeptide shares significant homology with nucleic acid encoding various serine protease proteins. Accordingly, it is presently believed that PR0382 polypeptide disclosed in the present application is a newly identified serine protease homolog.
11. Full-length PR0545 Polvp~,ptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0545. In particular, Applicants have identified and isolated cDNA
encoding a PR0545 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0545 polypeptide have significant homology with the sequences identified designated as; human metalloproteinase ("P W01825"), mouse meltrin alpha ("560257"), metalloprotease-disintegrin meltrin-alpha ("GEN13695"), ADAM 13 - Xenopus laevis ("XLU66003_1 "), mouse meltrin beta ("S60258"), rabbit metalloprotease-disintegrin meltrin-beta, ("GEN13696"), human meltrin S ("AF023477_1 "), human meltrin precursor ("AF023476 1 "), human ADAM 21 {"AF029900 1 "), and human ADAM 20 ("AF029899 1 "), thereby indicating that PR0545 may be a novel meltrin protein.
Accordingly, it is presently believed that the PR0545 polypeptide disclosed in the present application is a newly identified member of the meltrin family and possesses the cellular adhesiveness typical of the meItrin proteins which comprise both metalloprotease and disintegrin domains.
12. Full-length PR0617 Polvoentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR06i7. In particular, Applicants have identified and isolated cDNA
encoding a PR0617 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer. programs, Applicants found that the PRObl7 polypeptide shares significant homology with the CD24 protein. Applicants have also found that the DNA encoding the PR06I7 polypeptide has significant homology with DNA encoding the CD24 protein. Accordingly, it is presently believed that PR0617 polypeptide disclosed in the present application is a newly identified CD24 homolog.
13. Full-length PR0700 Polvoeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0700. In particular, Applicants have identified and isolated eDNA
encoding a PR0700 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0700 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0700 polypeptide possess significant sequence similarity to various protein disulfide isomerases. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced WO 99!46281 PCT/US99I05028 significant sequence similarity between the PR0700 amino acid sequence and the following Dayhoff sequences;
polypeptide with protein disulfide isomerase activity, designated as ("P
P80664"), human PDI, designated as ("P 851696"), human PDI, designated as (P 825297"), probable protein disulfide isomerase er-60 precursor, designated as ("ER60 SCHMA"), protein disulfide isomerase precursor -Drosophila melanogaster, designated as ("PDI DROME"), protein disulfide-isomerase precursor - Nicotiana tabaccum, designated as ("NTPDIGENE 1 "), protein disulfide isomerase - Onchocerca volvulus, designated as ("OVU 12440 1 "), human probable protein disulfide isomerase p5 precursor , designated as ("ERPS~HUMAN"), human protein disulfide isomerase-related protein 5, ("HSU79278_l "), and protein disulfide isomerase precursor l prolyl 4-hydroxy, ("PDI HUMAN"), thereby indicating that PR0700 may be a novel protein disulfide isomerase.
Accordingly, it is presently believed that PR0700 polypeptide disclosed in the present application is a newly identified member of the protein disulfide isomerase family and possesses the ability to catalyze the formation of disulfide bonds typical of the protein disulfide isomerase family.
14. dull-Length PR0702 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0702. In particular, Applicants have identified and isolated cDNA
encoding a PRO?02 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0702 polypeptide has significant similarity to the conglutinin protein. Accordingly, it is presently believed that PRO?02 polypeptide disclosed in the present application is a newly identified conglutinin homolog.
15. Full-IenEth PR0703 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0703. In particular, Applicants have identified and isolated cDNA
encoding a PR0703 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0703 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0703 polypeptide possess significant sequence similarity to the VLCAS
protein, thereby indicating that PR0703 may be a novel VLCAS protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0703 amino acid sequence arid the following Dayhoff sequences, human mRNA for very-long-chain aryl-CoA, ("D88308"), rat mRNA for very-long-chain acyl-CoA synthetase, ("D85100"), Mus musculus fatty acid transport protein, ("MMU15976"), human very-long-chain acyl-CoA synthetase., ("D88308!1 "), Mus musculus very-long-chain aryl-CoA synthetase, (°AF(133031 1 "), very-long-chain acyl-CoA
synthetase - Ramcs, ("D85100,I "), rat long-chain fatty acid transport protein, ("FA1'P_RAT"), mouse long-chain fatty acid transport protein, ("FATP MOUSE"), probable long-chain fatty acid transport protein, ("FAT! YEAST"), and fairy acid transporter protein, ("CHY15839 2") , thereby indicating that PR0703 may be a novel VLCAS.
Accordingly, it is presently believed that PR0703 polypeptide disclosed in the present application is a newly identified member of the VLCAS family and possesses the ability to facilitate the cellular transport of long and very long chain fatty acids typical of the VLCAS
family.

16. dull-IenQth PR0705 Poly~,e tR ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides.
referred to in the present application as PR0705: In particular, Applicants have identified and isolated cDNA
encoding a PR070S polypeptide. as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR070S
polypeptide has significant similarity to the K-glypican protein. Accordingly, it is presently believed that PR0705 polypeptide disclosed in the present application is a newly identified member of the glypican family of proteoglycan proteins.
17. Full-length PR0708 Polvoeutides The present invention provides newly identified and isolated nucleotide sequences encoding poiypeptides referred to in the present application as PR0708. In particular, Applicants have identified and isolated cDNA
encoding a PR0708 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0708 polypeptide has significant homology with the aryl sulfatase proteins. Applicants have also found that the DNA encoding the PR0708 polypeptide has significant homology with DNA encoding the aryl sulfatase proteins.
Accordingly, it is presently believed that PR0708 polypeptide disclosed in the present application is a newly identified aryl sulfatase homolog.
18. Full-lend PR0320 Polvpgptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0320. In particular, Applicants have identified and isolated eDNA
encoding a PR0320 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0320 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0320 polypeptide have significant homology to the fibulin protein. More specifically, an analysis of the Dayhoff database (version 35.45 Swissl'rot 3S) evidenced significant homology between the PR0320 amino acid sequence and the following Dayhoff sequences, human fibulin-2 precursor, 2S designated "FBL2 HUMAN", human fibulin-1 isoform a precursor, designated "FBLA HUMAN", ZK783.1 -Caenorhabditis elegans, designated "CELZK783_1", human-eotch2, designated "HSU77493~1", lVe1 protein precursor - rattus norvegicus, designated "NEL RAT", Mus musculus cell surface protein, designated "D32210 1 ", mouse (fragment) Notch B protein, designated "A4917S", CSOH2.3a -Caenorhabditis elegans, designated "CECSOH2 3", MEC-9L - Caenorhabditis elegans, designated "CEU33933,1 ", and Mus musculus notch 4, designated "10 MMMHC29N7 2", thereby indicating that PR0320 may be a novel fibulin or fibulin-like protein.
Accordingly, it is presently believed that PR0320 polypeptide disclosed in the present application is a newly identified member of the fibulin family and possesses biological activity typical of the fibuIin family.
Z9. Full-length J RP 0324 Po~qZe~ti~a ,~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0324. In particular, Applicants have identified and isolated cDNA
encoding a PR0324 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0324 polypeptide has significant similarity to oxidoreductases. Accordingly, it is presently believed that PR0324 poiypeptide disclosed in the present application is a newly identified oxidoreductase homolog.
20. Full-length PR0351 Po~!peptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0351. in particular, Applicants have identified and isolated cDNA
encoding a PR0351 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0351 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0351 polypeptide possess significant sequence similarity to the prostasin protein, thereby indicating that PR0351 may be a novel prostasin protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0351 amino acid sequence and the following Dayhoff sequences, "AC003965_1", "CELC07G1 7", "GEN12917", "HEPS HUMAN", "GEN14584", "MCT6 MOUSE", "HSU75329_1", "PLMN ERIEU", "TRYB
HUMAN", and "P W229$7". Accordingly, it is presently believed that PR0351 polypeptide disclosed in the present application is a newly identified member of the prostasin family and possesses properties and activities typical of the prostasin family.
21. dull-length PR0352 Poiypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0352. In particular, Applicants have identified and isolated cDNA
encoding a PR0352 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligtunent computer programs, Applicants found that the PR0352 polypeptide has significant similarity to the butyrophilin protein. Accordingly, it is presently believed that PR0352 polypeptide disclosed in the present application is a newly identified butyrophilin homolog.
22. Full-leng_,th PR0381 PolYpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0381. In particular, Applicants have identified and isolated cDNA
encoding a PR0381 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0381 polypeptide has significant similarity to immunophiIin proteins. Accordingly, it is presently believed that PR0381 polypeptide disclosed in the present application is a newly identified FKBP immunophilin homolog.
23. Full-leneth PR0386 Polvneotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0386. In particular, Applicants have identified and isolated cDNA
encoding a PR0386 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0386 polypeptide has significant similarity to the beta-2 subunit of a sodium chatmel protein. Accordingly, it is presently believed that PR0386 polypeptide disclosed in the present application is homolog of a beta-2 suhunit of a sodium channel expressed in mammalian cells.

Z4. ~u11-length ~R0540 PolxpgFt~ldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0540. In parcicutar, Applicants have identified and isolated cDNA
encoding a PR0540 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0540 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0540 polypeptide possess significant sequence similarity to the LCAT protein, thereby indicating that PR0540 may be a novel LCAT protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0540 amino acid sequence and the following Dayhoff sequences, phosphatidylchoIine-sterol acyltransferase, designated "LCAT HUMAN°, hypothetical 75.4 kd protein, designated "YN84'YEAST", Bacillus hcheniformis esterase, designated "BLU35855_1", macrotetrolide resistance protein - Strepromyces, designated "JH0655", T-cell receptor delta chain precursor, designated "C30583", Rhesus kringle 2, designated "P
W07551", RAGE-1 ORFS, designated "HSU46I9I 3", human Ig kappa chain VKII1-1K3, designated "HSU07466 1", and Alstroemeria inodora reverse transcriptase, designated "AL1223606 1 ". Accordingly, it is presently believed that PR0540 polypeptidc disclosed in the present application is a newly identified member of the LCAT protein family and possesses lipid transport capability typical of the LCAT family.
25. Fu1!-I~glh QROblS Pol_ypgntidg~
The present invention provides: newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0615. In particular, Applicants have identified and isolated cDNA
encoding a PR0615 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0615 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0615 polypeptide possess significant sequence similarity to the human synaptogyrin protein, thereby indicating that PR0615 may be a novel synaptogyrin protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0615 amino acid sequence and the following Dayhoff sequences, "AF039085_I", "RNU39549~I", "CELT08A9 8", "FSU62028~1", "573645", "Y348 MYCPN", "AC000103 5", "", "RTI2 LEITA", and "EBVLMP218 I". Accordingly, it is presently believed that PR0615 polypeptide disclosed in the present application is a newly identified member of the synaptogyrin family and possesses activity and properties typical of the synaptogyrin family.
25. Full-length PR0618 Poix~ tn ides .
The present invention provides newly identified and: isolated nucleotide sequences encoding polypeprides referred to in the present application as PR0618. in particular, Applicants have identified and isolated cDNA
encoding a PR0618 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0618 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0618 polypeptide possess significant sequence similarity to the enteropeptidase protein, thereby indicating that PR0618 may be a novel enteropeptidase. More specifically, an analysis of the Dayhoi~ database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0618 amino acid sequence and the following Dayhoff sequences, "P W22987", "KAL HUMAN", "ACtJ039b5_1", "GEN1291?", "ENTK_HUMAN", "FA11 HUMAN", "HSU75329_I"> "P
W2298b". and "PLMN HORSE". Accordingly, it is presently believed that PR0618 polypeptide disclosed in the present application is a newly identified member of the enteropeptidase family and possesses catalytic activity typical of the enteropeptidase family.
27.. Full-length PR0719 Pollrpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO719. In particular, Applicants have identified and isolated cDNA-encoding a PR0719 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0719 polypeptide has significant similarity to ' the lipoprotein lipase H protein. Accordingly, it is presently believed that PRO719 polypeptide disclosed in the present application is a newly identified lipoprotein lipase H homoiog.
28. Full-IenEth PR0724 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0724. In particular, Applicants have identified and isolated cDNA
encoding a PRO724 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PRO724 polypeptide has significant similarity to the human low density lipoprotein (LDL) receptor protein. Accordingly, it is presently believed that PRO?24 polypeptide disclosed in the present application is a newly identified LDL
receptor homolog.
29. Full-length PRO772 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO772. In particular, Applicants have identified and isolated cDNA
encoding a PRO??2 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PRO??2 polypeptide has significant similarity to the human A4 protein. Accordingly, it is presently believed that PRO772 polypeptide disclosed in the present application is a newly identified A4 protein homolog.
30. Full-leneth PR0852 PolyRe_ptides The present invention provides -newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as FR0852. In particular, Applicants have identified and isolated cDNA
encoding a PR0852 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0852 polypepride has significant similarity to various protease proteins. Accordingly, it is presently believed that PR0852 polypeptide disclosed in the present application is a newly identified protease enzyme hotnolog.
31. III-length PR085,~ Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the 'present application as PR0853. In particular, Applicants have identified and isolated cDNA

encoding a PR0853 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0853 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0853 polypeptide possess significant sequence similarity to the reductase protein, thereby indicating that PR0853 may be a novel reductase. More specifically, an analysis of the Dayhoff database (version 35:45 SwissProt 35) evidenced significant sequence similarity between the PR0853 amino acid sequence and the following Dayhoff sequences, "P W03198", "CEC15H11 6", "MT'V030_12", "P W15759", "542651", "ATAC00234314", "MTV022 13", "SCU43704 1", "CELE04F6w7", and "ALFA
1". Accordingly, it is presently believed that PR0853 polypeptide disclosed in the present application is a newly identified member of the reductase family and possesses the antioxidant enzymatic activity typical of the reductase family.
32. Full-length PR086b Polypeptides The present invention provides newsy identified and isolated nucleotide sequences encoding poiypeptides referred to in the present application as PRO$60. In particular, Applicants have identified and isolated cDNA
encoding a PR0860 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0860 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0860 polypeptide possess significant sequence similarity to the neurofascin protein, thereby indicating that PR0860 may be a novel neurofascin. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0860 amino acid sequence and the following Dayhoff sequences; "AF040990_1", "AF041053~1", "CELZK377 2", "RNU8103S_I", "D86983_1", "S26I80", "MMBIG2A 1 ", "S46216", and "RNU68726 1". Accordingly, it is presently believed that PR0860 polypeptide disclosed in the present application is a newly identified member of the neurofascin family and possesses the cellular adhesion properties typical of the neurofascin family.
33. Full-length PR0846 ~'ulvpeptid_g~
The present invention provides newly identified aml isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0846. In particular, Applicants have identified and isolated cDNA
encoding a PR0846 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0846 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0846 polypeptide possess significant sequence similarity to the CMRF35 protein, thereby indicating that PR0846 may be a novel CMRF35 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0846 amino acid sequence and the following Dayhoff sequences,"CM35'HUMAN°, "AF035963i1"; "PIGR RABIT", "AF043724~1", "RNU89744_1", "A52091,~1", ''S4884I", "ELK06A9 3", and "AF049588_1 ". Accordingly, it is presently believed that PR0846 polypeptide disclosed in the present application is a newly identified member of the CMRF35 protein family and possesses properties typical of the CMRF35 protein family.
34. Full-lenEth PR0862 Pol~rpe ti c The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0862. in particular, Applicants have identified and isolated cDNA
encoding a PR0862 polypeptide, as disclosed in further detail in the 3rxamples below. Analysis of the amino acid sequence of the full-length PR0862 polypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0862 polypeptide possess significant sequence similarity to the lysoryme protein, thereby indicating.that PR0862 may be a novel tysoryme protein. More specificahy, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0862 amino acid sequence and the following Dayhoff sequences, "P P90343", and "LYC'HUMAN.
Accordingly, it is presently believed that PR0862 polypeptide disclosed in the present application is a newly identified member of the lysoryme family and possesses catalytic activity typical of the lysozyme family.
35. Full-Ien~th PR0864 Polyp~ptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0864. In particular, Applicants have identified and isolated cDNA
encoding a PR0864 polypeptide, as disclosed in further detail in the Examples below. Analysis of the amino acid sequence of the full-length PR0864 poiypeptide using BLAST and FastA sequence alignment computer programs, suggests that various portions of the PR0864 polypeptide possess significant sequence similarity to the Wnt-4 protein, thereby indicating that PRO864 rnay be a novel Wnt-4 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant sequence similarity between the PR0864 amino acid sequence and the following Dayhoff sequences, "WNT4 MOUSE", "WNT3_MOUSE", "WNSAlHUMAN", "WN?B MOUSE",'WN3A MOUSE", "XLU66288 1", "WN13 HUMAN", "WNSB ORYLAp, "WNTZ,MOUSE°, and "WN7A MOUSE". Accordingly, it is presently believed that PR0864 polypeptide disclosed in the present application is a newly identified member of the Wnt-4 protein family and possesses properties typical of the Wnt-4 protein family.
36. Full-length PR0792 Pohepeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0792. In particular, Applicants have identified and isolated cDNA
encoding a PR0792 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0792 polypeptide has significant similarity to the CD23 protein. Accordingly, it is presently believed that PR0792 polypeptide disclosed in the present application is a newly identified CD23 homalog.
37. Ft~l1-length PR0866 Poly~eotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0866. In particular, Applicants have identified and isolated cDNA
encoding a PR0866 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0866 polypeptide has significant similarity to various mindin and spondin proteins. Accordingly, it is presently believed that PR0866 polypeptide disclosed in the present application is a newly identified mindin/spondin homolog.

WO 99146281 PCTlUS99I05028 38. Full-lengtt~R0871 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0871. In particular, Applicants have identified and isolated cDNA
encoding a PR0871 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0871 polypeptide has significant similarity to the CyP-60 protein. Accordingly, it is presently believed that PR0871 polypeptide disclosed in the present application is a newly identified member of the cyclophilin protein family and possesses activity typical of the cyclophilin protein family.
39. Full-length PRO873 Polypeptldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0873. In particular, Applicants have identified and isolated cDNA
encoding a PR0873 polypeptidc, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequetxe alignment computer programs, Applicants found that the PR0873 polypeptide has significant similarity to a human liver carboxylesterase: Accordingly, it is presently believed that PR0873 polypeptide disclosed in the present application is a newly identified member of the carboxylesterase family and possesses enzymatic activity typical of the carboxylesterase family.
40. Full-length PR0940 Polyp~tide~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0940. In particular, Applicants have identified and isolated cDNA
encoding a PR0940 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0940 polypeptide has significant similarity to CD33 and the OB binding protein 2. Accordingly, it is presently believed that PR0940 polypeptide disclosed in the present application is a newly CD33 andlor OB binding protein-2 homolog.
41. Full-length PR0941 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the presem application as PR0941. In particular, Applicants have identified and isolated cDNA
encoding a PR0941 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0941 polypeptide has significant similarity to o~ or more cadhetin proteins. Accordingly, it is preserttty believed that PR4941 poiypeptide disclosed in the present application is a newly identified cadherin homolog.
42. Full-length PRQ944 Polypeptide~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0944. In particular, Applicants have identified and isolated cDNA
encoding a PR0944 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aligrnnent computer programs, Applicants found that the PR0944 polypeptide has significant similarity to the CPE-R cell surface protein. Accordingly, it is presently believed that PRO944 polypeptide disclosed in the present application is a newly identified CPE-R homolog.
43. Full-length PR0983 Polvoentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0983. In particular, Applicants have identified and isolated cDNA
encoding a PR0983 polypeptide, as disclosed in further detail in the Examples beiow_ Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0983 polypeptide has significant similarity to the vesicle-associated protein, VAP-33. Accordingly, it is presently believed that PRO983 polypeptide disclosed in the present application is a newly identified member of the vesicle-associated membrane protein fancily and possesses activity typical of vesicle-associated membrane proteins.
44. Full-length PR01057 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01057. In particular, Applicants have identified and isolated cDNA
encoding a PR01057 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
i5 sequence alignment computer programs, Applicants found that the PR01057 polypeptide has significant similarity to various protease proteins. Accordingly, it is presently believed that PR01057 polypeptide disclosed in the present application is a newly identified protease homolog.
45. dull-leng~ PR01071 Poly~peptides The present invention provides newly identified and isolated nucleotide seguences encoding polypeptides referred to in the present application as PR01071. Tn particular, Applicants have identified and isolated cDNA
encoding a PR01071 polypeptide, as disclosed in further detail in the Examples below. Using Bi.AST and FastA
sequence alignment computer programs, Applicants found that the PR01071 polypeptide has significant similarity to the thrombospondin protein. Accordingly, it is presently believed that PROIO?I poiypeptide disclosed in the present application is a newly identified thrombospondin homolog.
46. Full-length PR0107Z Polvne t The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01072. in particular, Applicants have identified and isolated cDNA
encoding a PR01072 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR01072 polypeptide has significant similarity to various reductase proteins. Accordingly, it is presently believed that PR01072 polypeptide disclosed in the present application is a newly identified member of the reductase protein family 47. Full length PR01075 Polvuentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01075. In particular, Applicants have identified and isolated cDNA
encoding a PR01075 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR01075 polypeptide has significant similarity WO 99/4628! PCTIUS99/05028 to protein disulfide isomerase. Accordingly, it is presently believed that PR01075 polypeptide disclosed in the present application is a newly identified member of the protein disulfide isomerase family and possesses activity typical of that family.
48. Full-length PROI81 Polypeptide~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0181. In particular, Applicants have identified and isolated cDNA
encoding a PR0181 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0181 polypeptide has significant similarity to the cornichon protein. Accordingly, it is presently believed that PR0181 polypeptide disclosed in the present application is a newly identified cornichon homolog.
49. Full-. ength PP 0195 Pol~"peptidgs The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0195. In particular, Applicants have identified and isolated cDNA
encoding a PROI95 polypeptide, as disclosed in further detail in the Examples below. The PR019S-encoding clone was isolated from a human fetal placenta library using a trapping technique which selects for nucleotide sequences encoding secreted proteins. To Applicants present knowledge, the UNQ169 (DNA2b847-1395} nucleotide sequence encodes a novel factor; using BLAST and FastA sequence alignment computer programs, no sequence identities to airy known proteins were revealed.
50: Full-lenEth PR0865 ~olypg tl~des The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0865. In particular, Applicants have identified and isolated cDNA
encoding a PR0865 polypeptide, as disclosed in fiirther detail in the Examples below. The PR0865-encoding clone was isolated from a human fetal kidney library using a trapping technique which selects for nucleotide sequences encoding secreted proteins. Thus, the PR0865-encoding clone may encode a secreted factor. To Applicants present knowledge, the UNQ434 (DNAS3974-1401) nucleotide sequence encodes a novel factor; using BLAST and FasiA
sequence alignment computer programs, no sequence identities to any known proteins were revealed.
51. Full-length PR0827 Polvoentldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0827. In particular, Applicants have identified and isolated cDNA
encoding a PR0827 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0827 polypeptide has significant similarity to VLA Z and various other ituegrin proteins. Accordingly; it is presently believed that PR0827 polypeptide disclosed in the present application is a novel integrin protein or splice variant thereof.

52. Full-length PR01114 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01114. In particular, Applicants have identified and isolated cDNA
encoding a PR01114 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PROl I 14 polypeptide has significant similarity to the cytokine receptor family of proteins. Accordingly, it is presently believed that PROl l 14 polypeptide disclosed in the present application is a newly identified member of the cytokine receptor family of proteins and possesses activity typical of that family.
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01114 interferon receptor (UNQ557). In particular, cDNA encoding a PR01114 interferon receptor polypeptide has been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO
numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
However, for sake of simplicity, in the present specification the protein encoded by DNA57033-1403 as well as all further native homologues and variants included in the foregoing definition of PR01114 interferon receptor, will be referred to as "PROI 114 interferon receptor", regardless of their origin or mode of preparation.
Using the WU-BLAST2 sequence alignment computer program, it has been found that a full-length native sequence PR01114 interferon receptor polypeptide (shown in Figure 142 and SEQ
ID N0:352) has sequence identity with the other known interferon receptors. Accordingly, it is presently believed that PROI114 interferon receptor possesses activity typical of other interferon receptors.
53. Full-length PR0237 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0237. In particular, Applicants have identified and isolated cDNA
encoding a PR0237 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0237 polypeptide has significant similarity to carbonic anhydrase. Accordingly, it is presently believed that PR0237 polypeptide disclosed in the present application is a newly identified carbonic anhydrase homolog.
54. Full Length PRO541 Polyne ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0541. In particular, Applicants have identified and isolated cDNA
encoding a PR0541 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0541 polypeptide has significant similarity to a trypsin inhibitor protein. Accordingly, it is presently believed that PR0541 polypeptide disclosed in the present application is a newly identified member of the trypsin inhibitor protein family 55. Full-length PRQ273 PoivpgRh~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0273. In particular, Applicants have identified and isolated cDNA

encoding a PR0273 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0273 polypeptide have significant sequence identity with various chetnoldttes. Accordingly, it is presently believed that PR0273 polypeptide disclosed in the present application is a newly identified member of the chemokine family and possesses activity typical of the chemokine family_ 56. Full-length PR0701 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0701. In particular, Applicants have identified and isolated cDNA
encoding a PR0701 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0701 polypeptide have significant homology with the neuroIigins 1, 2 and 3 and esterases including carboxyesterases and acytlcholinesterases. Accordingly, it is presently believed that PR0701 polypeptide disclosed in the present application is a newly identified member of the neuroligin family and is -involved in mediating recognition processes between neurons andlor functions as a cell adhesin molecule as is typical of neuroligins.
57. Full-length PR0704 Polype-ptides The present invention provides newly identif:ed and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0704. In particular, Applicants have identified and isolated cDNA
encoding a PR0704 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0704 polypeptide have . significant homology with the VIP36 and GP36b: Accordingly, it is presently believed that PR0704 polypeptide disclosed in the present application is a newly identified member of the vesicular integral membrane protein family and possesses the ability to bind to sugars and cycle between the plasma membrane and the Golgi typical of this family.
58. FuII.Ig~sth PR0706 Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0706: In particular, Applicants have identified and isolated eDNA
encoding a PR0706 polypepiide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs; Applicants found that various portions of the PR0706 polypeptide have sequence identity with tht human prostatic acid phosphatase precursor and the human Iysosomal acid phosphatase precursor. Accordingly, it is presently believed that PR0706 polypeptide disclosed in the present application is a newly identified member of the humanprostatic acid phosphatase precursor family and possesses phosphacase typical of the acid phosphatase family.
59. Fvll-lenlen~,h PR0707 Polvoeotides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0707. In particular, Applicants have identified and isolated cDNA
encoding a PR0707 polypeptide; as disclosed in further detail in the Examples below. Using BLAST and FastA

WO 991d6281 PCT/US99/05028 sequence alignment computer programs, Applicants found that various portions of the PR0707 polypeptide have significant homology with cadherins, particularly cadherin FiB3 found in fibroblasts. Accordingly, it is presently believed that PR0707 polypeptide disclosed in the present application is a newly identified member of the cadherin family and possesses cell interaction signaling typical of the cadherin family.
S 60. Full-length PR~olypeptldes The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0322. In particular, Applicants have identified and isolated cDNA
encoding a PR0322 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0322 polypeptide have signi5cant homology with human neuropsin, serine protease, neurosin and trypsinogen. Accordingly, it is presently believed that PR0322 polypeptide disclosed in the present application is a newly identified member of the serine protease family and possesses protease activity typical of this family. It is also believed that PR0322 is involved in hippocampal plasticity and is associated with extracellular matrix modifications and cell migrations.
61. Full-len~tl~ PR0526 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0526. In particular, Applicants have identified and isolated cDNA
encoding a PR0526 polypeptide, as disclosed in further detail in the Examples below: Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR052ti polypeptide have significant homology with the acid labile subunit of the insulin-like growth factor complex (ALS), as well carboxypeptidase, SLIT, and platelet glycoprotein V. Accordingly, it is presently believed that PR0526 polypeptide disclosed in the present application is a newly identified member of the leucine-repeat rich superfamily, and possesses protein-protein interaction capabilities typical of this family.
62. Full-length PR0531 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0531. In particular, Applicants have identified and isolated cDNA
encoding a PR0531 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0531 polypeptide have significant sequence identity and similarity with members of the cadherin superfamily, particularly; protocadherin 3. Accordingly, it is presently believed that PR053 l polypeptide disclosed in the present application is a newly identified member of the cadherin superfamily, and is a protocadherin. PR0531 is a transtnembrane protein which has extracelhtlar cadherin motifs. PR0531 is believed to be involved in cell-cell activity, in particular, cell signaling.
63. Full-length PR053d Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0534. In particular, Applicants have identified and isolated cDNA
encoding a PR0~34 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0534 polypeptide have significant identity or similarity with the putative disulfide isomerase erp38 precursor and thioredoxin c-3.
Accordingly, it is presently believed that PROS34 polypeptide disclosed in the present application is a newly identified member of the disulfide isomerase family and possesses the ability to recognize and unscramble either intermediate or incorrect folding patterns typical of this family.
6d. Full-len~h PR0697 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as. PR0697. In particular, Applicants have identified and isolated cDNA
encoding a PR0697 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0697 poiypeptide have significant identity or similarity with sFRP-2, sFRP-1 and SARP-I, -2 and -3.
Accordingly, it is presently believed that PR0697 polypeptide disclosed in the present application is a newly identified member of the sFRP family and possesses activity related to the Wnt signal pathway.
65. Full-length PR0717 Poh~epti gc 1S The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the presem application as PR0717. In particular, Applicants have identified and isolated cDNA
encoding a PRO717 polypeptide, as disclosed in further detail in the Examples below. To Applicants present knowledge, the UNQ385 (DNAS0988-1326) nucleotide sequence encodes a novel factor; using BLAST and FastA
sequence alignment computer programs, no significant sequence identities to any known human proteins were revealed.
66. Full-length PRf~731 Pglypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0731.. In particular, Applicants have identified and isolated eDNA
encoding a PR0731 polypeptide, as disclosed in furthex detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0731 polypeptide have significant homology with the protocadherins 4, 68, 43, 42, 3, and 5.
Accordingly, it is presently believed that PR0731 polypeptide disclosed in the presern application is a newly identified member of the protocadherin family aad possesses cell-cell aggregation ox signaling activity or signal transduction involvement typical of this family.
67. Full-leng,~h_PR021~ Polvnentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0218. In particular, Applicants have identified and isolated cDNA
etroding a PR0218 polypeptide, as disclosed in further detail in the Examples below. The PR0218-encoding clone was isolated from a human fetal kidney library. To Applicants present knowledge, the UNQ192 (DNA30867-1335) nucleotide sequence encodes a novel factor; using BLAST and FastA sequence alignment computer programs, no significant sequence identities to any known proteins were revealed. Some sequence identity was found with membrane regulator proteins, indicating that PR0218 may function as a membrane regulator.

68. Full-length PR0768 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0768. In particular, Applicants have identified and isolated cDNA
encoding a PR0768 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0768 polypeptide have significant homology with integrins, including integrin 7 and 6. Accordingly, it is presently believed that PR0768 polypeptide disclosed in the present application is a newly identified member of the integrin family, either a homologue or a splice variant of integrin 7, and is involved with cell adhesion and communication between muscle cells and the exuacellular matrix.
69. Full-length PR077I Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0771. In particular, Applicants have identified and isolated cDNA
encoding a PR0771 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs. Applicants found that various portions of the PR07?1 polypeptide have significant sequence identity and similarity with testican. Accordingly, it is presently believed that PR0771 polypeptide disclosed in the present application is a newly identified member of the testican family and possesses cell signaling, binding, or adhesion properties, typical of this family.
70. dull-length PR0733 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0733. In particular, Applicants have identified and isolated eDNA
encoding a PR0733 goIypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0733 polypeptide have significant sequence identity with the T1/ST receptor binding protein.
Accordingly, it is presently believed that PR0733 polypeptide disclosed in the present application is a newly identified member of the interleukin-like family binding proteins which may be a cytokine and which may be involved in cell signaling. It is believed that PR0733 is an ApoAIV homologue.
7I. F,~11-lenQth~RQ,~62 olyneptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0162. In particular, Applicants have identified and isolated cDNA
encoding a PR0162 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0162 polypeptide have significant homology with human pancreatitis-associated protein (PAP).
Applicants have also found that the DNA
encodutg the PR0162 polypeptide has significant homology with bovine Iithostathine precursor and bovine pancreatic thread protein (PTP). Accordingly, it is presently believed that PR0162 polypeptide disclosed in the present application is a newly identified member of the pancreatitis-associated protein family and possesses activity typical of the pancreatitis-associated protein family.

WO 99/46281 PCTlUS99/05028 72. Full-length PR078$"~olypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO?88. In particular, Applicants have identified and isolated cDNA
encoding a PRO788 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR0788 polypeptide have significant homology with the anti-neoplastic urinary protein. Applicants have also found that the DNA encoding the PR0788 polypeptide has significant homology with human E48 antigen, human component B protein, and human prostate stem cell antigen. Accordingly, it is presently believed that PR0788 potypeptide disclosed in the present application is a newly identified member of the anti-neoplastic urinary protein family and possesses anti-neoplastic activity typical of the anti-neoplastic urinary protein family.
73. Full-length r,'RO~ Poly,peptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01008. In particular, Applicants have identified and isolated cDNA
encoding a PR01008 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR01008 polypeptide have significant sequence identity and similarity with mouse dkk-1 (mdkk-1).
Accordingly, it is presently believed that PROI008 polypeptide disclosed in the present application is a newly identified member of the dkk-i family and possesses head inducing activity typical of this family.

74. Fnll-lenQ,.,th PROIOl2 qlypgpxilles The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PROl0I2. In particular, Applicants have identified and isolated cDNA
encoding a PROIOI2 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR01012 polypeptide have sequence identity with disulfide isomerase. Accordingly, it is presently believed that PR01012 polypcptide disclosed in the present application is a newly identified member of the ER retained protein family and possesses activity related to the processing, production and/or folding of polypeptides typical of the disulfide isomerase family.

75. Full~length_,PR01014 Poh~ptidg~
The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01014. In particular, Applicants have identified and isolated cDNA
encoding a PR01014 poiypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence aIigtunent computer programs, Applicants found that various portions of the PR01014 polypeptide have sequence identity with reductase and dehydrogenase. Accordingly, it is presently believed that PR01014 poiypeptide disclosed in the present application is a newly identified member of the reductase super family and possesses reduction capabilities typical of this family.

7b. Full-length PROI01'7 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01017. 1n particular, Applicants have identified and isolated cDNA
encoding a PR01017 poIypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR01017 polypeptide have sequence identity with HNK-1 suifotransferase. Accordingly, it is presently believed that PR01017 polypeptide disclosed in the present application is a newly identified member of the HNK-I
sulfotransferase family and is involved with the synthesis of HNK-1 carbohydrate epitopes typical of this family.
?7. Full-length PR0474 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0474. In particular, Applicants have identified and isolated cDNA
encoding a PR0474 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR04?4 polypeptide have sequence identity with dehydrogenase, glucose dehydrogenase and oxidoreductase. Accordingly, it is presently believed that PR0474 polypeptide disclosed in the present application is a newly identified member of the dehydrogenase family and is involved in the oxidation of glucose.
?8. Full-length PR0~031 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01031. In particular, Applicants have identified and isolated cDNA
encoding a PR01031 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that various portions of the PR01031 polypeptide have sequence identity with IL-17 and CTLA-8. Accordingly, it is presently believed that PR01031 polygeptide disclosed in the present application is a newly identified member of the cytoldne family and thus may be involved in inflammation andJor the immune system.
79. dull-length PR0938 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0938. In particular, Applicants have identified and isolated cDNA
encoding a PR0938 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA
sequence alignment computer programs, Applicants found that the PR0938 polypeptide has significant similarity to protein disulfide isomerase. Accordingly, it is presently believed that PR0938 polypeptide disclosed in the present application is a newly identified member of the thioredoxin family proteins and possesses activity typical of protein disulfide isomerase.
80. Full length PR~1082 Polvneutides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01082. In particular, Applicants have identified and isolated cDNA
encoding a PR01082 polypepiide, as disclosed in further detail in the Examples below. Using BLAST and FastA

sequence alignment computer programs, Applicants found that various portions of the PROI082 polypeptide have sequence; identity with a lectin-like oxidized LDL receptor appearing in the database as "AB010710_1 ". Accordingly, it is presently believed that 1?R01082 polypeptide disclosed in the present application is a newly identified member of the LDL receptor family.
81. Full-length PR01083 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR01083. In particular, Applicants have identified and isolated cDNA
encoding a PROI083 polypeptide, as disclosed in further detail in the Examples below. The PRO10$3-encoding clone was isolated from a human fetal kidney library using a trapping technique which selects for nucleotide sequences IO encoding secreted proteins. To Applicants present knowledge, the UNQ540 (DNAS0921-1458) nucleotide sequence encodes a novel factor; using BLAST and FastA sequence alignment computer programs, some sequence identity with a 7TM receptor, latrophilin related protein 1 and a macrophage restricted cell surface glycoprotein was shown. The kinase phosphorylation site and G-coupled receptor domain shown in Figure 204 indicate that PR01083 is a novel member of the 7TM receptor superfamily.
82. Full-length PRO200 Poixpentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as VEGF-E. In particular, Applicants have identified and isolated cDNA
encoding a VEGF-E polypeptide, as disclosed in further detail in the Examples below. Using BLAST sequence alignment computer programs, Applicants found that the VEGF-E polypeptide has significant homology with VEGF
and bone morphogenetic protein 1. in particular, the cDNA sequence of VEGF-E
exhibits 24 % amino acid similarity with VEGF and has structural conservation. In addition, VEGF-E contains a N-terminal half which is not present in VEGF aril that has 28 % homology to bone morphogenetic protein 1.
ZS 83. 1Fu11-lenEth PR0285 and PR0286~'olvoentides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR02$5 and PR0286 In particular, Applicants have identified and isolated cDNAs encoding PR0285 and PR0286 polypeptides, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that the coding sequences of PR0285 and PR028fi are highly homologous to DNA sequences HSU88540 I; HSU88878,1, HSU88879 1, HSU88$80_I, and HSU8888I 1 in the GenBank database.
Accordingly, it is presently believed that the PR0285 and PR0286 proteins disclosed in the present application are newly identified human homologues of the Drosophilrt protein Toll, and are likely to play an important role in adaptive immunity. More specifically, PR0285 and PR028b may be involved in inflammation, septic shock, and response to pathogens, and play possible roles in diverse medical conditions that are aggravated by immune response, such as, for example, diabetes, ALS, cancer, rheumatoid arthritis, and ulcers. The role of PR0285 and PR0286 as pathogen pattern recognition receptors, sensing the presence of conserved molecular structures present on microbes, is further supported by the data disclosed in the present application, showing that a known human Toll-Like receptor, TLR2 is a direct mediator of LPS signaling.

84. Full-length PR0213-1. PR01330 arid PR01449 Polype tn ides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR02I3-1, PR01330 andtor PR01449. In particular, cDNA encoding a PR0213-1, PROi330 andlor PR01449 polypeptide has been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO
numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
However, for sake of simplicity, in the present specification the protein encoded by DNA30943-1163-1, DNA64907-1163-1 and DNA64908-I I63-1 as well as all further native homologues and variants included in the foregoing definition of PR0213-1, PR01330 andlor PR01449, will be referred to as "PR02I3-1, PR01330 andlor PR01449", regardless of their origin or mode of preparation.
85. Full-len~h PR0~8 Polvpeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0298. (it is noted that FR0298 is an arbitrary designation of a protein encoded by the nucleic acid shown in Figure 218. SEQ ID NO: 514, and having the amino acid sequence shown in Figure 219, SEQ ID NO:515. Further proteins having the same amino acid sequence but expressed in different rounds of expression, may be given different "PRO" numbers.) in particular, Applicants have identified and isolated cDNA encoding a PRO298 polypeptide; as disclosed in fiuttier detail in the Examples below. Using BLASTX 2.Oa8MP-WashU computer program, socring parameters:
T=12, S=68, S2=36, Matrix: BLOSUM62, Applicants found that the PR0298 protein specifically disclosed herein shows a limited (27-38 %) sequence identity with the following sequences found in the Gen$ank database: 559392 (probable membrane protein YLR246w - yeast); 558154 (hypothetical protein SPAC2F7.10 - yeast); CELF33D 11 9 (F33D11.9b - Caenorhabditis elegans); Y041~CAEEL (hypothetical 68.7 kd protein zk757.1); CEAC3~5 {AC3.4 Caenorhabditis elegatis); S52691 (probable transmembrane protein YDR126w -yeast}; ATT12H17'14 (protein Arabidopsis _thaliana); S55963 (probable membrane protein YNL326c - yeast);
CELC43H6 2 {C43H6.7 Caenorhabditis elegans); TM018A10_14 (A TM018A10.8 - Arabinosa thaliana).
86. Full teneth PR033? Polypentides The pzesem invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to un the present application as PRO337. In particular, Applicants have identified and isolated cDNA
encoding a PR0337 polypeptide, as disclosed in further detail in the Examples below. Using BLAST, BLAST-2 and FastA sequence aligzurtent computer programs, Applicants found that a full-length native sequence PR0337 has 97 ~
amino acid sequence identity with rat neuroaimiri, 85 % sequei>ce identity with chicken CEPU, 73 % sequence identity with chicken GSS, 59% homology with human LAMP and 84% homology with hu~naatt OFCAM. Accordingly, it is presently believed that PR0337 disclosed in the present application is a newly identified member of the IgLON
sub family of the immunoglobulin superfamily and may possess neurite growth and differentiation potentiating properties.

87. Full-lenEt~ PR(~i03 Polypeptides The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0403. In particular, Applicants have identified and isolated cDNA
encoding a PR0403 polypeptide, as disclosed in further detail in the Examples below. Using a BLAST, BLAST-2 and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PR0403 has 94~ identity to bovine ECE-2 and 64% identity to human ECE-1. Accordingly is presently believed that PR0403 is a new member of the ECE protein family and may posses ability to catalyze the production of active endothelia.
88. P)2,0 Poly,~eptide Variants Tn addition to the full-length native sequence PRO polypeptides described herein, it is contemplated that PRO
polypeptide variants can be prepared. PRO polypeptide variants can be prepared by introducing appropriate nucleotide changes into the PRO polypeptide DNA, or by synthesis of the desired PRO polypeptide. Thane skilled in the art will appreciate that amino acid changes may alter post-translational processes of the PRO polypeptides, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
Variations in the native full-length sequence PRO polypeptides or in various domains of the PRO
polypeptides described herein, can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U:S. Patent No.
5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the PRO
poiypeptide that results in a change in the amino acid sequence of the PRO polypeptide as compared with the native sequence PRO polypeptide. Optionally the variation is by substitution of at Least one amino acid with any other amino acid in one or more of the domains of the PRO polypeptide. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO polypeptide with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties; such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of 1 to 5 amino acids.
The variation allowed xnay be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity in the in vitro assay described in the Examples below.
In particular embodirnettrs, conservative substitutions of interest are shown in Table 1 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table I, or as further described below in reference to amino acid classes, are introduced and the products screened.

WO 99/4b281 PCT/US99/05028 Table 1 Original Exemplary Preferred Resi a S,~bstitutions Substitutions Ala (A) val; iett; ile val Arg (R) lys; gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu gIu Cys (C) ser ser Gin (Q) asn asn Glu (E} asp asp _ Gly {G) pro; ala ala His (H) asn; gln; lys; arg arg Ile (~ leu; val; met; ala; phe;

norleucine leu Leu (L) norleucine; ile; val;

met; ala; phe ile Lys (K) arg; gln; asn arg Met (M) leu; phe; ile leu Phe (l~ leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T} ser ser Trp (W) tyr; phe tyr Tyr (1~ trp; phe; thr; ser phe Val (V) ile; leu; met; phe;

ala; norleucine leu Substantial modifications in function or immunological identity of the PRO
poiypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties:
(1) hydrophobic: norleucine, met, ala, val, leu, ile;
(2) neutral hydrophilic: cys, ser, thr;
(3) acidic: asp, glu;
(4) basic: asn, gln, his, lys, arg;
(5) residues that influence chain orientation: gly, pro; and (b) aromatic: trp, tyr, phe.
Non-conservative substitutions will entail exchanging a member of one of these classes for another class-Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites.
The variations can be made using methods known in the art such as aIigonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl. Acids Res., x:4331 (1986); Zolier et al., Nucl. Acids Res., x:6487 (1987)], cassette mutagenesis [Wells et al., Gene, x:315 (1985)], restriction selectionmutagenesis [Wells et al., Philos. TransiR. Soc.
London SerA, X17:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the desired PRO
polypeptide variant DNA.

Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neutral amino acids. Such amino acids include a3anine, glycine, series, and cysteine. Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant. Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W.H.
Freeman & Co., N.Y.): Chothia, J_.
of Bio ., ~:l (1976)J. If aIanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.
89. Modifications of PRO Polvoentides Covalent modifications of PRO polypeptides are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of the PRO polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PRO
polypeptide. Derivatization with bifunctional agents is useful, for instance, for crosslinking a PRO polypeptide to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO polypeptide antibodies, and vice-versa. Commonly used crosslinking agents include, e.g., 1,I-bis(diazoaceryl}-2-phenylethane, glutaraldehyde, N-bydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'-dithiobis(succinimidylpropionate}, bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidopherryl}dithio]propioimidate.
Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl zesidues, respectively, hydroxylation of proline and lysine, phosphoryiation of hydroxyl groups of seryl or threonyl residues, methylation of the cx-amino groups of lysine, arginine, and histidine side chains [T,E.
Creighton, Proteins: Structure and Molecular Propetties, W.H. Freeman & Co., San Francisco, pp. 79-86 (/983)], acerylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.
Another type of covalent modification of the PRO polypeptides included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide.
"Altering the native glycosylation pattern" is intended for purposes herein to mean deleting one or more carbohydrate moieties found in a native sequence PRO
polypeptide, andlor adding one or more glycosylation sites that are not present in the native sequence PRO
polypeptide, andlor alteration of the ratio andlor composition of the sugar residues attached to the glycosylation site(s).
Addition of glycosylation sites to the PRO polypeptide may be accomplished by altering the amino acid sequence. The alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PRO polypeptide (for O-linked glycosylation sites). The PRO poIypeptide amino acid sequence may optionally be altered through changes at the DNA
level, particularly by mutating the DNA
encoding the PRO polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.
Another means of increasing the number of carbohydrate moieties on the PRO
polypeptide polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the an, e.g., in WO 87!05330 published 11 September 1987, and in Aplin and Wriston, CRC ~~~rit.
Rev. Bi~,chem., pp, 259-306 (1981}.

WO 99/46281 PCTIUS99lO5t128 Removal of carbohydrate moieties present on the PRO polypeptide tray be accomplished chemically or enzytttatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the an and described, for instance, by Hakimuddin, et al., Arch. Biochem. Bionhvs., 259:52 {1987) and by Edge et al., Anal.
Biochem., X18:131 (1981). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzvmol., I3$:3~0 (1987).
Another type of covalent modification of PRO polypeptides of the invention comprises linking the PRO
polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos. 4,640,835;
4,496,689: 4,301,144; 4,670,417;
4,791,192 or 4,179,337.
i0 The PRO polypeptides of the present invention may also be modified in a way to form a chimeric molecule comprising a PRO polypeptide fused to another, heterologous polypeptide or amino acid sequence. In one embodiment, such a chimeric molecule comprises a fusion of the PRO polypeptide with a tag poiypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl- terminus of the PRO polypeptide. The presence of such epitope-tagged forms of the PRO
golypeptide can be detected using an antibody against the tag polypeptide.
Also, provision of the epitope tag enables the PRO polypeptide to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. In an alternative embodiment, the chimeric molecule may comprise a fusion of the PRO polypeptide with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule, such a fusion could be to the Fc region of an IgG
molecule.
Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA
tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8_:2159-2165 {1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biolo~v, x:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineerine,_3_(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Iiopp et al., BioTechnology, _6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Scie c , 55:192-194 {1992)]; an a-tubulin epitope peptide [Skinner et al., J. Biol. Chem., x:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci.USA, 87:6393-6397 (1990)].
90. Prgnaration of PRO PolvtteMides The description below relates primarily to production of PRO polypeptides by culturing cells transformed or transfected with a vector containing the desired PRO polypeptide nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare the PRO polypeptide. For instance, the PRO polypeptide sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, CA
(1969); Merrifield, ~,.-Vim. Gh~tq oc., $_5:2149-2154 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster Ciry, CA) using manufacturer's instructions. Various portions of the desired PRO polypeptide may be chemically synthesized separately and combined using chemical or enzymatic methods to -w produce the full-length PRO poIypeptide.
A. Isolation of DNA Encoding PRO PoiYpeptides DNA encoding PRO polypeptides may be obtained from a cDNA library prepared from tissue believed tv possess the desired PRO polypeptide mRNA and to express it at a detectable level. Accordingly, human PRO
polypeptide DNA can be convenietuly obtained from a cDNA library prepared from human tissue, such as described in the Examples. The PRO polypeptide-encoding gene may also be obtained from a genomic library or by oligonucleotide synthesis.
Libraries can be screened with probes (such as antibodies to the desired PRO
polypeptide or oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genotnic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular Cloning: A i,aboratorv Manpal (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding the desired PRO
polypeptide is to use PCR methodology jSambrook et al., supra; Dieffenbach et al., PCR Primer:A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)j.
The Examples below describe techniques for screening a cDNA library. The oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels Iike'zP-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.
Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases.
Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined through sequence alignment using computer software programs such as BLAST, ALIGN, DNAstar, and INHERIT which employ various algorithms to measure homology.
Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional grittier extension procedures as desen'bed in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that tray not have been reverse-uanscribed into eDNA.
B. Selection and Transformatigi~of Host ells Host cells are transfected or uansforrned with expression or cloning vectors described herein for PRO
polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transfotTnants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology a Praeti~cg~~pproach, M. Butler, ed. (IRL
Fress, 1991) and Sambrook et al., WO 99146281 PCTIUS99l05028 Methods of transfection are known to the ordinarily skilled artisan, for example, CaPO, and electroporation.
Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells.
The calcium treatment employing calcium chloride, as described in Sambrook et al., suvra, or electroporation is generally used for prokaryotes or other cells that contain substantial cell-wall barriers. Infection with Agrvbacterium lumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 2~;315 (1983) and S WO 89105859 published 29 June 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eh, Virology, ,5,x:456-457 (1978) can be employed. General aspects of mammalian cell host system transformations have been described in U.S.
Patent No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et at., J. Bact., 130:946 (1977) and Hsiao et al., Proc. Natl Acads Sci ~, 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, may also be used. For various techniques for transforming mammalian cells, see Keown et al., Methods in Enzvmoloey, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988}.
Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include hut are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E, coti.
Various E. toll strains are publicly available, such as E. colt KI2 strain MM294 (ATCC 31,446); E. toll X177b (ATCC
31,537); E. toll strain W3110 (ATCC 2?,325) and KS 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. toll, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serroria, e.g., Serratia marcescarrs, and Shigella, as well as Bacilli such as B. subtilis and B. tichenifvrmis (e.g., B.
licheniformis 41P disclosed in DD 266,710 published I2 April 1989), Pseudomonas such as P. aeruginvsa, antl Streptorrryces. Various E. toll strains are publicly available, such as E.
toll K12 strain MM294 (ATCC 31,446); E.
toll X1776 (ATCC 31,537); E. coti strain W3110 (ATCC 27,325); and K5 772 (ATCC
53,635). These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. toll W3110 strain 1A2, which has the complete genotype tonA ; E. toll W3110 swain 9E4, which has the complete genotype tonA ptr3; E. toll W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA EIS (argF lac)1d9 degP
ornpT katt ; E. toll W3110 strain 37D6, which has the complete genotype tonA
ptr3 pJzoA EI S (argF lac)169 degP
ompT rbs7 ilvG kan ; E. toll W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. toll strain having mutant periplasmic protease disclosed in U.S. Patent No. 4,946,783 issued ?
August 1990. Alternatively, in vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable.
In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO polypeptide-encoding vectors: Saccluzromyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 2~: 140 [1981]; EP 139,383 published 2 May 1985); Kluyveromyces hosts {LJ.S. Patent No. 4,943,529; Fleer et al., Bio/TechnoloQV, ~: 968-975 (1991)) such as, e.g., K. tacos (MW98-8C, CBS683, CBS4574; Louvencourt et at., J_.
~a~teriol., 737 [1983]), K. fragitis (ATCC 12,424), K. butgaricus (ATCC
16,045), K. fvickeramii {ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technologv, _8: 135 (1990)), K . thermotoierans, and K, matxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J. .
Bash Micropiol., 2~: 265-27$ (1988J); Candida; Trichoderma reesia (EP
244,234); Neurospora crassa (Case et al., Proc. Natl. Aead. Sei. USA, 76: 5259-5263 (1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP
394,538 published 31 October 1990); and filamentous fungi such as, e.g:, Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 3anuary 1991), and Aspergillus hosts such as A.
nidulans {Ballance et al., Biochem.
Biophys. Res. Coltlmun., X1_2: 284-289 [1983]; Tilburn et al., Gene, ~: 205-221 [1983]; Yelton et al., Proc. Natl:
A~,ad. Sci. USA, $1: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO , 4: 475..479 [1985]).
Methylotropic yeasts are suitable herein and include, but are not iitnited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pirhia, Saccharomyces, Torulopsis, and Rhodotoruta. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, to Biochemistr~gMethylotropjis, 269 (1982).
Suitable host cells for the expression of glycosylated PRO polypeptides are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells.
i5 More specific examples include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol., 36;59 (1977)); Chinese hamster ovary cells/ DHFR (CHO, Urlaub and Chasin, Proc N~tl Acad Sci USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol~,)teprod., 23:243-251 (1980));
human lung cells (W138, ATCC CCL
75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCC CCL51). The selection of the appropriate host cell is deemed to be within the skill in the art.
C. Selection and Use of a Rgplicable Vector The nucleic acid (e.g., cDNA or genomic DNA) encoding a desired PRO
polypeptide may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression.
Various vectors are publicly available.
The vector may, far example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endorntdease sites) using techniques known in the art.
Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhattcer element, a promoter, and a transcription termination sequence.
Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan.
The PRO polypeptide of interest may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector; or it may be a pan of the PRO polypeptide DNA that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotozin I1 leaders. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Klttyveromyces a-factor leaders, the latter described in U.S. Patent No. 5,010,182), or acid phosphatase leader, the C.
albicans glucoamylase leader (EP
362,179 published 4 April 1990), or the signal described in WO 90113646 published 15 November 1990. In 1s1 WO 99!46281 PCTlUS99lOS028 mammalian cell expression, rztamrnalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.
Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2~c plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV
or BPV) are useful for cloning vectors in mammalian cells.
Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker.
Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c} supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the FRO polypeptide nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DNFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Nat!. Acad. Sci. USA, 77:4216 (1980). A suitable selection gene for use in yeast is the trill gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979);
Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, x:157 {1980)].
The trill gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, enetics, 8:12 (1977)].
Expression and cloning vectors usually contain a promoter operably linked to the PRO polypeptide nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known.
Promoters suitable for use with prokaryotic hosts include the (3-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., N re, 281:544 (1979)], alkaline phosphatase, a cryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8_:4057 (1980); EP 36,77b], and hybrid promoters such as the tac promoter [deBoer et al., Proc ,,'Nat! Acad. Sci. USA, 80:21-25 (1983)].
Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA
encoding the desired PRO polypeptide.
Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate ldnase [Hitzetnan et al., J Biol. Chcm., x:2073 (I980)] or other glycolytic enzymes [Hess et al., J. Adv, Enzyme Reg., 7:149. (1968); Holland, Biochemistry, 1?:4900 (1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pytuvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3 phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase; and glucokinase.
Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative einymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization.
Suitable vectors and promoters for use in yeast expression are farther described in EP 73,657.
FRO polypeptide transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published S
July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovitus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mamrnaiian promoters, e.g., the actin 1.52 WO 99/46281 PCT/US99l05028 promoter or an itrtnaunoglobulztt promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.
Transcription of a DNA encoding the desired PRO polypeptide by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many etthancer sequences are now known from mammalian genes (globin, elascase, albumin, a-fetoprotein, and insulin).
Typically, however, one will use an etthancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovitus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector as a position 5' or 3' to the PRO
polypeptide coding sequence, but is preferably located at a site 5' from the promoter.
Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO
polypeptides.
Still other methods, vectors, and host cells suitable for adaptation to the synthesis of PRO polypeptides in recombinant vertebrate cell culture are described in Gething et al., Nature, X93:620-625 (1981); Mantel et al., Nature, 2,x,8 :40-46 (1979); EP 117,060; and EP 117,058.
D. Detecting Gene AmnlificationlExpression Gene amplification andlor expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA
(Thomas, Proc. Nat(. Acad. Sci USA, x:5201-5205 (1980)), dot blotting (DNA analysis), or in sits hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.
Gene expression, altetitatively, may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining andlor assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently; the antibodies may be prepared against a native sequence PRO polype~tide or against a synthetic peptide based on the DNA
sequences provided herein or against exogenous sequence fused to a PRO polypeptide DNA and encoding a specific antibody epitope.
E. t:ri~cation ofgolvnentide Forms of.PRO polypeptides rnay be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergem solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO polypeptides can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.
It may be desired to purify PRO polypeptides from recombinant cell proteins oT
polypeptides. The foDowing WO 99!46281 PCT/US99/05028 procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a canon-exchange resin such as DEAF;
chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75;
protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO poIypeptide. Various methods of protein purification may be employed and such methods are lotown in the art and described for example in Deutscher, Methods in EnzymoloQV, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification steps) selected will depend, for example, on the nature of the production process used and the particular PRO polypeptide produced.
91. Uses for PRO Polvpeptides Nucleotide sequences (or their complement) encoding the PRO polypeptides of the present invention have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA. PRO polypeptide-encoding nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein.
The full-length native sequence PRO polypeptide-encoding nucleic acid or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO
polypeptide gene or to isolate still other genes (for instance, those encoding naturally-occurring variants of the PRO
polypeptide or PRO polypeptides from other species) which have a desired sequence identity to the PRO poiypeptide nucleic acid sequences. Optionally, the length of the probes will be about 20 to about 50 bases. The hybridization probes may be derived from the nucleotide sequence of any of the DNA molecules disclosed herein or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO polypeptide encoding DNA.
By way of example, a screening method will comprise isolating the coding region of the PRO polypeptide gene using the known DNA sequence to synthesize a selected probe of about 40 bases. Hybridization probes may be labeled by a variety of labels, including radionucleotides such as 32P or 35 S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidinlbiotin coupling systems. Labeled probes having a sequence complementary to that of the specific PRO
polypeptide gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA
to determine which members of such libraries the probe hybridizes to.
Hybridization techniques are described in further detail in the Examples below.
The ESTs disclosed in. the present application may similarly be employed as probes, using the methods disclosed herein.
The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO polypeptide sequences.
Nucleotide sequences encoding a PRO polypepude can also be used to construct hybridization probes for mapping the gene which encodes that PRO polypeptide and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries.
When the coding sequence for the PRO polypeptide encodes a protein which binds to another protein, the PRO polypeptide can be used in assays to identify its ligands. Similarly, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO polypeptide or a ligand for the PRO polypeptide. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays: immunoassays and cell based assays, which are well characterized in the art.
Nucleic acids which encode a PRO polypeptide or its modified forms can also be used to generate either transgenie animals or "knock out" anirrsals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an anisttal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops. In one embodiment, cDNA encoding a PRO polypeptide of interest can be used to clone genomic DNA
encoding the PRO polypeptide in accordance with established techniques and the genomic sequences used to generate uansgenic animals that contain cells which express DNA encoding the PRO
polypeptide. Methods for generating transgenie animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U,S. Patent Nos. 4,736,866 and 4,870,009. Typically, particular cells would be targeted for PRO
polypeptide transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding a PRO polypegtide introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding the PRO
polypeptide. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.
Alternatively, non-human homologues of PRO polypeptides can be used to construct a PRO polypeptide "knock out" animal which has a defective or ahered gene encoding the PRO
polypeptide of interest as a result of homologous recombination between the endogenous gene encoding the PRO
polypeptide and altered genomic DNA
enoodirtg the PRO polypeptide introduced into an embryonic cell of the animal.
For example, cDNA encoding a PRO
polypeptide can be used to clone genomic DNA encoding the PRO polypeptide in accordance with established techniques. A portion of the genomic DNA encoding a PRO polypeptide can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homoiogously recombined with the endogenous DNA are selected [see e.g., Li et al., e1 , øQ:9/5 (1992)]. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in Tercuocarcinomas and Embryonic Stem Cells: A Practical Approach, E. 7.
Robertson, ed. tZRL, Oxford, 1987), pp. 113-152]. A chirrberic embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a "knock out" animal. Progerry harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the animal WO 99!46281 PCTIUS99105028 contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the PRO polypeptide.
When in vivo administration of a PRO polypeptide is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mglkg of mammal body weight or more per day, preferably about 1 ~cg/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760;
5,206,344; or 5,225,212. It is anticipated that different formulations will he effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.
Where sustained-release administration of a PRO polypeptide is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of the PRO polypeptide, microencapsulation of the PRO polypeptide is contemplated- Microencagsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhIFN- ), interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2_: 795-799 (1996);
Yasuda. Biomed. Ther., ~; 1221-1223 (1993); Hora et al., Bio!'~'echnoloav. 8_: 755-758 (1990); Cleland, "Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems," in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newtnan, eds, (Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO
96/40072, WO 96/07399; and U.S Pat. No. 5,654,010.
The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibiIity and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer," in:
M. Chasin and R. Larger (Eds.), Biode r-g, adablgPolvmers as Drug Deliver~vstems (Marcel Dekker: New York, 1990}, pp. 1-41.
For example, for a formulation that can provide a dosing of approximately 80 g/kglday in mammals with a maximum body weight of 85 kg, the largest dosing would be approximately 6.8 mg of the PRO polypeptide per day.
In order to achieve this dosing level, a sustained- release formulation which contains a maximum possible protein loading (15-20% w/w PRO polypeptide) with the lowest possible initial burst ( < 20 h) is necessary. A continuous (zero-order) release of the PRO polypeptide from microparticles for 1-2 weeks is also desirable. In addition, the encapsulated protein to be released should maintain its integrity and stability over the desired release period.
PR0213 polypeptides and portions thereof which possess .the ability to regulate the growth induction cascade and/or the blood coagulation cascade may also be employed for such purposes both in vivo therapy and in vitro.
Those of ordinary skill in the art will well know how to employ PR0213 polypeptides for such uses.
PR0274 polypeptides and portions thereof which have homology to 7TM protein and Fn54 may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel 7TM
protein and Fn54-like molecules may have relevance to a number of human disorders which involve recognition of ligands and the subsequent signal transduction of information contained within those ligands in order to control cellular processes. Thus, the identification of new 7TM protein and Fn54-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as in various industrial applications.
As a result, there is particular scientific and medical interest in new molecules, such as PR0274.
PR0300 polypeptides and portions thereof which have homology to Diff 33 may also be useful for in vivo therapeutic purposes, as well as for various other applications, The identification of novel Diff 33-like molecules may have relevance to a number of human disorders such as the physiology of cancer. Thus, the identification of new Diff 33-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result; there is particular scientific and medical interest in new molecules, such as PR0300.
PR0296 polypeptides of the present invention which possess biological activity related to that of the sarcoma-amplified SAS protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0296 polypeptides of the present invention for such purposes.
PR0329 polypeptides of the present invention which possess biological activity related to that of immunoglobulin F~ receptor protein or subunit thereof may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR0329 polypeptides of the present invention for such purposes.
PR0362 poIypeptides of the present invention which possess biological activity related to that of the A33 antigen protein, HCAR protein or the NrCAM related cell adhesion molecule may be employed both in vivo for therapeutic purposes and in vitro.
PR0363 polypeptides of the present invention which possess biological activity related to that of the cell surface HCAR protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0363 poIypeptides of the present invention for such purposes.
Specifically, exuacellular domains derived from the PR0363 polypeptides may be employed therapeutically in vivo for lessening the effects of viral infection.
PR0868 polypeptides of the present invention which possess biological activity related to that of the tumor necrosis factor protein may be employed both in vivo for therapeutic proposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0868 polypeptides of the present invention for such purposes.
PR0382 polypeptides of t1~ present invention which possess biological activity related to that of the serine protease proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0382 polypeptides of the present invention for such purposes.
PR0545 polypeptides and portions thereof which have homology to meltrin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel molecules associated with cellular adhesion may be relevant to a number of human disorders. Given that the meltrin proteins may play an important mIe in a number of disease processes, the identification of new meltrin proteins and meltrin-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research, as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0545.

PR0617 polypeptides of the present invention which possess biological activity related to that of the CD24 protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0617 polypeptides of the present invention for such purposes, PR0700 polypeptides and portions thereof which have homology to protein disulfide isomerase may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel protein disulfide isomerases and related molecules may be relevant to a number of human disorders. Given that formation of disulfide bonds and protein folding play important roles in a number of biological processes, the identification of new protein disulfide isomerases and protein disulfide isomerase-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research, as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0700.
PR0702 polypeptides of the present invention which possess biological activity related to that of the conglutinin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO702 polypeptides of the present invention for such purposes. PR0702 polypeptides having conglutinin activity would be expected to be capable of inhibiting haemaggIutinin activity by i5 influenza viruses and/or function as immunoglobulin-independent defense molecules as a result of a complement-mediated mechanism.
PR0703 polypeptides of the present invention which possess biological activity related to that of the VLCAS
protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0703 polypeptides of the present invention for such purposes.
PR0703 polypeptides and portions thereof which have homology to VLCAS may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel VLCAS proteins and related molecules may be relevant to a number of httmatt disorders. Thus, the identification of new VLCAS proteins and VLCAS protein-like molecules is of special importance in that such proteins tray serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0703.
PR0705 polypeptides of the present invention which possess biological activity related to that of the K-glypican protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0705 polypeptides of the present invention for such purposes.
PRO?08 polypeptides of the present invention which possess biological activity related to that of the aryl sulfatase proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0708 polypegtides of the present invention for such purposes.
PR0320 polypeptides of the presern invention which possess biological activity related to that of the fibulin protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0320 polypeptides of the present invention for such purposes.
PR0320 polypeptides and portions thereof which have homology to fibulin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel fibulin proteins and related molecules may be relevant to a number of human disorders such as cancer or those involving connective tissue, attachment molecules and related mechanisms. Thus, the identification of new fibulin proteins and fibulin protein-Like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0320.
PR0324 poiypeptides of the present invention which possess biological activity related to that of oxidoreductases may be employed both tn vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0324 polypeptides of the presem invention for such purposes.
PR0351 poiypeptides of the present invention which possess biological activity related to that of the prostasin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0351 polypeptides of the present invention for such purposes.
I0 PR0351 polypeptides and portions thereof which have homology to prostasin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novelprostasin proteins and related molecules may be relevarn to a number of human disorders. Thus, the identification of new prostasin proteins and prostasin -like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0351.
PR0352 polypeptides of the present invention which possess biological activity related to that of the buryrophilin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO352 polypeptides of the present invention for such purposes.
PR0381 polypeptides of the present invention which possess biological activity related to that of one or more of the FKP$ immunophilin proteins may be employed both in vivo for therapeutic purposes and in vitro, for example for enhancing iinniunosuppressant activity andlor for axonal regeneration.
Those of ordinary skill in the an will well know how to employ the PR0381 polypeptides of the present invention for such purposes.
PR0386 polypeptides of the present invention which possess biological activity related to that of the beta-2 subunit of a sodium channel expressed in mammalian cells may be employed both in vivo for therapeutic purposes and it: vitro. Those of ordinary skill in the art will well know how to employ the PRO386 polypeptides of the present invention for such purposes.
PR0540 polypeptides of the present invention which possess biological activity related to that of the LCAT
protein tray be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0540 polypeptides of the present invention for such purposes.
PRO615 polypeptides of the present invention which possess biological activity related to that of the synaptogyrin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0615 polypeptides of the present invention for such purposes.
PR0615 polypeptides and portions thereof which have homology to synaptogyrin may also be useful for in vivo therapeutic purposes, as well as for various ocher applications. The identification of novel synaptogyrin proteins and related r»lecules may be relevant to a number of human disorders. Thus, the identification of new synaptogyrin proteins and synaptogyrin-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides tnay also play important roles in bioteeluiological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0615.
PR0618 polypeptides of the present invention which possess biological activity related to that of an enteropeptidase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0618 polypeptides of the present invention for such purposes.
PR0618 polypeptides and portions thereof which have homology to enteropeptidase may also be useful for in vivo therapeutic proposes, as well as for various other applications. The identification of novel enteropeptidase proteins and related molecules may be relevant to a number of human disorders.
Thus, the identification of new enteropeptidase proteins and enteropeptidase-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular 10' scientific and medical interest in new molecules, such as PR0618.
PRO719 polypeptides of the present invention which possess biological activity related to that of the lipoprotein lipase H protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0719 polypeptides of the present invention for such purposes.
PRO724 poIypeptides of the preseru invention which possess biological activity related to that of the human 1.DL receptor protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0724 polypeptides of the present invention for such purposes.
PR0772 polypeptides of the present invention which possess biological activity related to that of the human A4 protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PRO772 polypeptides of the present invention for such purposes.
PR0852 polypeptides of the present invention which possess biological activity related to that of certain protease protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0852 polypeptides of the present invention for such purposes.
PR0853 polypeptides of the present invention which possess biological activity related to that of the reductase protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0853 polypeptides of the present invention for such purposes.
PR0853 polypeptides and portions thereof which have homology to reductase proteins may also be useful for in vivo therapeutic purposes, as well as for various other applications.
Given that oxygen free radicals and antioxidants appear to play important roles in a number of disease processes, the identification of new reductase proteins and reductase-like molecules is of special itripor<ance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0853.
PR0860 polypeptides of the present invention which possess biological activity related to that of the neurofascin protein tnay be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0860 polypeptides of the present invention for such purposes.
PR0860 polypeptides and portions thereof which have homology to neurofascin may also be useful for in tdvo therapeutic purposes, as well as for various other applications. The identification of novel neurofascin proteins and related molecules may be relevant to a ntunber of human disorders which involve cellular adhesion. Thus, the identification of taw neurofascin proteins and neurofascin protein-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play irnportatit roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR08b0.
PR0846 polypeptides of the present invention which possess biological activity related to that of the CMRF35 protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0846 polypeptides of the present invention for such purposes.
PR0846 polypeptides and portions thereof which have homology to the CMRF35 protein may also be useful for in vivo therapeutic purposes, as well as for various other applications.
The identification of novel CMRF35 protein and related molecules may be relevant to a number of human disorders.
Thus, the identification of new CMRF35 protein and CMRF35 protein-like molecules is of special importance in that such proteins rnay serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as FR0845.
PR08b2 polypeptides of the present invention which possess biological activity related to that of the lysozyme protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0862 polypeptides of the present invention for such purposes.
PRO862 polypeptides and portions thereof which have homology to the lysozyme protein may also be useful for in vivo therapeutic purposes, as well as for various other applications.
The identification of novel lysozyme proteins and related molecules may be relevant to a number of human disorders.
Thus, the identification of new lysozymes and lysozyme-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PR0862.
PR0864 polypeptides of the present invention which possess biological activity related to that of the Wnt-4 protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0864 polypeptides of the present invention for such purposes.
PR0864 polypeptides and portions thereof which have homology to the Wnt-4 protein may also be useful for in vivo therapeutic purposes, as well as for various other applications.
The identification of novel Wnt-4 proteins arid related molecules may be relevant to a number of human disorders. Thus, the identification of new Wnt-4 protein and Wnt-4 protein-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As. a result, there is particular scientific and medical interest in new molecules, such as PR0864:
PRO'792 polypeptides of the present invention which possess biological activity related to that of the CD23 protein ritay be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0792 polypeptides of the present invention for such purposes PR0866 polypeptides of the present invention which possess biological activity related to that of mindin and/or spondin protein may be employed both in vivo for therapeutic purposes and in vi:rv. Those of ordinary skill in the art will well know how to employ the PR0866 polypeptides of the present invention for such purposes.

WO 99/46281 PCTNS99l05028 PR0871 polypeptides of the present invention which possess biological activity related to that of the cyclaphilin protein family may be employed both in vivo for therapeutic purposes and in vitro, Those of ordinary skill in the art will well know how to employ the PR0871 polypeptides of the present invention for such purposes.
PR0873 polypeptides of the present invention which possess biological activity related to that of carboxylesterases may be employed both in vivv for therapeutic purposes and in vitro. For example, they be used in conjunction with prodrugs to convert the prodrug to its active form (see Danks et al.,supra). They may be used to inhibit parasite infection (see van Pelt et al., supra). Methods for employ the PR0873 polypeptides of the present invention for these, and other purposes will be readily apparent to those of ordinary skill in the art.
PR0940 polypeptides of the present invention which possess biological activity related to that of the CD33 protein and/or OB binding protein-2 may be employed both in vivo for therapeutic purposes and in vitro. Those of .
ordinary skill in the art will well know how to employ the PR0940 polypeptides'of the present invention for such purposes.
PR0941 polypeptides of the present invention which possess biological activity related to that of a cadherin protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0941 polypeptides of the present invention for such purposes.
PR0944 polypeptides of the present invention which possess biological activity related to that of the CPE-R
protein may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PRO944 polypeptides of the present invention for such purposes. PR0944 polypeptides of the present invention that function to bind w Clostridium per&ingens enterotoxin (CPE) may find use for effectively ueating infection by the CPE endotoxin.
PR09$3 polypeptides of the presem invention which possess biological activity related to that of the vesicle-associated membrane protein, VAP-33, may be employed both in vfvo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR0983 polypeptides of the present invention for such purposes.
PR01057 polypeptides of the present invention which possess biological activity related to that of protease proteins may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR01057 polypeptides of the presem invention for such purposes, PR01071 polypeptides of the present invention which possess biological activity related to that of the thrornbospondin protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR01071 polypeptides of the present invention for such purposes.
PR01072 polypeptides of the present invention which possess biological activity related to that of reductase proteins may be employed both in vivo for therapeutic purposes. and in vitro.
Those of ordinary skill in the art will well know how to employ the PR01072 polypeptides of the present invention for such purposes.
PR01075 polypeptides of the present invention which possess biological activity related to that of protein disulfide isomerase may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR01075 polypeptides of the present invention for such purposes.
PR0181 polypeptides of the presem invention which possess biological activity related to that of the cornichon protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR018i polypeptides of the present invention for such purposes.

WO 99/4b2$1 PCTIUS99/0502$
PR0827 polypeptides of the present invention which possess biological activity related to that of various integrin proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0827 polypeptides of the present invention for such purposes.
PROs 114 polypeptides of the present invention which possess biological activity related to that of the cytokine receptor family of proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ozditrary skill in the art will well know how to employ the PROl 114 polypeptides of the present invention for such purposes.
In addition to the above, the PR01114 interferon receptor polypeptides may be employed in applications, both in vivo and in vitro, where the ability to bind to an interferon ligand is desired. Such applications will be well within the skill level in the art.
PR0237 polypepudes of the present irrverttion which possess biological activity related to that of the carbonic anhydrase protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0237 polypeptides of the present invention for such purposes.
PR0541 polypeptides of the present invention which possess biological activity related to that of a trypsin inhibitor protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PROS41 polypeptides of the present invention for such purposes.
PR0273 polypeptides can be used in assays that other chemokines would be used in to perform comparative assays. The results can be used accordingly.
PR0701 polypeptides of the present invention which possess biological activity related to that of the neuroligin family may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0701 polypeptides of the present invention for such purposes.
PR0701 can be used in assays with neurons and its activity thereon can be compared with that of neuroligins 1, 2 and 3. The results can be applied accordingly.
PRO704 poiypeptides of the present invention which possess biological activity related to that of vesicular integral membrane proteins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0704 polypeptides of the present invention for such purposes.
PR0704 can be used in assays wish the polypeptides to which they have identity with to determine the relative activities. The resuhs can be applied accordingly. PR0704 can be tagged or measured for activity to measure endocytosis activity and thereby used to screen for agents which effect endocytosis.
PR0706 polypeptides of the present invention which possess biological activity related to that of the endogenous prostatic acid phosphatase precursor may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PRO706 polypeptides of the present invention for such purposes.
PR0706 can be used in assays with human prostatic acid phosphatase or human lysosomal acid phosphatase and its activity thereon can be compared with that of human prostatic acid phosphatase or hutnan lysosomal acid phosphatase. The results can be applied accordingly.
PR0707 poiypeptides of the present invention which possess biological activity related to that of cadherins may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0707 poIypeptides of the present invention for such purposes.

WO 99!46281 PCT/US99l05028 PRO?07 can be used in assays to determine its activity in relation to other cadherins, particularly cadherin FIB3. The results can be applied accordingly.
PR0322 polypeptides of the present invention which possess biological activity related to that of neuropsin may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO322 polypeptides of the present invention for such purposes.
PR0322 can be used in assays to determine its activity relative to neuropsin, trypsinogen, serine protease and neurosin, and the results applied accordingly.
PR0526 polypeptides of the present invention which possess biological activity related to that of protein-protein binding proteins may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR052b polypeptides of the present invention for such purposes.
Assays can be performed with growth factors and other proteins which are known to form complexes to determine whether PRO526 binds thereto and whether there is increased half life due to such binding. The results can be used accordingly.
PR0531 poiypeptides of the present invention which possess biological activity related to that of the protocadherins may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO531 polypeptides of the present invention for such purposes.
PR053I can be used in assays against protocadherin 3 and other protocadherins, to determine their relative activities. The results can be applied accordingly.
FR0534 polypeptides of the present invention which possess biological activity related to that of the protein disulfide isomerase may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0534 polypeptides of the present invention for such purposes.
PR0534 can be used in assays with protein disulfide isomerase to determine the relative activities. The results can be applied accordingly.
PR0697 polypeptides of the present invention which possess biological activity related to that of the sFRP
family may be employed both in viva for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0697 polypeptides of the present invention for such purposes.
PR0697 can be used in assays with sFRPs and SARPs to determine the relative activities. The results can be applied accordingly.
PR0731 polypeptides of the present invention which possess biological activity related to that of any protocadherin may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO?31 polypeptides of the present invention for such purposes.
PRO?31 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PRO758 polypeptides of the present invention which possess biological activity related to that of integrins may be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR07b8 polypeptides of the present invention for such purposes.
PR07b8 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0771 poIypeptides of the present invention which possess biological activity related to that of the testican protein may be employed both in viva for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR0771 polypeptides of the present invention for such purposes.
PR0771 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0733 polypeptides of the present invention which possess biological activity related to that of the proteins which bind the T11ST2 receptor may be employed both in vivo for therapeutic purposes and fn vitro. Those of ordinary skill in the art will well know how to employ the PR0733 polypeptides of the present invention for such purposes.
PR0733 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0162 poiypeptides of the present invention which possess biological activity related to that of the IO pancreatitis-associated protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0162 polypeptides of the present invention for such purposes.
PROlb2 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR0788 polypeptides of the present invention which possess biological activity related to that of the anti-IS neoplastic urinary protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art wilt well know how to employ the PR0788 polypeptides of the present invention for such purposes, PR0788 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR01008 polypeptides of the present invention which possess biological activity related to that of dkk-1 may 20 be employed both in viva for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PROI008 polypeptides of the present invention for such purposes.
PR01008 can be used in assays with the polypeptides to which they have identity with to detem~ine the relative activities. The results can be applied accordingly.
PROl0I2 polypepiides of the present invention which possess biological activity related to that of the protein 25 disulfide isomerase may be employed both in vivo and in vitro purposes.
Those of ordinary skill in the art will well know how to employ the PR01012 polypeptides of the present invention for such purposes.
PROI012 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results. can be applied accordingly.
PROI014 polypeptides of the present invention which possess biological activity related to that of reductase 30 may be employed both in vivv for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR010i4 polypeptides of the present invention for such purposes.
PR01014 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. Inhibitors of PR01014 are particularly preferred. The results can be applied accordingly.
PR01017 polypeptides of the present invention which possess biological activity related to that of 35 sulfotransferase may be employed both in vivo for therapeutic purposes and in viaro. Those of ordinary skill in the art will well know how to employ the PR01017 polypeptides of the present invention for such purposes.
PR01017 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.

w WO 99!46281 PCTlUS99/05028 PR0474 polypeptides of the present invention which possess biological activity related to that of dehydrogenase may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR0474 polypeptides of the present invention for such purposes.
PR04?4 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly.
PR01031 polypeptides of the present invention which possess biological activity related to that of IL-1? may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PR01031 polypeptides of the present invention for such purposes.
PR01031 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. 'The results can be applied accordingly.
PR0938 polypeptides of the present invention which possess biological activity related to that of protein disulfide isomerase znay be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the an will well know how to employ the PR0938 polypeptides of the present invention for such purposes.
PR01082 polypeptides of the present invention which possess biological activity related to that of the LDL
receptor may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art wil!
well know how to employ the PR01082 polypeptides of the present invention for such purposes.
PR01082 can be used in assays with the polypeptides to which they have identity with to determine the relative activities. The results can be applied accordingly. PR01082 can also be used in assays to identify candidate agents which modulate the receptors.
PR01083 polypeptides of the present invention which possess biological activity related to that of ?TM
receptors may be employed both in vivo for therapeutic purposes and in vitro.
Those of ordinary skill in the art will well know how to employ the PR01083 polypeptides of the present invention for such purposes.
In particular PR01083 can be used in assays to determine candidate agents which control or modulate PR01083, i.e., have an effect on the receptor.
The VEGF-E molecules herein have a number of therapeutic uses associated with survival, proliferation and/or differention of cells. Such uses include the treatment of umbilical vein endothelial cells, in view of the demonstrated ability of VEGF-E to increase survival of human umbilical vein endothelial cells. Treatmem may be needed if the vein were subjected to traumata, or situations wherein artificial means are employed to enhance the survival of the umbilical vein, for example, where it is weak> diseased, based on an artificial matrix, or in an artiFtcial environment. Other physiological conditions that could be improved based on the selective mitogenic character of VEGF-E are also included herein. Uses also include the treatment of fibroblasts and myocytes, in view of the demonstrated ability of VEGF-E to induce proliferation of fibroblasts and hypertrophy in myocytes. In particular, VEGF-E can be used in wound healing, tissue growth and musclt generation and regeneration.
Far the indications referred to above, the VEGF-E molecule will be formulated and dosed in a fashion consistent with good medical practice taking into account the specific disorder to be ueated, the condition of the individual patient, the site of delivery of the VEGF-E, the method of administration, and other factors known to practitioners. Thus, for purposes herein, the "therapeutically effective amount" of the VEGF-E is an amouat that is effective either to prevent, lessen the worsening of, alleviate, or cure the treated condition, in particular that amount which is sufficient to enhance the survival, proliferation and/or differentiation of the treated cells in vivo.

VEGF-E amino acid variant sequences and derivatives that are immunologically crossreactive with antibodies raised against native VEGF are useful in immunoassays for VEGF-E as standards, or, when labeled, as competitive reagents.
The VEGF-E is prepared for storage or administration by mixing VEGF-E having the desired degree of purity with physiologically acceptable carriers, excipients, or stabilizers.
Such materials are non-toxic to recipients at the dosages and concentrations employed. if the VEGF-E is water soluble, it may be formulated in a buffer such as phosphate or other organic acid salt preferably at a pH of about 7 to 8. If the VEGF-E is only partially soluble in water, it may be prepared as a microemulsion by formulating it with a nonionic surfactant such as Tween, Plur~onics, or PEG, e.g., Tween 80, in an amount of 0.04-0.OS°rb (w/v), to. increase its solubility.
Optionally other ingredients may be added such as antioxidants, e.g., ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutarrtic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; and sugar alcohols such as mannitol or sorbitol.
The VEGF-E to be used for therapeutic administration must be sterile.
Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes).
The VEGF-E ordinarily will be stored in lyophili2ed form or as an aqueous solution if it is highly stable to thermal and oxidative denaturation. The pH of the VEGF-E preparations typically will be about from 6 to 8, although higher or lower pH values may also be appropriate in certain instances. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of salts of the VEGF-E.
if the VEGF-E is to be used parenterally, therapeutic compositions containing the VEGF-E generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
Generally, where the disorder permits, one should formulate and dose the VEGF-E for site-specific delivery.
This is convenient in the case of wounds and ulcers.
Sustained release formulations may also be prepared, and include the formation of microcapsular particles and implantable articles. Far preparing sustained-release VEGF-E compositions, the VEGF-E is preferably incorporated into a biodegradable matrix or microcapsule. A suitable material for this purpose is a polylactide, although, other polymers of poly-(a-hydroxycarboxylic acids), such as poly-D-(-)-3-hydroxybutyric acid (EP 133,988A), can be used.
Other biodegradable polymers include poly(lactones), poly(acetals), poly(orthoesters), or poly(orthocarbonates). The initial consideration here must be that the carrier itself, or its degradation products, is nontoxic in the target tissue and will not further aggravate the condition. This can be determined by routine screening in animal models of the target disorder or, if such models are unavailable, in normal animals.
Numerous scientific publications documem such animal models.
For examples of sustained release compositions, see U.S. Patent No. 3,273,919, EP 58,481A, U.S. Patent No. 3,887,699, EP 158,277A, Canadian Patent No. 1176565, U. Sidman et al., Biopolymers 22, 547 [1983), and R. Langer et al., them. Tech. 12, 98 [I982].
When applied topically, the VEGF-E is suitably combined with other ingredients, such as carriers andlor adjuvants, There are no limitations on the nature of such other ingredients, except that they must be pharmaceutically WO 99/46281 PCT/t1S99/05028 acceptable and efficacious for their intended administration, and cannot degrade the activity of the active ingredients of the composition. Examples of suitable vehicles include ointments, creams, gels, or suspensions, with or without purified collagen. The compositions also may be impregnated into transdermal patches, plasters, and bandages, preferably in liquid or semi-liquid form.
For obtaining a gel formulation, the VEGF-E formulated in a liquid composition may be mixed with an effective amount of a water-soluble polysaccharide or synthetic polymer such as polyethylene glycol to form a gel of the proper viscosity to be applied topically. The polysaccharide that tray be used includes, for example, cellulose derivatives such as etherified cellulose derivatives; including alkyl celluloses, hydroxyallryl celluloses, and alkylhydroxyalkyl celluloses, for example, methylcellulose, hydroxyethyl cellulose, carboxymethyi cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; starch and fractionated starch; agar; aiginic acid and alginates; gum arabic; pullullan; agarose; carrageenan; dextrans; dextrins;
fructans; inulin; mannans; xylans;
arabinans; chitosans; glycogens; glucans; and synthetic biopolymers; as well as gums such as xanthan gtun; guar gum; locust bean gum; gum arabic; tragacanth gum; and karaya gum; and derivatives and mixtures thereof. The preferred gelling agent herein is one that is inert to biological systems, nontoxic, simple to prepare, and not too runny or viscous, and will not destabilize the VEGF-E held within it.
IS Preferably the polysaccharide is an etherified cellulose derivative, more preferably one that is well defined, purified, and listed in USP, e.g., methylcellulose and the hydroxyaikyl cellulose derivatives, such as hydroxypropyl ceDulose, hydroxyethyl cellulose, and hydroxypropyl methylcellulose. Most preferred herein is methylcellulose.
The polyethylene glycol useful for gelling is typically a mixture of low and high molecular weight polyethylene glycols to obtain the proper viscosity. For example, a mixture of a polyethylene glycol of molecular weight 400-600 with one of molecular weight 1500 would be effective for this purpose when mixed in the proper ratio to obtain a paste.
The term "water soluble" as applied to the polysaccharides and polyethylene glycols is meant to include colloidal solutions and dispersions. In general, the solubility of the cellulose derivatives is determined by the degree of substitution of ether groups, and the stabilizing derivatives useful herein should have a sufficient quantity of such ether groups per anhydroglucose unit in the cellulose chain to render the derivatives water soluble. A degree of ether substitution of at least 0.35 ether groups per anhydroglucose unit is generally sufficient. Additionally, the cellulose derivatives may be in. the form of alkali metal salts, for example, the Li, Na, K, or Cs salts.
If methylcellulose is employed in the gel, preferably it comprises about 2-S~, more preferably about 3 k, of the gel and the VEGF is present in an amount of about 300-1000 mg per ml of gel.
The dosage to be employed is dependent upon the factors described above. As a general proposition, the VEGF-E is formulated and delivered to the target site or tissue at a dosage capable of establishing in the tissue a VEGF-E level greater than about 0.1 nglcc up to a maximum dose that is efficacious but not unduly toxic. This intra-tissue concentration should be maintained if possible by continuous infusion, sustained release, topical application, or injection at empirically determined frequencies.
It is within the scope hereof to combine the VEGF-E therapy with other novel or conventional therapies (e.g., growth factors such as VEGF, aFGF, bFGF, PDGF, IGF, NGF, anabolic steroids, EGF or TGF-a) for enhancing the activity of any of the growth factors, including VEGF-E, in promoting cell proliferation, survival, differentiation and repair. It is not necessary that such cotreatment drugs be inchtded per se in the compositions of this invention, although this will be convenient where such drugs are proteinaceous. Such admixtures are suitably WO 99/4b281 PCTNS99/05028 administered in the same manner and for the same purposes as the VEGF-E used alone. The useful molar ratio of VEGF-E to such secondary growth factors is typically 1:0.1-10, with about equimolar amounts being preferred.
The compounds of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO polypeptide hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle. Suitable carrier vehicles and their formulation, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in Remington's Pharmaceutical Sciences, I6th ed., 1980, Mack Publishing Co., edited by Oslo et al. the disclosure of which is hereby incorporated by reference. The VEGF-E herein may be administered parenterally to subjects suffering from cardiovascular diseases or conditions, or by other methods that ensure its delivery to the bloodsueam in an effective form.
Compositions particularly well suited for the clinical administration of VEGF-E hereof employed in the practice of the present invention include, for example, sterile aqueous solutions, or sterile hydratable powders such as lyophilized protein. It is generally desirable to include further in the formulation an appropriate amount of a pharnnaceutically acceptable salt, generally in an amourn sufficient to render the formulation isotonic. A pH regulator such as arginine base, and phosphoric acid, are also typically included in sufficient quantities to maintain an appropriate pH, generally from 5.5 to 7.5. Moreover, for improvement of shelf life or stability of aqueous formulations, it may also be desirable to include further agents such as glycerol. In this manner, variant t-PA
formulations are rendered appropriate for parenteral administration, and, in particular, intravenous administration.
Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. For example, in the treatment of deep vein thrombosis or peripheral vascular disease, "bolus" doses, will typically be preferred with subsequent adminisuations being given to maintain an approximately constant blood level, preferably on the order of about 3 ~cgJml.
However, for use in cormection with emergency medical care facilities where infusion capability is generally not available and due to the generally critical nature of the underlying disease (e.g., embolism, infarct), it will generally be desirable to provide somewhat larger initial doses, such as an intravenous bolus.
For the various therapeutic indications referred to for the compounds hereof, the VEGF-E molecules will be formulated and dosed in a fashion consistent with good medical practice taking into account the specific disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners in the respective art. Thus, for purposes herein, the "therapeutically effective amount"
of the VEGF-E molecules hereof is an amount that is effective either to prevent, lessen the worsening of, alleviate, or cure the treated condition, in particular that amount which is sufficient to enhance the survival, proliferation or differenriation of targeted cells in vivo. In general a dosage is employed capable of establishing in the tissue that is the target for the therapeutic indication being treated a level of a. ~'EGF-E
hereof greater than about 0.1 nglcm' up to a maximum dose that is efficacious but not unduly toxic. It is contemplated that intro-tissue administration may be the choice for certain of the therapeutic indications for the compounds hereof.
The human Toll proteins of the present invention can also be used in assays to identify other proteins or molecules involved in Toll-mediated signal transduction. For example, PR0285 and PR0286 are useful in identifying the as of yet unknown natural ligands of human Tolls, or other factors that participate (directly or indirectly) in the activation of andlor signaling through a human Toll receptor, such as potential Toll receptor associated kitoases. In addition, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.
Ib9 Screening assays can be designed to find lead compounds that mimic the biological activity of a native Toll polypeptide or a ligand for a native ToII polypeptide. Such screening assays will include assays amenable to high-througliput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.
In vitro assays employ a mixture of components including a Toll receptor polypeptide, which may be part of fusion product with another peptide or polypeptide, e.g., a tag for detecting or anchoring, etc. The assay mixtures may further comprise (for binding assays) a natural intra- or extracellular Toll binding target (i.e. a Toll ligand, or another molecule known to activate andlor signal through the Toll receptor).
While native binding targets may be used, it is frequently preferred to use portion of such native binding targets (e.g. peptides), so long as the portion provides binding affinity and avidity to the subject Toll protein conveniently measurable in the assay. The assay mixture also contains a candidate pharmacological agent. Candidate agents encompass numerous chemical classes, through typically they are organic compounds, preferably small organic compounds, and are obtained from a wide variety of sources, including libraries of synthetic or natural compounds. A
variety of other reagents may also be included in the mixture, such as, salts, buffers, neutral proteins, e.g.
albumin, detergents, protease inhibitors, nuclease inhibitors, antimicrobial agents, etc.
In in vitro binding assays, the resultant mixture is incubated under conditions whereby, but for the presence of the candidate molecule, the Toll protein specifically binds the cellular binding target, portion or analog, with a reference binding affinity. The mixture components can be added in any order that provides for the requisite bindings 2Q and incubations may be performed at any temperature which facilitates optimal binding. Incubation periods are likewise selected for optimal binding but also minimized to facilitate rapid high-throughput screening.
After incubation, the agent-biased binding between the ToII protein and one or more binding targets is detected by any convenient technique. For cell-free binding type assays; a separation step is often used to separate bound from unbound components. Separation may be effected by precipitation (e.g. TCA precipitation, immunoprecipitation, etc.), immobilization (e.g on a solid substrate), etc., followed by washing by, for example, membrane filtration (e.g. Whatman's P-18 ion exchange paper, Polyfiltronic's hydrophobic GFC membrane, etc.), gel chromatography (e.g. gel filtration, affinity, etc.). For Toll-dependent transcription assays, binding is detected by a change in the expression of a Toll-dependent reporter.
Detection may be effected in any convenient way. For cell-free binding assays, one of the components usually comprises or is coupled to a label. The label may provide for direct detection as radioactivity, luminescence, optical or electron density, etc., or indirect detection, such as, an epitope tag, an enzyme, etc. A variety of methods may be used to detect the Label depending on the nature of the label and other assay components, e.g. through optical or electron density, radiative emissions, nonradiative energy transfers, etc.
or indirectly detected with antibody conjugates, etc.
Nucleic acid encoding the Toll polypeptides disclosed herein may also be used in gene therapy. In gene therapy applications, genes are introduced into cells in order to achieve in viva synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. "Gene therapy" includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the adminisuation of gene therapeutic agenu, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Antisense WO 99146281 PC'TIUS99105028 RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low inuacellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al., Proc. Null. cad. Sci. USA 83, 4143-414b (198b]). The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups.
'there are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, elecuoporation, microinjection, cell fusion, DEAF-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated uansfection (Dzau et al., trends iyiotechnologv ,1~", 205-210 (1993)). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cel! surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where Liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g. capsid pxoteins or fragments thereof uopic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target inuacellular localization and enhance inuaceiluIar half life. The technique of receptor-mediated endocytosis is described, for example; by Wu et al., J. Biol. Ch_em. 26 , 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sc,~, SA ~7, 341Q-3414 (1990). For review of the currently known gene marking and gene therapy protocols see Anderson et ad., l c ~, 80&813 (1992).
The various uses listed in connection with the Toll proteins herein, are also available for agonists of the native Toll receptors, which mimic at least one biological function of a native Toll receptor.
Neuxotrimin as well as other members of the Igl..ON subfamily of the immtmoglobulin superfamily have been identified to have effect upon neural patterning, differentiation, maturation and growth. As a result, PR0337 the human neurotrimin homolog polypeptides would be expected to have utility in diseases which are characterized by neural disfunction. For example, motoneuron disorders such as arnyouophic Lateral sclerosis (Lou Gehrig's disease), Bell's palsy, and various conditions involving spinal muscular atrophy, or paralysis. NGF variant formuaations of the invention can be used to treat human neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's chorea, Down's Syndrome, nerve deafness; and Meiniere's disease. Moreover PR0337 polypeptide rnay also be used as a cognitive enhancer, to enhance learning particularly in dementia or trauma, such as those associated with the above diseases.
Further, PR0337 may be employed to neat neuropathy; and especially peripheral neuropathy. "Peripheral neuropathy" refers to a disorder affecting the peripheral nervous system, most often manifested as one or a combination of motor, sensory, sensorimotor, or autonomic neural dysfunction.
The wide variety of morphologies exhibited by peripheral neuropathies can each be attributed uniquely to an equally wide rntmber of causes. For exatnpie, peripheral neuropathies can be genetically acquired, can result from a systemic disease, or can be induced by a toxic agent_ Examples include hut are not limited to diabetic peripheral neuropathy, distal sensorimotor neuropathy, or autonomic neuropathies such as reduced motility of the gastrointestinal uact or stony of the urinary bladder. Examples of ~uropathies associated with systemic disease include post-polio syndrome or AIDS-associated neuropathy; examples of hereditary neuropathies include Charcot-Marie-Tooth disease, Refsum's disease, Abetalipoproteinemia, Tangier disease, Krabbe's disease, Metachromatic leukodysuophy, Fabry's disease, and Dejerine-Sutras syndrome; and examples of neuropathies caused by a toxic agent include those caused by treatment with a chemotherapeutic agent such as vincristine, cisplatin, methotrexate, or 3'-azido-3'-deoxytttymidine.
Correspondingly, neurotrimin antagonists would be expected to have utility in diseases characterized by excessive neuronal activity.
Endothelia is generated from inactive intermediates, the big endothelins, by a unique processing event catalyzed by the zinc metalloprotease, endothelia converting enzyme (ECE). ECE
was recently cloned, and its structure was shown to be a single pass transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. ECEs cleave the endothelia propeptide between Trp73 and Va174 producing the active peptide, ET; which appears to function as a ; local rather than a circulating hormone (Rubanyi, G.M. & Polokoff, M.A., Phatmachological Reviews 46: 325-415 (1994). Thus ECE activity is a potential site of regulation of endothelia production and a possible target for therapeutic intervention in the endothelia system. By blocking ECE activity, it is possible stop the production of ET-1 by inhibiting the conversion of the relatively inactive precursor, big ET-1, to the physiologically active form.
ECE-2 is. 64% identical to bovine ECE-2 at the amino acid level. ECE-2 is closely related to ECE-1 (63%
identical; 80 % conserved), neutral endopeptidase 24.11 and the Kell blood group protein. Bovine ECE-2 is a type Il membrane-bound metalloproteinase localized in the traps-Golgi network where it acts as an intracellular enzyme converting endogenous big endothelia-1 into active endothelia (Emoto, N. and Yanangisawa, M., 1. Biol. Chem. 270:
15262-15268 (1995). The bovine ECE-2 mRNA expression is highest in parts of the brain, cerebral cortex, cerebellum and adrenal medulla. 1t is expressed al lower levels in mymetrium, testes, ovary, and endothelial cells.
Bovine ECE-2 and ECE-I both are more active on ET-1 as a substrate compared to ET-2 or ET-3, Emoto and Yanangisawa, supra.
Human ECE-2 is 736 amino acids in length with a 31 residue amino-terminal tail, a 23 residue transmembrane helix and a G82 carboxy-terminal domain. It is 94°k identical to bovine ECE-2 and 64% identical to human ECE-1. The predicted uansmembrane domain is highly conserved between the human and bovine ECE-2 proteins and between human ECE-1 and human ECE-2, as are the putative N-linked glycosylation sites, Cys residues conserved in the neutral endopeptidase 24.11 and the Kell blood group protein family and the putative zinc binding motif. The sequence suggests, that like other members of the NEP-ECE-Kell family, hutnatt ECE-2 encodes a type D
uaasmembrane zinc-binding metalloproteinase, which, by extrapolation from what is known about bovine ECE-2, is an intracellular enzyme located within the secretory pathway which processes endogenously produced big ET-1 while it is still in the secretory vesicles. Emoto and Yanangisawa, supra.
The expression pattern of ECE-2 differs from that observed for ECE-1. Northern blot analysis of mRNA
levels indicated low levels of expression of a 3.3 kb transcript in adult brain (highest in the cerebellum, putarnen, medulla and temporal lobe, and lower in the cerebral cortex, occipital lobe and frontal lobe), spinal cord, lung and pancreas and higher levels of a 4.5 kb transcript in fetal brain and kidney.
The two uanscript sizes probably represent the use of alternative polyadenylation sites as has been observed for bovine ECE-2 (Emoto and Yanangisawa, supra) and ECE-1 (Xu et al., Cell 78: 473-485 (1994). PCR on cDNA
libraries indicated low levels of expression in fetal brain, fetal kidney, fetal small intestine and adult testis. Fetal liver, fetal lung and adult pancreas were all negative.

The endothelin (ET) family of peptides have potent vascular, cardiac and renal actions which may be of pathophysiological importance in many human disease states. ET-1 is expressed as an inactive 212 amino acid prepropeptide. The prepropeptide is first cleaved at Arg52-Cys53 and Arg92-A1a93 and then the carboxy terminal Lys91 and Arg92 are trimmed from the protein to generate the propeptide big ET-1. ECEs then cleave the propeptide between Trp73 and Va174, producing the active peptide, ET, which appears to function as a local rather than a circulating hormone (Rubanyi and Polokoff, Pharma. R. 46: 325-415 (1994).
Endothelins may play roles in the pathophysiology of a number of disease states including: 1) cardiovascular diseases (vasospasm, hypertension, myocardial ischemia; reperfusion injury and acute myochardial infarction, stroke (cerebral ischemia), congestive heart failure, shock, atherosclerosis, vascular thickening); 2) kidney disease (acute and chronic renal failure, glomerulonephritis, cirrhosis); 3) lung disease (bronchial asthma, pulmonary hypertension);
4) gastrointestinal disorders (gastric ulcer, inflammatory bowel diseases); 5) reproductive disorders (premature labor, dysmenorhea, preeclampsia) and 6) carcinogenesis. Rubanyi & Polokoff, supra.
Diseases can be evaluated for the impact of ET upon them by examining: 1) increased production of ETs;
2) increased reactivity to ETs; andlor 3) efficacy of an ET receptor antagonist, antibody or ECE inhibitor. Response to the previous criteria suggest that ETs Likely play roles in cerebral vasospasm following subarachnoid hemorrhage, hypertension (fulrninantJcomplications), acute renal failure and congestive heart failure. While inhibitors of ET
production or activity have trot been used in models of coronary vasospasm, acute myocardial infarction, and atherosclerosis, they do have elevated ET levels and increase reactivity to ETs. Shock and pulmonary hypertension also exhibit elevated ET levels (Rubanyi and PoIokoff, supra). Inhibition of ECEs in these conditions may be of therapeutic value.
The expression pattern of ECE-2 differs from that observed for ECE-1. ECE-2 was observed at low levels in the adult brain, lung and pancreas and higher levels in fetal brain and kidney by Northern blot analysis (Fig. 8). PCR
revealed low levels of expression in additional tissues: fetal lung, fetal small intestine and adult testis. Fetal liver was negative. A similar pattern was reported for bovine ECE-2 (Etnoto and Yanangisawa, supra). 1t is expressed in brain tissues (cerebral cortex, cerebellum and adrenal medulla), myometrium and testis, and in low levels in ovary and very low levels in many other tissues. Bovine ECE-1 (Xu eYal, supra) is more widely and more abundantly expressed.
it is observed in vascular endothelial cells of most organs and in some parenchyma) cells. With the exception for brain, bovine ECE 2 mRNA was preseru at lower levels than ECE-1. Applicants believe ECE-2 to be a particularly good target for the therapeutic intervention for diseases such as cerebral vasospasm following subarachnoid hemorrhage and stroke.
92. Ant!-PRO,)Poly~eptidg Antibodies The present invention further provides anti-PRO polypeptide antibodies.
Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies.
A. Polyclonal Antibodies The anti-PRO polypeptide antibodies may comprise polyclonal antibodies.
Methods of preparing polyclonai antibodies are known to the skilled artisan. Polyclonai antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and; if desired, an adjuvant.
Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injecrions. The immunizing agent may include the FRO polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM
adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation.
B. Monoclonal Antibodies The anti-PRO polypeptide antibodies may, alternatively, be monoclonal antibodies. Monoclonal antibodies may be prepared using hybridoma methods, .such as those described by Kohler and Milstein, Nature, 25:495 (1975).
i0 in a hybridorna method, a mouse, hamster, or other appropriate host animal, is typically immunized with an iitnmtnizutg agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro.
The immunizing agent will typically include the PRO golypeptide of interest or a fusion protein thereof.
Generally, either peripheral blood lymphocytes ("PBIs") are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human matrtma)ian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [coding, Monoclonal Antibodies Principles and Practice, Academic Press, (1986) pp. 59-143J. Immortalized cell lines are usually transformed mamrtta3ian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cel3 lines are employed. The hybridoma cells tnay be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells.
Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are marine myeloma lines, which can be obtained, for instance, from the SaIk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Rockville, Maryland. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Anribodv Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63J.
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the PRO polypeptide of interest.
Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immtutoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such technigues and assays are known in the art. The binding affmiry of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biocttem., 1:220 (1980).
After the desired hybridotna cells are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods [coding, ~nral. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown w0 99~a628t PCTIUS99i05028 in vivo as ascites in a mammal.
The monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglohuIin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of marine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also tray be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous marine sequences [U.S. Patent No. 4,816,567;
Morrison et al., ~upral or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-im~tnunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
The antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For exatnpie, one method involves recombinant expression of immunoglobulin Light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinldng.
In vitro methods are also suitable for preparing monovalent antibodies.
Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art.
C. ~-Iuttsanized Antibodies The anti-PRO polypeptide antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non human (e.g., marine) antibodies are chimeric immunoglobulins, immunogiobuiin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')z or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from notrhuman inununoglobulin. Humanized antibodies include human itnmunoglobulins (recipient antibody) in which residues frora a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody wil3 comprise substantially aII
of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human itnmunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin jJones et at., Nature, 3 I : 522-525 (1986); Riechmann et al., i7s WO 99146281 PCTJUS99l05028 Nature, ,32:323-329 (1988): and Presta, Curr. Op. Struct. Blot., 2_:593-596 (1992)].
Methods for humanizing non-human antibodies are well known in the art.
Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are o8en referred to as "import" residues, which are typically taken from an "import" variable domain.
Httmanization can be essential3y performed following the method of Winter and co-workers (Jones et al., Nature, X21:
522-525 (1986); Riechtnann e1 al., Nature, X3_2:323-327 {1988); Verhoeyen et al., Science, 239:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (LJ.S. Patent No.
4,816,557), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR
residues are substituted by residues from analogous sites in rodent antibodies.
Human antibodies can also be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mot. Biol., x:381 (1991); Marks er al., J. Ma!. Biol., x:581 (1991)]. The techniques of Cole et al, and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Anriboriies anri Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. lmmunol. , 147 1 :86-95 (1991)].
D. ~ispecitic Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for the PRO
polypeptide, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor submit.
Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 05:537-539 (1983)]. Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93108829, published 13. May 1993, and in Traunecker et al., EMBO J., ~Q:3655-3659 (1991).
Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to itnmunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions.
It is preferred to have the first heavy chain constant region (t'_'Hl) containing the site necessary for light-chain binding present in at least one of the fusions.
DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate exgression vectors, and are co-transfected into a suitable host organism. For ftuther details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, ,)a?1.:210 (1986).
E. Neteroconiue~te Antibodies Het~eroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO
91100360; WO 921200373; EP 03089]. It is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mereaptoburyrimidate and those disclosed, for example, in U.S.
Patent No. 4,676,980.
93. Uses for Anti-PRO Pol~peptide Antibodies The anti-PRO poiypeptide antibodies of the invention have various utilities.
For example, anti-PRO
polypeptide antibodies may be used in diagnostic assays for a PRO polypeptide, e.g., detecting its expression in specific cells, tissues, or serum. Various diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclo~l Antibodies A Manual of Techniques, CRC Press, lne.
(1987) pp. 147-158]. The antibodies used in the diagnostic assays can be labeled with a detectable moiety. The detectable moiety should be capable of producing, either directly or indirectly, a detectable signal, For example, the detectable moiety may be a radioisotope, such as 'H, '°C,;2 P,'S S, oisu I, a fluorescent or chemiluminescent compotuid, such as fluorescein isbthiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase. Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al., Nature, x:945 (1962);
David et al., Biochemistry, X3:1014 (1974); Pain et al., J. Immunol. Meth., 40_:219 (1981); and Nygren, J.
l~isrochem. and G~tochem:, ~Q:407 (1982).
Anti-PRO polypeptide antibodies also are useful :for the affinity purification of PRO polypeptide from recombinant cell culture or natural sources. In this process, the antibodies against the PRO polypeptide are immobilized on a suitable support, such a Scphadex resin or filter paper, using methods well known in the art. The immobilized antibody then is contacted with a sample containing the PRO
polypeptide to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the PRO polypeptide, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO polypeptide from the antibody.
Anti-Toll receptor (i.e., anti-PR0285 and anti-PR0286 antibodies) may also be useful in blocking the biological activities of the respective Toll receptors. The primary function of the family of Toll receptors is believed to ix to act as pathogen pattern recognition receptors sensing the presence of conserved molecular pattern present on microbes. Lipopolysaccharides (LPS, also known as endotoxins), potentially lethal molecules produced by various bacteria, bind to the lipopolysaccharide binding protein (LBP) in the blood. The complex formed then activates a receptor known as CD14. There is no consensus in the art about what happens next. According to a ltypotitesis, CD14 does not directly instruct macrophages to produce cytokines, cell adhesion proteins and enzymes involved in the production of lower molecular weight proinflammatory mediators, rather enables LPS to activate a second receptor. Alternatively, it has been suggested that LPS may activate certain receptors directly, without help from L,BP or CD14. The data disclosed in the present application indicate that the human toll-like receptors are signaling receptors that are activated by LPS in an LBP and CDl4 responsive manner. As this mechanism, under pathophysiologic conditions can Lead to an often fatal syndrome called septic shock, anti-Toll receptor antibodies (just as other Toll.receptor antagonists) might be useful in the ueatment of septic shock. h is foreseen that the different Toll receptors might recognize different pathogens, e.g., various strains of Gram-negative or Gram-positive bacteria.
Accordingly, in certain situations, combination therapy with a mixture of antibodies specifically binding different Toll receptors, or the use of bispecific anti-Toll antibodies may be desirable.
It is specifically demonstrated that anti-huTLR2 antibodies are believed to be specifically useful in blocking the induction of this receptor by LPS. As it has been shown that LPS exposure can lead to septic shock (Parrillo, N. Eng~,J. Med. 328, 1471-1477 [1993]), anti-huTLR2 antibodies are potentially useful in the treatment of septic shock.
The foregoing therapeutic and diagnostic uses listed in connection with the anti-Toll receptor antibodies are also applicable to other Toll antagonists, i.e., other molecules (proteins, peptides, small organic molecules, etc.) that : block Toll receptor activation and/or signal transduction mediated by Toll receptors.
In view of their therapeutic potentials, the Toll proteins (including variants of the native Toll homologues), and their agonists and antagonists (including but not limited to anti-Toll antibodies) are incorporated in compositions suitable for therapeutic use. Therapeutic compositions are pzepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th Edition, Osol, A. Ed. 1980) in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobuIins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mantiitol or sorbitol; salt-forming counterions such as sodium; andlor nonionic surfactants such as Tween, Pluronics or PEG.
The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, supra.
The formulations to be used for in vfvo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution.
Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
The route of administration is in accord with known methods, e.g. injection or infusion by intravenous, intraperitoneal, intracerebrai, intramuscular, intraocular, intraarcerial or intralesional routes, topical administration, or by sustained release systems.
3$ Suitable examples of sustained release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained, release matrices include polyesters, hydrogels, polylactides (U.S. Patent 3,?73,919, EP 58,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (i1.
Sidtnan ~r al., Hiop_Qlymers ~ (1): 547-556 [1983]), poly (2-hydroxyethyl-methacrylate) (R.. Langer, _e/ al., J.
Biome [, Mater, Res. 15: 167-277 [1981] and R. Larger, the . ech. )~: 98-105 [1982]), ethylene vinyl acetate (R. Larger e~ a_1., Id.) or poly-D-(-~3-hydroxybutyric acid (EP 133,988).
Sustained release compositions also include liposomes. Liposomes containing a molecule within the scope of the present invemion are prepared by methods known per se: DE 3.2/8,/21; Epstein et al., Pros. Natl. Acad. Set. U~ ~; 3688-3692 (1985); Hwang pt ~1., Proc. Natl. Acad. Set. USA ~: 4030-4034 (1980); EP 52322; EP 36676A; EP 88046;
EP 143949; EP 142641;
Japanese patent application 83-118008; U.S. patents 4,485,045 and 4,544,545;
and EP 102,324. Ordinarily the S liposomes are of the small (about 200-800 Angstroms) uniiamelar type in which the lipid content is greater than about 30 mol. % cholesterol, the selected proportion being adjusted for the optimal NT-4 therapy.
An effective amount of the active ingredient will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it will be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. A typical daily IO dosage might range from about 1 Pglkg to up to 100 mglkg or more, depending on the factors mentioned above.
Typically, the clinician will administer a molecule of the present invention until a dosage is reached that provides the required biological effect. The progress of this therapy is easily monitored by conventional assays.
The following examples are offered for illustrative purposes only, and are not intended to Iimit the scope of the present invention in any way.
1S All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.
EXAMPLES
Commercially available reagents referred to in the examples were used according to manufacturer's 20 instructions unless otherwise indicated. The source of those cells identified in the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Rockvihe, Maryland.
EXAMPLE 1: Extracellular Domain HomologvScreenine to Identify Novel Polvventides and cDNA Enco 25 The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 9S0 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQT"", lncyte Pharmaceuticals, Palo Alto, CA). The search was performed using the computer program BLAST or BLAST2 {Altschul and Gish, Methods in Enzv~ology ~: 460-480 (1996)) as a comparison of the ECD protein sequences 30 to a 6 frame translation of the EST sequences. Those comparisons with a Blast score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, WA;
(http:llbozetnan.mbt.washington.edulphrap.docslphrap.html).
Using this extracellular domain homology screen, consensus DNA sequences were assembled relative to 35 the other identified EST sequences using phrap: in addition, the consensus DNA sequences obtained were often (but not always) extended using repeated cycles of BLAST and phrap to extend the consensus sequence as far as possible using the sources of EST sequences discussed above.
Based upon the consensus sequences obtained as described above, oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate WO 99/46281 PCTlUS99I05028 a clone of the full-length coding sequence for a PRO polypeptide. Forward (.f) and reverse (.r) PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR
product of about 100-1000 by in length. The probe (.p) sequences are typically 40-55 by in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.Skbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.
The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA.
The cDNA was primed with oligo dT containing a.NotI site, linked with bluntao SaII hemikinased adaptors, cleaved with NatI, sited appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD;
pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., Scie ce, 25:1278-1280 (1991)) in the unique Xhol and NotI sites.
EXAMPLE 2: Isolation of c~NA cones by Amylase Screening 1. Preparation of olieo dT primed cDNA library mRNA was isolated from a human tissue of interest using reagents and protocols from Invitrogen, San Diego, CA (Fast Track 2). This RNA was used to generate an oligo dT primed cDNA library in the vector pRKSD
using reagents and protocols from Life Technologies, Gaithersburg, MD (Super Script Plasmid System). In this procedure, the double stranded cDNA was sized to greater than 1000 by and the SaII/NotI Tinkered cDNA was cloned into XhoI/Notl cleaved vector. pRKSD is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoI/Not1 cDNA cloning sites.
2. Preparation of random primed cDNA librar~r A secondary cDNA library was generated in order to preferentially represent the 5' ends of the primary cDNA clones. Sp6 RNA was generated from the primary library (described above), and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY.O using reagents and protocols from Life Technologies (Super Script Piasmid System, referenced above). In this procedure the double stranded cDNA was sized to 500-1000 bp, Tinkered with blunt to NotI adaptors, cleaved with SfiI, and cloned into SfiIINotI cleaved vector. pSST-AMY.O is a cloning vector that has a yeast alcohol dehydrogenase promoter preceding the cDNA
cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase ternainator, after the cloning sites. Thus, cDNAs cloned into this vector that are fused in frame with amylase sequence will lead to the secretion of amylase from appropriately transfected yeast colonies.
3. Tra_n~formation and Detection DNA from the library described in paragraph 2 above was chilled on ice to which was added electrocompetent DH10B bacteria (Life Technologies, 20 ml). The bacteria and vector mixture was then electroporated as recominetttied by the manufacturer. Subsequently, SOC media (Life Technologies, 1 ml) was added and the mixture was incubated at 37°C for 30 minutes. The transfotmants were then plated onto 20 standard I50 mm LB plates containing ampicillin and incubated for 16 hours (37°C}.
Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e.g. CsCI-gradient. The purified DNA
was then carried on to the yeast protocols below.
The yeast methods were divided into three categories: (1) Transformation of yeast with the plasmidIcDNA
combined vector; (2) Detection and isolation of yeast clones secreting amylase; and (3) PCR amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and farther analysis.
The yeast strain used was HD56-SA (ATCC-90785). This strain has the following genotype: MAT alpha, ura3-52, leu2-3, leu2-I12, his3-11, his3-15, MAL', SUC+, GAL+. Preferably, yeast mutants can be employed that have deficient post-translational pathways. Such,mutants may have translocation deficient alleles in sec7l, sec72, sec62, with tnincated sec71 being most preferred. Alternatively, antagonists (including antisense nucleotides and/or ligands) which interfere with the normal operation of these genes, other proteins implicated in this post translation pathway (e.g., SEC6lp, SEC72p, SEC62p, SEC63p, TD) 1p or SSAIplIp) or the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.
Transformation was performed based on the protocol outlined by Gietz et al., Nucl. Acid. Red, 2Q:1425 (1992). Transformed cells were then inoculated from agar into YEPD complex media broth (100 ml) and grown overnight at 30°C. The YEPD broth was prepared as described in Kaiser et al., Methods in Yeast Gei)eticc, Cold 1S Spring Harbor Press, Cold Spring Harbor, NY, p. 207 (1994). The overnight culture was then diluted to about x 106 cellslml (approx. ODD=0.1) into fresh Y'EPD broth (500 ml) and regrown to 1 x' 10 cellslml (approx.
ODD=0.4-0.x).
The cells were then harvested and prepared for transformation by transfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5 minutes, the supernatant discarded, and then resuspended into sterile water, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in a Beckman GS-6KR
centrifuge. The supernatant was discarded and the cells were subsequently washed with LiAcITE (10 ml, 10 mM
Tris-HCI, I mM EDTA pH 7.5, 100 mM Li~00CCH,), and resuspended into LiAcITE (2.5 ml).
Transformation took place by mixing the prepared cells (100 ~I) with freshly denatured single stranded salmon testes DNA (L.ofstrand Labs, Gaithersburg, MD) and transforming DNA (1 ~cg, vol. < 10 ~l) in microfuge tubes. The mixture was mixed briefly by vortexing, then 40% PEGITE (6001c1, 4090 polyethylene glycol-4000, 10 mM Tris-HCI, 1 mM EDTA, 100 mM IazOOCCH3, pH 7.5) was added. This mixture was gently mixed and incubated at 30°C while agitating for 30 minutes. The cells were then heat shocked at 42°C for 15 minutes, and the reaction vessel centrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted and resuspended into TE (500 pI, 10 mM Tris-HCI, 1 tnM EDTA pH 7.5~ followed by recentrifugation. The cells were then diluted into TE (1 mt) and aliquots (200 u1) were spread onto the selective media previously prepared in 150 mm growth plates (VWR).
Alternatively, instead of multiple small reactions, the transfotanation was performed using a single, large scale reaction, wherein reagent amounts were scaled up accordingly.
The selective media used was a synthetic complete dextrose agar lacking uracil (SCD-Ura) prepared as described in Kaiser et al., Methods in Yeast genetics, Cold Spring Harbor Press, Cold Spring Harbor, NY, p. 208-210 (1994). Transformants were grown at 30°C for 2-3 days.
The detection of colonies secreting amylase was performed by including red starch in the selective growth media. Starch was coupled to the red dye (Reactive Red-120, Sigma) as per the procedure described by Biely et al., Anal. Biochem , 1 2:176-179 (1988). The coupled starch was incorporated into the SCD-Ura agar plates at a final concentration of O.15 q6 (w/v), and was buffered with potassium phosphate to a pH of 7.0' (50-100 mM final WO 99!46281 PCT/US99I05028 concentration).
The positive colonies were picked and streaked across fresh selective media (onto I50 mm plates) in order to obtain well isolated and identifiable single colonies. Well isolated single colonies positive for amylase secretion were detected by direct incorporation of red starch into buffered SCD-Ura agar. Positive colonies were determined by their ability to break down starch resulting in a clear halo around the positive colony visualized directly.
~1. Isolation of DNA by PCR Ampl_ificgtion When a positive colony was isolated, a portion of it was picked by a toothpick and diluted into sterile water (30 ~.1) in a 96 well plate. At this time, the positive colonies were either frozen and stored for subsequent analysis or immediately amplified. An aliguot of cells (5 ~cl) was used as a template for the PCR reaction in a 25 u! volume containing: 0.5 ~1 Klentaq (Clontech, Palo Alto, CA); 4.0 u! I0 mM dNTP's (Perkin Elmer-Cetus); 2.5 u! Kentaq buffer (Clontech); 0.25 g.1 forward oligo 1; 0.25 ~cl reverse oligo 2; 12.5 u!
distilled water. The sequence of the forward oIigonucleotide 1 was:
5'-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3' (SEQ ID N0:324}
The sequence of reverse oligonucleotide 2 was:
5'-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3' (SEQ ID N0:325) PCR was then performed as follows:
a. Denature 92°C, 5 minutes b. 3 cycles of: Denature 92°C, 30 seconds Anneal 59°C, 30 seconds Extend 72°C, 60 seconds c. 3 cycles of: Denature 92°C, 30 seconds Anneal 57°C, 30 seconds Extend 72 ° C, 60 seconds d. 25 cycles of: Denature 92°C, 30 seconds Anneal 55°C, 30 seconds Extend 72°C, 60 seconds e. Hold 4°C
The underlined regions of the oligonucleotides annealed to the ADH promoter region and the amylase region, respectively, and amplified a 307 by region from vector pSST-AMY.O
when no insert was present. Typically, the first 18 twcleotides of the 5' end of these oligonucleotides contained annealing sites for the sequencing primers.
Thus, the total product of the PCR reaction from an empty vector was 343 bp.
However, signal sequence-fused cDNA resulted in considerably longer nucleotide sequences.
Following the PCR, an aliquot of the reaction (5 ~I) was examined by agarose gel electrophoresis in a 1 ~
agarose gel using a Tris-Borate-EDTA (TBE) buffering system as described by Sambrook et al., su r . Clones resulting in a single strong FCR product larger than 400 by were further analyzed by DNA sequencing after purification with a 96 Qiaquick PCR clean-up column (Qiagen Inc., Chatsworth, CA).
1$2 EXAMPLE 3: Isolation of cDNA Clones Encoding Human PR0213 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA28735. Based on the DNA28735 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR02I3.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR grimer 5'-TGGAGCAGCAATATGCCAGCC-3' (SEQ ID N0:3) reverse PCR primer 5'-TTTTCCACTCCTGTCGGGTTGG-3' (SEQ ID N0:4) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28735 sequetxe which had the following nucleotide sequence hybridization probe 5'-GGTGACACTTGCCAGTCAGATGTGGATGAATGCAGTGCTAGGAGGG-3' (SEQ ID N0:5) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer gait identified above. A positive library was then used to isolate clones encoding the PR0213 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0213 (herein designated as UNQ187 (DNA30943-1163)] (SEQ ID NO:1) and the derived protein sequence for PR0213.
The entire nucleotide sequence of UNQ187 (DNA30943-1163) is shown in Figure 1 (SEQ ID NO:1). Clone UNQ187 (DNA30943-1163) contains a single open reading frame with an apparent translationat initiation site at nucleotide positions 336-338 and ending at the stop codon at nucleotide positions 1221-1223 (Figure 1). The predicted polypeptide precursor is 295 amino acids long (Figure 2). Clone UNQ187 (DNA30943-1163) has been deposited with ATCC.
Analysis of the amino acid sequence of the full-length PR0213 polypeptide suggests that a portion of it possesses significarn homology to the human growth arrest-specific gene 6 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0213 amino acid sequence and the following Dayhoff sequences, HSMHC3W5t1_6 and B48089.
~MP)~E 4: Isolation of cDNA hones ,~..ncoding Hula 80274 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above;
wherein the consensus sequence obtained is herein designated DNA36469. Based on the DNA36469 consensus sequence, oligonucleotides were synthesized: 1) to identify by 1'C8 a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0274. ESTs proprietary to Genentech were employed in the consensus assembly. The ESTs are shown in Figures 5-7 and are herein designated DNA17873, DNA36157 and DNA28929, respectively.
Pairs of PCR primers (forward and reverse) were synthesized:
forward PCR primer 1 13646~~ 5'-CTGATCCGGTTCTTGGTGCCCCTG-3' (SEQ ID NO:11) forward PCR p~~ (,6469 f2) 5'-GCTCTGTCACTCACGCTC-3' (SEQ ID N0:12) forward P primer _~,~ 69 f3) 5'-TCATCTCTTCCCTCTCCC-3' (SEQ ID NO:I3) fold PCR r~mer 4 136469 f4) 5 -CCTTCCGCCACGGAGTTC-3' (SEQ ID NO:14) is3 reverse PCR primer 1 136469.r1) 5'-GGCAAAGTCCACTCCGATGATGTC-3' (SEQ ID NO:15) reverse ~C~t~rimer~36469.r215'-GCCTGCTGTGGTCACAGGTCTCCG-3' (SEQ ID N0:16) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA36469 sequence which had the following nucleotide sequence h brid~ationJ~robe136469.~1 5'-TCGGGGAGCAGGCCTTGAACCGGGGCATTGCTGCTGTCAAGGAGG-3' (SEQ ID N0:17) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0274 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0274 [herein designated as UNQ241 (DNA39987-1184)] (SEQ ID NO:l) and the derived protein sequence for PR02?4.
The entire nucleotide sequence of UNQ241 (DNA39987-1184} is shown in Figure 3 (SEQ ID N0:6). Clone UNQ241 (DNA39987-1184) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 83-85 and ending at the stop codon at nucleotide positions 1559-1561 (Figure 3). The predicted polypeptide precursor is 492 amino acids long (Figure 4), has an estimated molecular weight of about 54,241 daltons and an estimated pI of about 8.21. Clone UNQ241 (DNA39987-1184) has been deposited with ATCC and is assigned ATCC deposit no. 209786.
Analysis of the amino acid sequence of the full-length PR0274 polypeptide suggests that it possesses significant homology to the Fn54 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0274 amino acid sequence and the following Dayhoff sequences, MMFN54S2_l, MMFN54S1_l, CELF48C1 8, CEF38B7 6, PRP3 RAT, INL3 PIG, MTCY07A7_13, YNAX KLEAE, A47234 and HME2 MOUSE.
EXAMPLE 5: Isolation of eDNA Clones Encoding~lumgn PR0300 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA35930. Based on the DNA35930 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0300.
Forward and reverse PCR primers were synthesized:
forward PCR nrimer~ (35930.f1) 5'-GCCGCCTCATCTTCACGTTCTTCC-3' (SEQ 1D N0:20}
forward PCR primer 2 f35930.f2,~ 5'-TCATCCAGCTGGTGCTGCTC-3' (SEQ ID N0:21) forward PCR primer 3 (35930.f315'-CTTCTTCCACTTCTGCCTGG-3' (SEQ ID N0:22) Forward PCR primer 4 35930.f~ 5'-CCTGGGCAAAAATGCAAC-3' (SEQ ID N0:23) reverse PCR primer 1 f35930.r1) 5'-CAGGAATGTAGAAGGCACCCACGG-3' (SEQ ID N0:24) reverse PCR prime, 2 ~5930.r2) 5'-TGGCACAGATCTTCACCCACACGG-3' (SEQ ID N0:25) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35930 sequence which had the following nucleotide sequence hybridization probe 135930.n1) 5'-TGTCCATCATTATGCTGAGCCCGGGCGTGGAGAGTCAGCTCTACAAGCTG-3' (SEQ ID N0:26) WO 99!46281 PCT/US99/05028 In order to screen everal libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR atnglification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0300 gene using the probe oligomtcleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.
DNA sequencing of the clones isolated as described above gage the full-length DNA sequence for PR0300 [herein designated as UNQ263 (DNA40625-1189)] (SEQ ID N0:18) and the derived protein sequence for PR0300.
The entire nucleotide sequence of UNQ263 (DNA4062S-1189) is shown in Figure 8 (SEQ ID NO:1$):
Clone UNQ263 (DNA40625-1189) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 45-47 and ending at the stop colon at nucleotide positions 1416-1418 (Figure 8). The predicted polypeptide precursor is 457 amino acids long (Figure 9). Clone UNQ263 (DNA40625-1189) has been deposited with ATCC and is assigned ATCC deposit no. 209788.
Analysis of the amino acid sequence of the full-length PR0300 polypeptide suggests 'that portions of it possess significant homology to the Diff 33 protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0300 amino acid sequence and the following Dayhoff sequence, HSU49188_ 1.
IS
EXAMPLE 6: Isolation gf cDN~1 Cones ~, tt-c,Qdirig Human PR0284 Two cDNA sequences were isolated in the amylase screen described in Example 2 and those cDNA
sequences are herein designated DNA12982 (see Figure 12; human placenta-derived) and DNA15886 (see Figure 13; human salivary gland-derived). The DNA12982 and DNA15886 sequences were then clustered and aligned, giving rise to a consensus nucleotide sequence herein designated DNAi8832.
Based on the DNA18832 consensus sequence, oligonucleotide probes were generated and used to screen a human phicerua library (LIB89) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., Sc' ce, ~53:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 1 (,~i~ 2.est.f) 5'-TCGTACAGTTACGCTCTCCC-3' (SEQ ID N0:31) forward P~R~rimer 2 L8832.f1 S'-CTTGAGGAGCGTCAGAAGCG-3' (SEQ ID N0:32) reverse PCR primer.,118832.r15'-ATAACGAATGAAGCCTCGTG-3' (SEQ ID N0:33) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA18832 sequence which had the following nucleotide sequence hvbridiza~on probe 118832.01 5'-GCTAATATCTGTAAGACGGCAGCTACAGCAGGCATCATTG-3' (SEQ ID N0:34) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PR0284 gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone: was identified that contained a single open reading frame with an apparent transiational initiation site at nucleotide positions 167-169 and ending at the stop colon found at rnicleotide positions 1022-1024 (Figure i0; SEQ ID N0:27). The predicted polypeptide precursor is 285 amino acids long, has a calculated molecular weight of approximately 32,190 daltons and an estimated pI of approximately 9.03. Analysis of the full-1$5 WO 99/46281 PCTlUS99105028 length PR0284 sequence shown in Figure 11 (SEQ ID N0:28) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 24, transmembrane domains from about amino acid 76 to about amino acid 96 and from about amino acid i71 to about amino acid 195 and a potential N-glycosylation site from about amino acid 153 to about amino acid 156. Clone UNQ247 (DNA23318-I211) has been deposited with ATCC on April 21, 1998 and is assigned ATCC deposit no. 209787.
Analysis of the amino acid sequence of the full-length PR0284 polypeptide suggests that it possesses no significant sequence similarity to any laiown protein. However, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced some degree of homology between the PR0284 amino acid sequence and the following Dayhoff sequences, JQ0124, CELE04A4 5, AB006451~1, AF030162_1, IM23 YEAST, S71194, NIA_CUCMA, IM17 YEAST, I50479 and HUMZFHP 1.
EXAMPLE 7: Isolation of cDNA Clones Encoding Human PR0296 A cDNA sequence isolated in the amylase screen as described in Example 2 above was found, by BLAST
and FastA sequence alignment, to have sequence homology to a nucleotide sequence encoding sarcoma-associated protein SAS. This cDNA sequence is herein designated DNA23020 (see Figure 16).
The DNA23020 sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQT"', Incyte Pharmaceuticals, Palo Alto, CA) to identify existing homologies. Tt>e homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (/996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode lrnown proteins were clustered and assembled into a consensus DNA
sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Washington;
http:l/bowman.mbt.washington.edu/phrap.docs/phrap.html). The consensus sequence obtained therefrom is herein designated DNA35858. Two proprietary Genentech ESTs were employed in the assembly wherein those EST
sequences are herein identified as DNA2197I (Figure 17; SEQ ID N0:38) and DNA29037 (Figure 18; SEQ ID
N0:39).
Based on the DNA35858 consensus sequence, oligonucleotide probes were generated and used to screen a human kidney library (LIB228) library prepared as described in paragraph 1 of Exattrple 2 above. The cloning rector was pRKSB (pRKSB is a precursor of pRK3D that does not contain the SfiI
site; see; Holmes et al., Science, x:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward atxl reverse) were synthesized:
~twvard PCR primer I (35858.f115'-ACCCACGTCTGCGTTGCTGCC-3' (SEQ ID N0:40) forward PCR primer 2 (,95858.f2) S'-GAGAATATGCTGGAGAGG-3' (SEQ ID N0:41) revere PCR primer (35858.r1) 5'-AGGAATGCACTAGGATTCGCGCGG-3' (SEQ ID N0:42) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35858 sequence which had the following nucleotide sequence ~tybridizatiQn probe 135858.n/) 5'-GGCCCCAAAGGCAAGGACAAAGCAGCTGTCAGGGAACCTCCGCCG-3' (SEQ ID N0:43) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR attiplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR029b gene using the probe ~oligonucleotide and one of the PCR
primers.

A full length clone was identified that contained a single open reading frame with an.apparent translational initiation site at nucleotide positions 174-176 and ending at the stop codon found at nucleotide positions 786-788 (Figure 14; SEQ ID N0:35). The predicted palypeptide precursor is 204 amino acids long, has a calculated molecular weight of approximately 22,147 daltons and an estimated pI of approximately 8.37. Analysis of the full-length PR0296 sequence shown in Figure IS (SEQ ID N0:36) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 34 and transmembrane domains from about amino acid 47 to about amino acid 63, from about amino acid 72 to about amino acid.95 and from about amino acid 162 to about amino acid 182. Clone UNQ260 (DNA39979-1213) has been deposited with ATCC on April 21, 1998 and is assigned ATCC deposit no. 209789.
Analysis of the amino acid sequence of the full-length PR0296 polypeptide suggests that it possesses significant sequence similarity to the sarcoma-amplified SAS protein, thereby indicating that PR0296 may be a novel SAS homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0296 amino acid sequence and the following Dayhoff sequences, I5839I, GEN11061, SSC2B04 1, HSU81031 2, CD63,RAT, CD63 MOUSE, CD63 HUMAN, AF022813 1, CD63 RABIT and C002 HUMAN.
'~X~1MP~,E 8: Isolation of~D,V~~ Clones Enco~ine Human PR0~29 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA35612. Based on the DNA356i2 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0329.
PCR primers (forward and reverse) were synthesized:
forwa,~d PCR grimer 1 f3S61~,f115'-TGGGCTGTGTCCTCATGG-3' (SEQ ID N0:46) forward PCR primer 2 (35612.f2) 5'-TTTCCAGCGCCAATTCTC-3' (SEQ ID N0:47) reverse PCR ~~rimer 1 135612.r1) 5'-AGTTCTTGGACTGTGATAGCCAC-3' (SEQ ID N0:48) reverse PC~grimer 2 135612.r2) 5'-AAACTTGGTTGTCCTCAGTGGCTG-3' (SEQ ID N0:49) Additionally, a synthetic oiigonucleotide hybridization probe was constructed from the consensus DNA35612 sequence which had the following nucleotide sequence bridization Rr_o~e,(~56I2.n1) 5'-GTGAGGGACCTGTCTGCACTGAGGAGAGCAGCTGCCACACGGAGG-3' (SEQ ID N0:50) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones eroding the PR0329 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB6).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0329 33 [herein designated as UNQ291 (DNA40594-1233)] (SEQ ID N0:44) and the derived protein sequence for PR0329.
The entire nucleotide sequence of UNQ291 (DNA40594-1233) is shown in Figure 19 (SEQ ID N0:44).
Clone UNQ291 (DNA40594-1233) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 9-11 and ending at the stop codon at nucleotide positions 1086-1088 (Figure 19). The predicted polypeptide precursor is 359 amino acids long (Figure 20). The full-length PR0329 protein shown in 18~

WO 99!46281 PCT/US99l05028 Figure 20 has an estimated molecular weight of about 38,899 daltons and a pI
of about 5.21. Clone UNQ291 (DNA40594-1233) has been deposited with ATCC on February 5, 1998 and is assigned ATCC deposit no. 209617.
Analysis of the amino acid sequence of the full-length PR0329 polypeptide suggests that it possesses significant sequence similarity to a high affinity immunoglobulin F~ receptor protein. More specifically, an analysis of the Dayhoff database (version 35.45 Swissl'rot 35) evidenced significant homology between the PR0329 amino acid sequence and the following Dayhoff sequences, FCGl HUMAN, FCGO HUMAN, P
891439, P 822549, F 891438, P W00859, P 820811. P 822550, HUMCD6406 I and FCG1 MOUSE.
EXAMPLE 9: Isolation of cDNA Clones EncodingHuman PR0362 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42257. Based on the DNA42257 consensus .
sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0362.
PCR primers (forward and reverse) were synthesized:
forward PCR Rrimer 1 (42257.f1) 5'-TATCCCTCCAATTGAGCACCCTGG-3' (SEQ ID N0:53) forward' PCR primer 2 (42257.f2) 5'-GTCGGAAGACATCCCAACAAG-3' (SEQ ID N0:54) reverse PCR primer 1 (42257.r1) 5'-CTTCACAATGTCGCTGTGCTGCTC-3' (SEQ ID NO:55) reverse PCR primer 2 (42257. r2) 5'-AGCCAAATCCAGCAGCTGGCTTAC-3' (SEQ ID N0:56) Additionally, a synthetic oligonucieotide hybridization probe was constructed from the consensus DNA42257 sequence which had the following nucleotide sequence h bridization probe (42257.n1) 5'-TGGATGACCGGAGCCACTACACGTGTGAAGTCACCTGGCAGACTCCTGAT-3' (SEQ ID N0:57) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened' by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PR0362 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from hurnan fetal brain tissue (LIB153).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0362 [herein designated as UNQ317 (DNA45416-1251)) (SEQ ID NO:51) and the derived protein sequence for PR0362.
The entire nucleotide sequence of UNQ31? (DNA45416-1251) is shown in Figure 21 (SEQ ID NO:51).
Clone UNQ317 {DNA45416-1251) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 119-121 and ending at the stop codon at nucleotide positions 1082-1084 (Figure 21 ). The predicted polypeptide precursor is 321 amino acids long (Figure 22). The full-length PR0362 protein shown in Figure 2 has an estimated molecular weight of about 35,544 daltons and a pI of about 8_51. Analysis of the full-Length PR0362 polypeptide as shown in Figure 22 evidences the presence of a glycosaminoglycan attachment site at about amino acid 149 to about amino acid 152 and a transmembrane domain from about amino acid 276 to about amino acid 306. Clone UNQ317 (DNA45416-1251) has been deposited with ATCC on February 5, 1998 and is assigned ATCC
degosit no. 209620.
Analysis of the amino acid sequence of the full-length PR0362 polypeptide suggests that it possesses significant sequence similarity to the A33 antigen protein and the HCAR
protein. Mare specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0362 amino acid sequence and the following Dayhoff sequences, AB002341_1, HSU552S8_l, NSC71~RCAM_1, RNU81037-l, A33 HUMAN, P W141S8, NMNCAMRI 1, HSTITINN2 1, S71824 1 and HSU63041 1.
EXAMPLE 10: Isolation of cDNA Clones Encodine Human PR0363 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42828. Based on the DNA42828 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0363.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR ~ri~,ne~s~2828.f1) 5'-CCAGTGCACAGCAGGCAACGAAGC-3' (SEQ ID N0:60) reverse PCR Qrimer i(,~2828.r1) S'-ACTAGGCTGTATGCCTGGGTGGGC-3' (SEQ ID N0:6I) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA42828 sequence which had the following nucleotide sequence hybridization probe~4~828.n1) S'-GTATGTACAAAGCATCGGCATGGTTGCAGGAGCAGTGACAGGC-3' (SEQ ID N0:62) IS In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the FCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0363 gene using the probe oiigonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal itidney tissue (LIB227):
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0363 [herein designated as UNQ3f 8 (DNA4S4I9-1252)] (SEQ ID NO:SB) and the derived protein sequence for PR0363.
The entire nucleotide sequence of UNQ318 (DNA4S419-1252) is shown in Figure 23 (SEQ ID NO:SB).
Clone UNQ318 (DNA45419-1252) contains a single open reading frame with an apparent uanslationai initiation site at nucleotide positions 1~=192 and ending at the stop codon at nucleotide positions 1309-1311 (Figure 23). The predicted polypeptide precursor is 373 amino acids long (Figure 24). The full-length PR0363 protein shown in 2S Figure 24 has an estimated molecular weight of about 41,281 daltons and a pI of about 8.33. A transmembrane domain exists at amino acids 221 to 2S4 of the amino acid sequence shown in Figure 24 (SEQ ID N0:59). The PR0363 polypeptide also possesses at least two myelin PO protein domains from about amino acids 15 to 56 and from about amino acids 87 to I 16. , Clone UNQ3I8 (DNA4S419-1252) has been deposited with ATCC on February S, 1998 and is assigned ATCC deposit no. 209616.
Analysis of the amino acid sequence of the foil-length PR0363 polypeptide suggests that it possesses significant sequence similarity to the cell surface protein HCAR, thereby indicating that PR0363 may be a novel HGAR homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0363 amino acid sequence and the following Dayhoff sequences, H546KDA_i, HSU90716 1; MMCARH 1, MMCARHOM_l, MMU90715_l, A33,HUMAN, P W14146, P_WI4158, 3S and B42632.
EXAMPLE 1 I : Isolation of cDNA Clones ncodir,~g, Human PR086A
A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA38133. Based on the DNA38I33 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0868.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer (38133.f1) S'-GTAGCAGTGCACATGGGGTGTTGG-3' (SEQ ID NO:65) reverse PCR primer (38133.r1) S'-ACCGCACATCCTCAGTCTCTGTCC-3' (SEQ ID NO:b6) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA38I33 sequence which had the following nucleotide sequence hybridization probe (38133.u1) 5'-ACGATGATCGCGGGCTCCCTTCTCCTGCTTGGATTCCTTAGCACCACCAC-3' (SEQ ID N0:67) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0868 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (L1B227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0868 [herein designated as UNQ437 (DNA52S94-1270)] (SEQ ID N0:63) and the derived protein sequence for PR0868.
The entire nucleotide sequence of UNQ437 (DNA52594-1270) is shown in Figure 25 (SEQ ID N0:63).
Clone UNQ437 (DNA52594-1270) contains a single open reading frame with an apparent translationaI initiation site at nucleotide positions 325-327 and ending at the stop codon at nucleotide positions 2290-2292 (Figure 25). The predicted polypeptide precursor is 655 amino acids long (Figure 26). The full-length PR0868 protein shown in Figure 26 has an estimated molecular weight of about 71,845 daltons and a pI
of about 8.22. Analysis of the full-length PR0868 polypeptide sequence demonstrates the presence of conserved cysteine-containing domains from about amino acid 66 to about amino acid 78 and from about amino acid 123 to about amino acid 134 of the sequence shown in Figure 26 {SEQ ID N0:3), a TNFR death domain from about amino acid 85 to about amino acid 110, a FASA mouse death domain block from about amino acid 159 to about amino acid 175 and a transmembrane domain from about amino acid 347 to about amino acid 375. Clone UNQ437 (DNA52594-1270) has been deposited with ATCC on March 17, 1998 and is assigned ATCC deposit no. 209679 Analysis of the amino acid sequence of the full-length PR0868 polypeptide suggests that it possesses significant sequence similarity to the tumor necrosis factor receptor protein, thereby indicating that PR0868 may be a novel member of the tumor necrosis factor receptor family. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProi 35) evidenced significant homology between the PR0868 amino acid sequence and the following Dayhoff sequences, RNU94330~1, P 899933, P 899945, P 899950, HSU94332 1, CD40 HUMAN, S63368_l, TNR2 HUMAN, MVU87844_1 AND CVU87837_l.
EXAMPLE 12: Isolation o~ cDN Clones Encoding Human PTj0382 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30892. Based on the DNA30892 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0382.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer S'-TGACATCGCCCTTATGAAGCTGGC-3' (SEQ 1D N0:70) reverse PAR primer 5'-TACACGTCCCTGTGGTTGCAGATC-3' (SEQ 1D N0:71) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30892 sequence which had the following nucleotide sequence hybridization probe 5'-CGTTCAATGCAGAAATGATCCAGCCTGTGTGCCTGCCCAACTCTGAAGAG-3' (SEQ ID N0:72) In order to screen several libraries for a source of a full-length clone; DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0382 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0382 [herein designated as UNQ323 (DNA45234-1277)] (SEQ ID N0:68) and the derived protein sequence for PR0382.
The entire nucleotide sequence of UNQ323 (DNA45234-1277) is shown in Figure 27 (SEQ ID N0:68).
Clone UNQ323 (DNA45234-1277) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 126-128 and ending at the stop colon at nucleotide positions 1485-1487 (Figure 27). The predicted poiypeptide precursor is 453 amino acids long (Figure 28). The full-length PR0382 protein shown in Figure 28 has an estimated molecular weight of about 49,334 daltons and a pI
of about 6.32. Analysis of the native PR0382 amino acid sequence shown in Figure 28 (SEQ ID N0:69) indicates the presence of a putative transasembrane domain from about amino acid 240 to about amino acid 284, a putative signal peptide at about amino acid 1 to about amino acid 20, a putative apple domain at about amino acid 386 to about amino acid 419, a putative Kringle domain at about amino acid 394 to about amino acid 406 and a histidine-containing protease active sits at about amino acid 253 to about amino acid 258. Clone UNQ323 (DNA45234-1277) has been deposited with ATCC
on March 5, 1998 and is assigned ATCC deposit no. 209654.
Analysis of the amino acid sequence of the full-length PR0382 polypeptide suggests that it possess significant homology to serine protease proteins, thereby indicating that PR0382 may be a novel serine protease.
Specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0382 amino acid sequence and the following Dayhoff sequences, HSU75329~1, ENTK MOUSE, HEPS HUMAN, AF030065 1, REPS RAT, PLMN PIG, P 889430, P 889435, PLM1~T_HORSE, PLMN BOVIN
and P 883959.
EX PLE 13_: Isolation, of cDNA Tones En~dine Human PR0545 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA44706. An EST
proprietary to Genentech was employed in the consensus assembly and is herein designated DNA13217 (Figure 31; SEQ ID NO:?5). Based on the DNA44706 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0545.
Forward and reverse PCR primers were synthesized:
forward PCR Timer I 5'-GTCTCAGCACGTGTTCTGGTCTCAGGG-3' (SEQ ID N0:76) forward PCR primer 2 5'-CATGAGCATGTGCACGGC-3' (SEQ ID N0:77) forward PCR~rimer 3 5'-TACCTGCACGATGGGCAC-3' (SEQ ID N0:78) WO 99146281 PCTlUS99/05028 forward PCR primer 4 5'-CACTGGGCACCTCCCTTC-3' (SEQ ID N0:79) reverse PCR primer 1 5'-CTCCAGGCTGGTCTCCAAGTCCTTCC-3' (SEQ ID N0:80) reverse PCR primer 2 5'-TCCCTGTTGGACTCTGCAGCTTCC-3' (SEQ ID N0:81) reverse PCR primer 3 5'-CTTCGCTGGGAAGAGTTTG-3' (SEQ iD N0:82) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA44706 sequence which had the following nucleotide sequence hvbridization~robe S'-GTGCAACCAACAGATACAAACTCTTCCCAGCGAAGAAGCTGAAAAGCGTC-3' (SEQ ID N0:83) In order to screen several libraries.for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0545 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human placenta tissue (LIB90}.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0545 [herein designated as UNQ346 (DNA49624-12?9)] (SEQ ID N0:73) and the derived protein sequence for PR0545.
The entire nucleotide sequence of UNQ346 (DNA49624-1279) is shown in Figure 29 (SEQ ID N0:73).
Clone UNQ346 (DNA49624-1279) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 311-313 and ending at the stop codon at nucleotide positions 2516-2518 (Figure 29). The predicted polypeptide precursor is 735 amino acids long (Figure 30). The full-length PR0545 protein shown in Figure 30 has an estimated molecular weight of about 80,177 daltons and a pI
of about 7.08. Important regions of the PR0545 amino acid sequence include the signal peptide, corresponding to amino acids 1-28, Eve potential N-glycosylation sites, from about amino acid 111-114, amino acids 146-149, amino acids 348-351, amino acids 449-452, and amino acids 648-651, and a neutral zinc metailopeptidase, zinc-binding region signature sequence, from about amino acids 344-353. Clone UNQ346 (DNA49624-1279) has been deposited with ATCC and is assigned ATCC deposit no. 209655.
EXAMPLE 14: Isolation of cDNA Clones Encoding Human PR06I7 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42798. Based on the DNA42798 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRObl7.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR p 'timer 5'-ACGGGCACACTGGATCCCAAATG-3' (SEQ ID N0:86) reverse PCR primer 5'-GGTAGAGATGTAGAAGGGCAAGCAAGACC-3' (SEQ ID N0:87}
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA42798 sequence which had the following nucleotide sequence hybridization probe 5'-GCTCCCTACCCGTGCAGGTTTCTTCATTTGTTCCTTTAACCAGTATGCCG-3' (SEQ ID N0:88) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0617 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LiB227}.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0617 therein designated as UNQ353 (DNA48309-1280)] (SEQ ID NO:I) and the derived protein sequence for PRObl7.
The entire nucleotide sequence of UNQ353 (DNA48309-1280) is shown in Figure 32 (SEQ ID NG:84).
Clone UNQ353 (DNA48309-1280) contains a single open reading frame with an apparent iranslational initiation site at nucleotide positions 723-725 and ending at the stop codon at nucleotide positions 924-926 (Figure 32), The predicted polypeptide precursor is 67 amino acids long (Figure 33). The full-length PR0617 protein shown in Figure 33 has an estimated molecular weight of about 6,981 daltans and a pt of about 7.47. Analypjs of the PR0617 amino acid sequence also evidences the existence of a putative signal peptide from about amino acid 15 to about amino acid 27 and a putative protein kinase C phosphorylation site from about amino acid 41 to about amino acid 43. Clone UNQ353 (DNA48309-1280) has been deposited on March 5, 1998 with ATCC and is assigned ATCC deposit no.
209656.
Analysis of the amino acid sequence of the full-Length PR0617 polypeptide suggests that it possesses significant homology to the CD24 protein, thereby indicating that PR0617 may be a novel CD24 homolog. More IS specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR06I7 amino acid sequence and the following Dayhoff sequences, CD24 HUMAN, CD24,MOUSE, S15785, CD24 RAT, VGE BPG4, MSES HUMAN, HSMHC3W36A 2, MLU15184 8, P 8850?5, SEPL HUMAN
and MTCY63 13.
EXAMPLE 15: Isolation of cDNA Clones Encoding Human ~R0700 A consensus seque~e was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30837. Based on the DNA30837 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0700.
Forward and reverse PCR primers were synthesized:
f twvard PQR rimer 15'-ATGTTCTTCGCGCCCTGGTG-3' (SEQ ID NO:91) forward PQR~rimer 2 5'-CCAAGCCAACACACTCTACAG-3' (SEQ ID N0:92) reverse PCR,~.'-,mer I 5'-AAGTGGTCGCCTTGTGCAACGTGC-3' (SEQ ID N0:93) reverse PCR primer 2 5'-GGTCAA,AGGGGATATATCGCCAC-3' (SEQ ID N0:94) Additiottaliy, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30837 sequence which had the following nucleotide sequence hybridization probe 5'-GCATGGAAGATGCCAAAGTCTATGTGGCT'AAAGTGGACTGCACGGCCCA-3' (SEQ ID N0:95) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0700 gene using the probe oIigonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal Iddney tissue (LIB227).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0700 [herein designated as UNQ364 (DNA46776-1284)] (SEQ ID N0:89) and the derived protein sequence for PR0700.
The entire nucleotide sequence of UNQ364 (DNA46776-1284) is shown in Figure 34 (SEQ ID N0:89).
Clone UNQ3b4 (DNA46776-1284) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 33-35 and ending at the stop colon at nucleotide positions 1329-1331 (Figure 34). The predicted polypeptide precursor is 432 amino acids long (Figure 35). The full-length PR0700 protein shown in Figure 35 has an estimated molecular weight of about 47,629 daltons and a pI
of about 5.90. Impor~tattt regions of the amino acid sequence of PR0700 include the signal peptide, corresponding to amino acids from about 1 to 33, regions homologous to disulfide isomerase, corresponding to amino acids from about 82-99. 210-255, and 34S-360, a tyrosine kinase phosphorylation site, corresponding to amino acids from about 143-151, and an endoplasmic reticulum targeting sequence, corresponding to amino acids from about 429-432.
Clone UNQ364 (DNA46?76-1284) has been deposited with ATCC and is assigned ATCC Deposit No. 209721.
EXAMPLE 16: Isolation of cDNA Clones Encoding Human PR0702 A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA36623. Based on the DNA3b623 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0702.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer (36623.f1) 5'-CGCTGACTATGTTGCCAAGAGTGG-3' (SEQ ID N0:98) reve;se PCR,primer (36623.r1) S'-GATGATGGAGGCTCCATACCTCAG-3' (SEQ ID N0:99) Additionally, a synthetic oligonucleotide hybridization pxobe was constructed from the consensus DNA36623 sequence which had the following nucleotide sequence I~ybridization"probe (36623.01) S'-GTGTTCATTGGCGTGAATGACCTTGAAAGGGAGGGACAGTACATGTTCAC-3' (SEQ ID NO:100) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones et>codittg the PR0702 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated.from human fetal liver tissue (LIB229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0702 [herein designated as UNQ366 (DNA50980-1286)] (SEQ ID N0:96) and the derived protein sequence for PR0702.
The entire nucleotide sequence of UNQ366 (DNAS0980-1286) is shown in Figure 36 (SEQ ID N0:96) Clone UNQ366 (DNA50980-1286) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 22-24 and ending at the stop colon at nucleotide positions 853-85S (Figure 36). The predicted polypeptide precursor is 277 amino acids long (Figure 37). The full-length PRO702 protein shown in Figure 37 has an estimated molecular weight of about 30,645 daltons and a p/ of about 7.47.
Analysis of the full-length native PR0702 amino acid sequence evidences the presence of a putative signal peptide from about amino acid I to about amino acid 25, potential N-glycosyiation sites from about amino acid 230 to about amino acid 233 and from about amino acid 258 to about amino acid 261 and a C-type lectin domain signature sequence from about amuno acid 248 to about amino acid 270. Clone UNQ366 (DNA50980-1286) has been deposited with ATCC on March 31, 1998 and WO 99/4b281 PCT/US99145028 is assigned ATCC deposit no. 209717.
'Analysis of the amino acid sequence of the full-length PR0702 polypeptide suggests that it possesses significant sequence similarity to the conglutinin protein; thereby indicating that PRO?02 may be a novel conglutinin homolog: More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0702 amino acid sequence and the following Dayhoff sequences, 532436, P;R75b42, P
W18780, P W18781, A53330, AC002528,1, HSPPA2IC0_1, CA21_HUMAN, CA14 HUMAN and A61262.
EXAMPLE 17: IsolaticZr~of cDNA Clones Encodi~tg Human PRO203 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43047. Based on the DNA43047 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0703.
Forward and reverse PCR primers were synthesized:
forward PCR primer 5'-GAGAGCCATGGGGCTCCACCTG-3' (SEQ ID N0:103) reverse SCR primer 1 5'-GGAGAATGTGGCCACAAC-3' (SEQ ID N0:104) reve~str,P_CRprirrZ,e~ 5'-GCCCTGGCACAGTGACTCCATAGACG-3' (SEQ ID NO:105) reverse PCR primer 3 5'-ATCCACTTCAGCGGACAC-3' (SEQ ID N0:106) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40654 sequence which had the following nucleotide sequence hyrridization probe 5'-CCAGTGCCAGGATACCTCTCTTCCCCCCAGAGCATAACAGACACG-3' (SEQ ID N0:107) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0703 gene using the probe oIigonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal Iddney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0703 jherein designated as UNQ367 (DNA50913-1287)) (SEQ ID NO:101) and the derived protein sequence for PR0703.
The entire nucleotide sequence of UNQ367 (DNA50913-1287) is shown in Figure 38 (SEQ ID N0:101).
Clone UNQ367 (DNA50913-1287) contains a single open reading frame with an agparent translational initiation site at nucleotide positions 115-1 I7 and ending at the stop codon at nucleotide positions 2305-2307 (Figure 38). The predicted polypeptide precursor is 730 amino acids long (Figure 39). The full-length PR0703 protein shown in Figure 39 has an estimated molecular weight of about 78,644 dollops, and a p1 of about: 7.65. Important regions of the PR0703 amino acid sequence include the signal peptide, a cAMP- and cGMP=dependent protein kinase phosphoryiation site, a CUB domain protein motif, N-glycosylation sites and a putative AMP-binding domain signature. Clone UNQ367 (DNA50913-1287) has been deposited with ATCC and is assigned ATCC deposit no.
209716.

EXAMPLE I8: Isolation of cDNA Clones Encoding Human PRO?05 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43437. Based on the DNA43437 consensus sequence, oligonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0705.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-AAGCGTGACAGCGGGCACGTC-3' (SEQ ID NO:110) reverse PCR primer 5'-TGCACAGTCTCTGCAGTGCCCAGG-3' (SEQ ID NO:111) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43437 sequence which had the following nucleotide sequence hybridization probe 143437.n1~
5'-GAATGCTGGAACGGGCACAGCAAAGCCAGATACTTGCCTG-3' (SEQ ID N0:112) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0705 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0705 [herein designated as UNQ369 (DNA50914-1289)] (SEQ ID N0:108) and the derived protein sequence for PR0705.
The entire nucleotide sequence of UNQ369 (DNA50914-1289) is shown in Figure 40 (SEQ ID N0:108).
Clone UNQ369 (DNA50914-1289) contains a single open reading frame with an apparent translationat initiation site at nucleotide positions 566-568 and ending at the stop codon at nucleotide positions 2231-2233 (Figure 40). The predicted polypeptide precursor is 555 amino acids long (Figure 41). The full-length PR0705 protein shown in Figure 41 has an estimated molecular weight of about 62,736 dollops and a pI
of about 5.36. Analysis of the full-length PR0705 sequence as shown in Figure 41 evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 23, a eukaryotic DNA topoisomerase I active site from about amino acid 418 to about amino acid 436, and various regions that show homology to various glypican proteins from about amino acid 237 to about amino acid 279, about amino acid 421 to about amino acid 458, about amino acid 53 to about amino acid 74, about amino acid 466 to about amino acid 504; about amino acid 308 to about amino acid 355, about amino acid 104 to about amino acid 156 and about amino acid 379 to about amino acid 410.
Clone UNQ369 (DNA50914-1289) has been deposited with ATCC on March 31, 1998 and is assigned ATCC deposit no.2Q9722.
Analysis of the amino acid sequence of the full-length PR0705 polypeptide suggests that it possesses significant sequence sinnilarity to the K-glygican protein, thereby indicating that PR0705 may be a novel glypican protein family member. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0705 amino acid sequence and the following Dayhoff sequences, GPCK _ - -MOUSE, GLYP CHICK, GLYP~RAT, GLYP HUMAN, GPC2 RAT, GPCS HUMAN, GPC3 HUMAN, GPC3 RAT, P 830168 and CEC03H 12 2.
~A_MPLE 19: ~,solation of cDNA Clones Encodine Human PR0708 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34024. Based on the DNA34024 consensus WO 99!46281 PCTIUS99l05028 sequence, oligonueleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0708.
A pair of PCR primers (forward and reverse) were synthesized:
forward PQR primer 5'-CCCAACCCAACTGTTTACCTCTGG-3' (SEQ ID N0:115) reverse PCR primer 5'-CTCTCTGAGTGTACATCTGTGTGG-3' (SEQ ID NO:I 16) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA34024 sequence which had the following nucleotide sequence hybridization probe 5'-GCCACCCTACCTCAGAAACTGAAGGAGGTTGGNTATTCAACGCATATGGTCGG-3' (SEQ ID N0:117) In order to screen several 3ibraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0708 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0708 [herein designated as UNQ372 (DNA48296-1292)) (SEQ ID NO:1I3) and the derived protein sequence for PR0708.
The entire nucleotide sequence of UNQ372 (DNA48296-1292) is shown in Figures 42A-B (SEQ ID
NO:113). Clone UNQ372 (DNA48296-1292) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 891-893 and ending at the stop codon at nucleotide positions 2436-2438 (Figures 42A-B). The predicted polypepdde precursor is 515 amino acids long (Figure 43). The foil-length PR0708 protein shown in Figure 43 has an estimated molecular weight of about 56,885 daltons and a pI of about 6.49. Analysis of the PR0708 amino acid sequence shown in Figure 43 (SEQ ID N0:114) evidences the existence of a putative signal peptide at about amino acid l to about amino acid 37, putative sulfatase signature sequences at about amino acid 120 to about amino acid 132 and about amino acid 168 to about amino acid 177, a putative tyrosine ldnase phosphorylation site from about amino acid 163 to about amino acid 169 and potential N-glycosylation sites from about amino acid 157 to about amino acid 160, about amino acid 306 to about amino acid 309 and about amino acid 318 to about amino acid 321. Clone UNQ372 (DNA48296-1292) has been deposited with ATCC on March 11, 1998 and is assigned ATCC deposit no. 209668.
Analysis of the amino acid sequence of the full-length PR0708 polypeptide suggests that it possesses significant homology to the aryl sulfatase proteins, thereby indicating that PR0708 may be a novel aryl sulfatase homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0708 amino acid sequence and the following Dayhoff sequences, ARSB~HUMAN, CELC54D2 2, G0285'7, STS,HUMAN, I3?186, I37187, GEN12648, CELD1014 7, GAGS
HUMAN and SPHM HUMAN.
EXAMPLE 20: Isolation of cD~_t(.~ Clones Enc~di~g-~j mu ~aq, PR0320 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA28739. Based on the DNA28739 consensus sequence, oIigonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0320.

A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CCTCAGTGGCCACATGCTCATG-3' (SEQ ID N0:120) reverse PCR vrimer 5'-GGCTGCACGTATGGCTATCCATAG-3' (SEQ ID N0:121) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28739 sequence which had the following nucleotide sequence S hybridization ,robe 5'-GATAAACTGTCAGTACAGCTGTGAAGACACAGAAGAAGGGCCACAGTGCC-3' (SEQ ID NO:I22) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0320 gene using the probe .oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB25).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0320 [herein designated as UNQ281 (DNA32284-1307)) {SEQ ID N0:118) and the derived protein sequence for PR0320.
The entire nucleotide sequence of UNQ281 (DNA32284-1307) is shown in Figure 44 (SEQ ID N0:118).
Clone UNQ281 (DNA32284-1307) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 135-137 and ending at the stop codon at nucleotide positions 1149-1151 (Figure 44). The predicted polypeptide precursor is 338 amino acids long (Figure 45). The full-length PR0320 protein shown in Figure 45 has an estimated molecular weight of about 37,143 daltons and a pI
of about 8.92. Important regions of the PR0320 amino acid sequence include the signal peptide, corresponding to amino acids 1-21, an EGF-like domain cysteine pattern signature, corresponding to amino acids 80-91, and three calcium-binding EGF-like domains, corresponding to amino acids 103-124, 230-151 and 185-206, respectively. Clone UNQ281 (DNA32284-1307) has been deposited with ATCC and is assigned ATCC deposit no. 209670.
EXAMPLE 21: Isolation of cDNA Clones Encodiy Human~R0324 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34347. Based on the DNA34347 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO324.
PCR primers (forward and reverse) were synthesized:
forward PCR primer I 5'-GCAATGAACTGGGAGCTGC-3' (SEQ ID N0:125) forward PCR primer 2 5'-CTGTGAATAGCATCCTGGG-3' (SEQ ID N0:126) forward PCR primer 3 5'-CTTTTCAAGCCACTGGAGGG-3' . (SEQ ID N0:127) reverse PCR,grimer 1 5'-CTGTAGACATCCAAGCTGGTATCC-3' (SEQ ID N0:128}
reversg PCR grimer 2 5'-AAGAGTCTGCATCCACACCACTC-3' (SEQ ID N0:129) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA34347 sequence which had the following nucleotide sequence hybrid' aeon probe 5'-ACCTGACGCTACTATGGGCCGAGTGGCAGGGACGACGCCCAGAATG-3' (SEQ ID N0:130) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate WO 99/46281 PCTlUS99105028 clones encoding the PR0324 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (L186).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0324 [herein designated as UNQ285 (DNA36343-1310)] (SEQ ID N0:123) and the derived protein sequence for PR0324.
The entire nucleotide sequence of UNQ285 (DNA36343-1310) is shown in Figure 46 (SEQ ID N0:123).
Clone UNQ285 (DNA36343-1310) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 144-I46 and ending at the stop codon at nucleotide positions 1011-1013 (Figure 46). The predicted polypeptide precursor is 289 amino acids long (Figure 47). The full-length PR0324 protein shown in Figure 47 has an estimated molecular weight of about 32,268 daltons and a pI
of about 9.21. Analysis of the PR0324 polypeptide sequence shown in Figure 47 {SEQ ID NQ: i24) evidence the presence of the following: a signal peptide from about amino acid 1 to about amino acid 31, a transmembrane domain from about amino acid 136 to about amino acid I57, tyrosine Itinase phosphorylation sites from about amino acid 106 or about amino acid I07 to about amino acid 113 and regions that are homologous to short-chain alcohol dehydrogenase regions from about amino acid 80 to about amino acid 90, from about amino acid 131 to about amino acid 168, from about amino acid 1 to about amino acid 13 and from about amino acid 176 to about amino acid 185. Clone UNQ285 (DNA36343-1310) has been deposited with ATCC on March 30, 1998 and is assigned ATCC deposit no. 209718.
Analysis of the amino acid sequence of the full-length PR0324 polypeptide suggests that it possesses significant sequence similarity to oxidoreductases, thereby indicating that PR0324 may be a novel oxidoreductase homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0324 amino acid sequence and the following Dayhoff seguences, B61209, A69965, YQJQ,BACSU, D69930, S76124, FABG ECOLI. C70023, S77280; FABG VIBHA and MTYOI3 6.
E3tAMPL~22: Isolation of DNA Clones encoding Human PR0351 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA35950. Based on the DNA35950 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0351.
Forward and reverse PCR primers were synthesized:
forward ~R_ rn imP,~ 5'-CCTGTGCTGTGCCTCGAGCCTGAC-3' (SEQ ID N0:133) reverse PCR brim r 5'-GTGGGCAGCAGTTAGCACCGCCTC-3' (SEQ ID N0:134) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35950 sequence which had the following nucleotide sequence hybridization rn obc 5'-GGCTGGCATCATCAGCTTTGCATCAAGCTGTGCCCAGGAGGACGC-3' {SEQ ID N0:135) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0351 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB230):

WO 99/46281 PCTlUS99l05028 DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0351 [herein designated as UNQ308 (DNA40571-1315)j (SEQ ID N0:131) and the derived protein sequence for PR0351.
The entire nucleotide sequence of UNQ308 {DNA40571-1315) is shown in Figure 48 (SEQ ID N0:131).
Clone UNQ308 {DNA4057I-1315) contains two open reading frames with an apparent translational initiation site at nucleotide positions 189-191 and a second open reading frame beginning at nucleotide 470, with the two open reading frames ending at the stop codons at nucleotide positions 363-365 and 2009-2011, respectively (Figure 48). The predicted polypeptide precursor is 571 amino acids long (Figure 49). Important regions of the amino acid sequence of PR0351 include the signal peptide, regions having sequence similarity to serine proteases of the trypsin family, two N-glycosylation sites, and three Kringle domains. Clone UNQ308 {DNA40571-1315) has been deposited with ATCC and is assigned ATCC deposit no. 209784.
I~X~MPLE ~3: Isolation of cDNA Clones Encoding Human PR0352 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA36950. Based on the DNA36950 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0352.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 1 5'-CTGGCACAGCTCAACCTCATCTGG-3' (SEQ ID > ;138) ]'onward PCR primer 2 5'-GCTGTCTGTCTGTCTCATTG-3' (SEQ 1D N0:139) forward PCR primer 3 5'-GGACACAGTATACTGACCAC-3' (SEQ ID N0:140) Ieverse PCR prime,L 1 5'-TGCGAACCAGGCAGCTGTAAGTGC-3' (SEQ ID N0:141) reverse PC Rrimer 2 5'-TGGAAGAAGAGGGTGGTGATGTGG-3' (SEQ ID N0:142) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA36950 sequence which had the following nucleotide sequence l~ridization probe 5'-CAGCTGACAGACACCAAACAGCTGGTGCACAGTTTCACCGAAGGC-3' (SEQ ID N0:143) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0352 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0352 [herein designated as UNQ309 (DNA41386-1316)] (SEQ ID N0:136) and the derived protein sequence for PR0352.
The entire nucleotide sequence of UNQ309 t',DNA41386-1316) is shown in Figure 50 (SEQ ID NO:I36).
Clone UNQ309 (DNA4138Cr1316) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 152-154 and ending at the stop eodon at nucleotide positions 11011-1102 (Figure 50). The predicted polypeptide precursor is 316 amino acids long (Figure 51). The full-length PR0352 protein shown in Figure 2 has an estimated pI of about 4.62. Analysis of the full-length PR0352 sequence evidences the presence of a signal peptide from about amino acid 1 to about amino acid 28, a transmembrane domain from about amino acid 251 to about amino acid 270, potential N-glycosylation sites from about amino acid 91 to about amino acid 94, about amino acid 104 to about amino acid 107, about amino acid 189 to about amino acid 192 and about amino acid 215 to about amino acid 218 and a region having homology to immunoglabulins and MHC from about amino acid 217 to about amino acid 234. Clone UNQ309 (DNA41386-1316) has been deposited with ATCC on March 26, 1998 and is assigned ATCC deposit no. 209703.
Analysis of the amino acid sequence of the full-length PR0352 polypeptide suggests that it possesses significant sequence simitariry to the buryrophilin protein, thereby indicating that PR0352 is a novel butyrophilin homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0352 amino acid sequence and the following Dayhoff sequences, BUTY~HUMAN, HSB73_1, GGCD80 1, I46690, A33~HUMAN, P 867988, CD86 MOUSE, P 871360, B39371 and D50558_l.
EXAMPL 24: Isolation of cDNA Clones Encoding Humg~ P~t0381 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39651. Based on the DNA39651 consensus sequence, oIigonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0381.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR grimer 5'-CTTTCCTTGCTTCAGCAACATGAGGC-3' (SEQ 1D N0:146) Levgrse PCR Crimea 5'-GCCCAGAGCAGGAGGAATGATGAGC-3' (SEQ ID N0:147) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39651 sequence which had the following nucleotide sequence hybrid,~ation probe 5'-GTGGAACGCGGTCTTGACTCTGTTCGTCACTTCTTTGATTGGGGCTTTG-3' (SEQ ID NO:I48) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by P'CR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR038I gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lddney tissue (LI$227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0381 [herein designated as UNQ322 (DNA44194-1317)) (SEQ ID N0:144) and the derived protein sequence for PR0381.
The entire nucleotide sequence of UNQ322 (DNA44194-1317) is shown in Figure 52 (SEQ ID N0:144).
Clone UNQ322 (DNA44194-1317) contains a single open reading frame with an apparent translationat initiation site at nucleotide positions 174-176 and ending at the stop codon at nucleotide positions 807-809 (Figure 52). The predicted poIypeptide precursor is 211 amino acids long (Figure 53). The full-length PR0381 protein shown in Figure 53 has an estimated molecular weight of about 24,172-daitons and a pI
of about 5.99. Analysis of the full-length PR0381 polypeptide shown in Figure 53 (SEQ ID N0:145) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 20, a potential N-glycosylation site from about amino acid 176 to about amino acid 179, potential casein Icinase II phosphoryladon sites from about amino acid 143 to about amino acid 146, from about amino acid 156 to about amino acid 159, from about amine acid 178 to about amino acid 181, and from about amino acid 200 to about amino acid 203, an endoplasmic reticuhun targeting seguence from about amuno acid 208 tn about amino acid 211; FK$P-type peptidyl-prolyl cis-traps isomerase sites from about amino acid '~8 to about amino acid 114 and from about amino acid 118 to about amino acid 131, EF-hand calcium binding ''vins from about amino acid 191 to about amino acid 203, from about amino acid I84 to about amino acid 203 rr WO 99/46281 PCTlUS9910~028 and from about amino acid 140 to about amino acid 159, and an S-i00lICaBP type calcium binding domain from about amino acid I83 to about amino acid 203. Clone UNQ322 {DNA44194-1317) has been deposited with ATCC
on April 28, 1998 and is assigned ATCC deposit no. 209808.
Analysis of the amino acid sequence of the full-length PR0381 polypeptide suggests that it possesses significant sequence similarity to FKBP immunopltilitt proteins, thereby indicating that PR0381 may be a novel FKBP
immunophilin homoiog. More specifically, an analysis of the Dayhoff database {version 35.45 SwissProt 35) evidenced significant homology between the PR0381 amino acid sequence and the following Dayhoff sequences, AF040252_l, I49669, P 893551, 571238, CELCOSC8_l, CEU27353~1, MIP TRYCR, CEZC455 3, FKB4 HUMAN and 140718.
EXAMPLE 25: Isolation of cDNA Clones Encoding Human PR0386 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA40674. Two proprietary Genentech EST
sequences were employed in the consensus sequence assembly, wherein those EST
sequences are herein designated DNA23350 (Figure 56; SEQ ID N0:151) and DNA23536 (Figure 57; SEQ ID N0:152).
Based on the DNA40674 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0386.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCRprimer 5'-ACGGAGCATGGAGGTCCACAGTAC-3' (SEQ ID N0:153) reverse PCR primer 5'-GCACGTTTCTCAGCATCACCGAC-3' (SEQ ID N0:154) Additionally, a synthetic oligonucleotide hybridization probe was constructed froth the consensus DNA40674 sequence which had the following nucleotide sequence hybridization vrobe 5'-CGCCTGCCCTGCACCTTCAACTCCTGCTACACAGTGAACCACAAACAGTT-3' (SEQ ID N0:155) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0386 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB153).
DNA sequencing of the,clones isolated as described above gave the full-length DNA sequence for PR0386 jherein designated as UNQ326 (DNA45415-1318)] {SEQ 1D N0:149) and the derived protein sequence for PR0386.
T'he entire nucleotide sequence of ~UNQ326 (DNA454I5-1318} is shown in Figure 54 (SEQ ID N0:149).
Clone UNQ326 (DNA45415-1318) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 14b-148 and ending at the stop codon at nucleotide positions 791-793 {Figure 54). The predicted polypeptide precursor is 215 amino acids long (Figure 55). The full-length PR0386 protein shown in Figtue 55 has an estimated molecular weight of about 24,326 daltons and a pI
of about 6.32. Analysis of the full-length PRO386 sequence shown in Figure 55 (SEQ ID N0:150) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20, a uansmembrane domain from about amino acid 161 to about amino acid 1?9, an immunoglobulin-like fold from about amino acid 83 to about amino acid 127 and potential N-glycosylation sites from about amino acid 42 to about amino acid 45, from about amino acid 66 to about amino acid 69 and from about amino acid 74 to about amino acid 77. Clone UNQ326 (DNA45415-1318) has been deposited with ATCC on April 28, 1998 and is assigned ATCC deposit no. 209810.
Analysis of the amino acid sequence of the full-length PR0386 polypeptide suggests that it possesses significant sequence similarity to the sodium channel beta-2 subunit, thereby indicating that PR0386 is a novel homolog thereof. More specifically, an analysis of the Dayhoff database (version 35.45 SvrissProt 35) evidenced significant homology between the PR0386 amino acid sequence and the following Dayhoff sequences, AS7843, S MYPO HUMAN, GEN14S31, IC4024, HS46KDA_l, HSU90716 1, D86996 2, MUSIGLVD_l, and 519247.
EXAM_PL~26: Isojation of cDNA Clones Encoditlg HumaZt ~R0~40 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA3963I. Based on the DNA39631 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0540.
Forward and reverse PCR primers were synthesized:
forward PCR primer S'-CTGGGGCTACACACGGGGTGAGG-3' (SEQ ID N0:158) IS reverse PCR primer S'-GGTGCCGCTGCAGAAAGTAGAGCG-3' (SEQ ID NO:IS9) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40654 sequence which had the following nucleotide sequetxe jib ~dizg_tion probe S'-GCCCCAAATGAAAACGGGCCCTACTTCCTGGCCGTCCGCGAGATG-3' (SEQ ID NO:1 b0) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0540 gene using the probe oligortucteotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0540 [herein designated as UNQ341 (DNA44189-1322)] (SEQ LD NO:1S6) and the derived protein sequence for PROS40.
The entire nucleotide sequence of UNQ341 (DNA44189-1322) is shown in Figure S8 (SEQ ID NO:1S6).
Cline UNQ34i (DNA44189-1322) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 2I-23 and ending at the stop codon at nucleotide positions 1257-1259 (Figure 58). The predicted polypeptide precursor is 412 amino acids long (Figure 59). The full-length PR0540 protein shown in Figure 59 has an estimated molecular weight of about 46,658 daltons and a pI
of about 6.65. Important regions of the amino acid sequence of PR0540 include the signal peptide, potential N-glycosylation sites, a potential lipid substrate binding site, a sequence typical of lipases and serine proteins, and a beta-transducin family Trp-Asp repeat.
Clone UNQ341 (DNA44189-1322) has been deposited with ATCC and is assigned ATCC
deposit no. 209699.
EXAMPLE 27: Isolation of cDNA Clones Enr~dinQ Huma_n_ PR0615 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42240. Based on the DNA42240 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0615.
Forward and reverse PCR primers were synthesized:
forward PCR her 5'-TGGTCTTCGCCTTGATCGTGTTCT-3' (SEQ ID NO:163) forward PCR vrimer S'-GTGTACTGAGCGGCGGTTAG-3' (SEQ ID N0:164) reverse PCR primer 5'-CTGAAGGTGATGGCTGCCCTCAC-3' (SEQ ID N0:165) reverse PCR,p_rimer 5'-CCAGGAGGCTCATGGGAAAGTCC-3' (SEQ ID NO:I66) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA42240 sequence which had the following nucleotide sequence:
hXbridization probe 5'-CCACGAGTCTAAGCAGATGTACTGCGTGTTCAACCGCAACGAGGATGCCT-3' (SEQ ID N0:167) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0615 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0615 (herein designated as UNQ352 (DNA48304-1323)] (SEQ ID N0:16I) and the derived protein sequence for PR0615.
The entire nucleotide sequence of UNQ352 (DNA48304-1323) is shown in Figure 60 (SEQ ID N0:161).
Clone UNQ352 (DNA48304-1323) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 51-53 and ending at the stop codon at nucleotide positions 723-725 (Figure 60). The predicted polypeptide precursor is 224 amino acids long (Figure b1). The full-length PR0615 protein shown in Figure 6I has an estimated molecular weight of about 24,8I0 dahons and a pI of about 4.75.
Important regions of the amino acid sequence of PR0615 include a type II transmembrane domain, corresponding to about amino acids 24-43, other transmembrane domains, corresponding to about amino acids 74-90, 108-126, and 145-161, respectively, and a potential N-glycosylation site, corresponding to about amino acids 97-100.
Clone UNQ352 (DNA48304-1323) has been deposited with ATCC and is assigned ATCC deposit no. 209811.
EXAMPLE 28: Isolation of cDNA Clones Encoding Human PRQ618 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30900. Based on the DNA30900 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0618.
Forward and reverse PCR primers were synthesized:
J'otwvard PCR primer 5'-TAACAGCTGCCCACTGCTTCCAGG-3' (SEQ ID N0:171) reverse PCR nritner 5'-TAATCCAGCAGTGCAGGCCGGG-3' (SEQ ID N0:172) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30900 sequence which had the following nucleotide sequence hybridization probe 5'-ATGGCCTCCACGGTGCTGTGGACCGTGTTCCTGGGCAAGGTGTGGCAGAA-3' (SEQ 1D NO:I73) Screening of the above described library gave rise to the partial cDNA clone designated herein DNA35597 (SEQ ID N0:170). Extension of this sequence using repeated cycles of BLAST and phrap gave rise to a nucleotide sequence designated herein as DNA43335. Primers based upon the DNA43335 consensus sequence were then prepared as follows.
forward PCR primer 5'-TGCCTATGCACTGAGGAGGCAGAAG-3' (SEQ ID N0:174) reverse PCR primer 5'-AGGCAGGGACACAGAGTCCATTCAC-3' (SEQ ID NO:175) Additionally, a synthetic oligonucleotide hybridization probe was constntcted from the consensus DNA43335 sequence which had the following nucleotide sequence ~vbridizatiorl_probe 5'-AGTATGATTTGCCGTGCACCCAGGGCCAGTGGACGATCCAGAACAGGAGG-3' IO (SEQ ID N0:176) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate full length clones encoding the PR0618 gene using the second probe oligonucleotide and one of the second set of PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (L18229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR06I8 (herein designated as UNQ354 (DNA49152-1324)] (SEQ ID N0:168) and the derived protein sequence for PR0618.
The entire nucleotide sequence of UNQ354 (DNA49IS2-1324) is shown in Figure 62 (SEQ ID NO; I68).
Clone UNQ354 (DNA49152-1324) contains a single open reading frame with an apparent transIational initiation site at rnicleotide positions 73-75 and ending at the stop codon at nucleotide positions 2479-2481 (Figure 62). The predicted polypeptide precursor is 802 amino acids long (Figure 63). The full-length PR0618 protein shown in Figure 63 has an estimated molecular weight of about 88,846 daltons and a pi of about 6.41. Important regions of the amino acid sequence of PR06I8 include type II transmembrane domain, a sequence typical of a protease, trypsin family, histidine active site, multiple N-glycosylation sites, two sequences typical of a Kringle domain, two regions having sequence similarity to KalliIQein light chain, and a region having sequence similarity to low-density lipoprotein receptor. Clone UNQ354 (DNA49152-1324) has been deposited with ATCC and is assigned ATCC deposit no.
209813.
EXAMPLE 29: Isolation of eDNA CIQnes ncodi~g Human PR0719 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA44851. Based on the DNA44851 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0719.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GTGAGCATGAGCGAGCCGTCCAC-3' (SEQ ID N0:179) reverse PCR ri r 5'-GCTATTACAACGGTTCTTGCGGCAGC-3' (SEQ ID N0:180) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA44851 sequence which had the following nucleotide sequence hvbrid~~lation probe 5'-TTGACTCTCTGGTGAATCAGGACAAGCCGAGTTTTGCCTTCCAG-3' (SEQ ID N0:181) w In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0719 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from htunan placenta tissue (LIB90).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence far PR0719 (herein designated as UNQ387 (DNA49646-1327)] (SEQ TD N0:177) and the derived protein sequence for PR0719.
The entire nucleotide sequence of UNQ387 (DNA49646-1327) is shown in Figure 65 (SEQ ID N0:177}.
Clone UNQ387 (DNA49646-1327) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 223-225 and ending at the stop codon at nucleotide positions 1285-1287 (Figure 65). The predicted polypeptide precursor is 354 amino acids long (Figure 66). The full-length PRO719 protein shown in Figure 66 has an estimated molecular weight of about 39,362 daltons and a pi of about 8.35. Analysis of the full length PR0719 sequence evidences the presence of a signal peptide from about amino acid 1 to about amino acid 16 as shown in Figure 64 (SEQ ID N0:178), a lipase-associated serine-containing active site at about amino acid 163 to about amino acid 172, and two potential N-glycosylation sites from about amino acid 80 to about amino acid 83 and about amino acid 136 to about amino acid 139. Clone UNQ387 (DNA49646-1327) has been deposited with ATCC on March 26, 1998 and is assigned ATCC deposit no. 209705.
Analysis of the amino acid sequence of the full-length PR0719 polypeptide suggests that it possesses significant sequence similarity to the lipoprotein lipase H protein, thereby indicating that PR0719 may be a novel lipoprotein lipase'homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0719 amino acid sequence and the following Dayhoff sequences, LIPL HUMAN, LIPH HUMAN, D83548~l, A24059~1, PlR30740, D88666_l, A43357, A46696, B43357 and A49488.
EXAMPLE 30: Isolation of cDNI~ Clones Encodine Human PR0724 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA35603. Based on the DNA35603 consensus sequence, oligonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0724.
Pairs of PCR primers (forward and reverse) were synthesized:
forward P~,R.,primer I 5'-GGCTGTCACTGTGGAGACAC-3' (SEQ ID N0:184) forward PCR primer 2 5'-GCAAGGTCATTACAGCTG-3' (SEQ ID N0:185) reverse PCB Britner 1 5'-AGAACATAGGAGCAGTCCCACTC-3' (SEQ ID N0:186) reverse PCR p~mer 2 5'-TGCCTGCTGCTGCACAATCTCAG-3' (SEQ ID N0:187) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35603 sequence which had the following nucleotide sequence hybridization r 5'- .GGCTATTGCTTGCCTTGGGACAGACCCTGTGGCTTAGGCTCTGGC-3' (SEQ ID N0:188) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PR0724 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO724 [herein designated as UNQ389 (DNA49631-1328)] (SEQ ID N0:182) and the derived protein sequence for PR0724.
The entire nucleotide sequence of UNQ389 (DNA49631-1328) is shown in Figure 67 (SEQ ID N0:182).
Clone UNQ389 (DNA49631-1328) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 546-548 and ending at the stop colon at nucleotide positions 2685-2687 (Figure 67). The predicted polypeptide precursor is 713 amino acids long (Figure 68). The full-length PR0724 protein shown in Figure 68 has an estimated molecular weight of about 76,193 daltons and a pI
of about 5.42. Analysis of the full-Iengtli PRO?24 amino acid sequence shown in Figure 68 (SEQ ID N0:183) evidences the presence of the following:
a signal peptide from about amino acid 1 to about amino acid 16, a transmembrane domain from about amino acid 442 to about amino acid 462 and LDL receptor class A domain regions from about amino acid 152 to about amino acid 171, about amino acid 331 to about amino acid 350, about amino acid 374 to about amino acid 393 and about amino acid 411 to about amino acid 430. Clone UNQ389 (DNA49631-1328) has been deposited with ATCC on April 28, 1998 and is assigned ATCC deposit no. 209806 Analysis of the amino acid sequence of the full-length PR0724 polypeptide suggests that it possesses significant sequence similarity to the human LDL receptor protein, thereby indicating that PR0724 may be a novel LDL receptor homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0724 amino acid sequence and the following Dayhoff sequences, P 848547, MMAM2R 1, LRP2 RAT, P 864517, P R4786I, P 805533, A44513,~1, A30363;
P 874692 and LMLIPOPHO 1.
EXAMPIrE 3I : Isolation of cDNA C~o,~es Encoding ]human PR0772 One cDNA sequence was isolated in the amylase screen described in Example 2, wherein that cDNA
sequence is herein designated DNA43509 (see Figure 7I). Based on the DNA43509 sequence, oligonucleotide probes were generated and used to screen a human fetal lung library (LIB25) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB is a precursor of pRKSD
that does not contain the SfiI
site; see, Holmes et al., ien e, 25:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
A pair of PCR primers (forward and reverse) were synthesized based on the DNA43509 sequence:
forward PCR primer 5'-CGTTTTGCAGAACCTACTCAGGCAG-3' (SEQ ID NO:192) reverse PCR primer 5'-CCTCCACCAACTGTCAATGTTGTGG-3' (SEQ ID N0:193) Additionally, a synthetic oligorntcleotide hybridization probe was constructed from the consensus DNA43509 sequence which had the following nucleotide sequence hybridization 7Lbg 5'-AAAGTGCTGCTGCTGGGTCTGCAGACGCGATGGATAACGT-3' (SEQ ID N0:194) Using the above descn'bed primers and fbrary, a full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 131-133 and ending at the stop colon found at nucleotide positions 587-589 (Figure 69; SEQ ID N0:189). The predicted polypeptide precursor is 152 amino acids long, has a calculated molecular weight of approximately 17,170 daltons and an estimated p1 of approximately 9.62. ,Analysis of the full-length PR0772 sequence shown in Figure 70 (SEQ ID N0:190) evidences the presence of the following: a potential type II transmembrane domain From about amino acid 26 to about amino acid 42, other potential transmembrane domains from about amino acid 44 to about amino acid 55, from about amino acid 81 to about amino acid 101 and from about amino acid 109 to about amino acid 129, leucine zipper pattern sequences from about amino. acid 78 to about amino acid 99 and from about amino acid 85 to about amino acid 106.
Clone UNQ410 (DNA49645-1347) has been deposited with ATCC on April 28, 1998 and is assigned ATCC deposit no. 209809.
Analysis of the amino acid sequence of the full-length PR0772 polypeptide suggests that it possesses significant sequence similarity to the human A4 protein, thereby indicating that PR0772 may be a novel A4 protein homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0772 amino acid sequence and the following Dayhoff sequences, HSU93305_l, A4P HUMAN, CELB0454a2, VPU JSRV, CELC12D12 2, OCCM AGRTl, LBPHIG1E 50, YIGK
ECOLI, S76245 and P 850807.
EXAMPLE 32: Isolation of cDNA Clones Encoding Human PR0852 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34364. Based on the DNA34364 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) fot use as probes to isolate a clone of the full-length coding sequence for PR0852.
PCR primers (forward and reverse) were synthesized:
forward primer 1 5'-CGCAGAAGCTACAGATTCTCG-3' (SEQ ID N0:197) PCR

forward primer 2 5'-GGAAATTGGAGGCCAAAGC-3' (SEQ ID N0:198) PCR

forward primer 3 5'-GGATGTAGCCAGCAACTGTG-3' (SEQ ID N0:199) PCR

forward primer 4 5'-GCCTTGGCTCGTTCTCTTC-3' (SEQ ID N0:200) PCR

forward primer 5 5'-GGTCCTGTGCCTGGATGG-3' (SEQ ID N0:201) PCR

reverse Qrimer 1 5'-GACAAGACTACCTCCGTTGGTC-3' (SEQ ID N0:202) PCR

reverse primer 2 5'-TGATGCACAGTTCAGCACCTGTTG-3' (SEQ ID N0:203) PCR

Additionally,a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA34364 sequence which had the following nucleotide sequence hvbridization~robe 5'-CGCTCCAAGGGCTTTGACGTCACAGTGAAGTACACACAAGGAAGCTG-3' (SEQ ID N0:204) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0852 gene using the probe oiigonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB228).
DNA seque~ing of dte clones isolated as described above gave the full-length DNA sequence For PR0852 [herein designated as UNQ418 (DNA45493-1349)] (SEQ ID N0:195) and the derived protein sequence for PR0852.
The entire nucleotide sequence of UNQ418 (DNA45493-1349) is shown in Figure 72 (SEQ ID N0:195).
Clone UNQ418 (DNA45493-1349) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 94-96 and ending at the stop codon at nucleotide positions 16748-1650 (Figure 72). 'The predicted polypeptide precursor is 518 amino acids long (Figure ?3). The full-length PR0852 protein shown in Figure 73 has an estimated molecular weight of about 56,180 daltons and a pI
of about 5.08. Analysis of the full-..r Length PR0852 sequence shown in Figure 73 (SEQ ID N0:196) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20, a transmembrane domain from about amino acid 466 to about amino acid 494, potential N-glycosylation sites from about amino acid 170 to about amino acid 173 and about amino acid 366 to about amino acid 369, leucine zipper sequence pattern blocks from about amino acid 10 to about amino acid 3I and from about amino acid 197 to about amino acid 218 and blocks of amino acids having sequence homology to eukaryotic and viral asparryl proteases from about amino acid 109 to about amino acid 118, from about amino acid 252 to about amino acid 261 and from about amino acid 298 to about amino acid 310. Clone UNQ418 (DNA45493-1349) has been deposited with ATCC on April 28> 1998 and is assigned ATCC deposit no. 209805.
Analysis of the amino acid sequence of the full-length PR0852 polypeptide suggests that it possesses significant sequence similarity to various protease proteins, thereby indicating that PR0852 may be a novel protease protein or homolog thereof. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0852 amino acid sequence and the following Dayhoff sequences, PEPC HUMAN, S66516, S66517, PEPS CHICK, CATD,HUMAN, P 874207, CARP YEAST, PEP2_RABIT, CATS HUMAN and RENI MOUSE.
EXAMPLE 33: Isolatio~ oo f cDN,~ Clones Encodin~,Human PR0853 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43050. Based on the DNA43050 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence'of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0853.
Forward and reverse PCR primers were synthesized:
forward PAR nnmer 5'-CTTCATGGCCTTGGACTTGGCCAG-3' (SEQ ID N0:207) reverse PCR primer 5'-ACGCCAGTGGCCTCAAGCTGGTTG-3' (SEQ ID N0:208) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43050 sequence which had the following nucleotide sequence ~vbridiz~,ti robe 5'-CTTTCTGAGCTCTGAGCCACGGTTGGACATCCTCATCCACAATGC-3' (SEQ ID N0:209) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0853 gene using the probe oligorntcleotide and one of the PCR primers. RNA for construction of the cDNA Libraries was isolated from human fetal kidney tissue (LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0853 jherein designated as UNQ4I9 (DNA48227-1350)] (SEQ ID N0:205) and the derived protein sequence for PR0853.
The entire nucleotide sequence of UNQ419 (DNA48227-1350) is shown in Figure 74 (SEQ ID N0:205).
Clone UNQ419 (DNA48227-1350) contains a single open reading frame with an apparent translatiottal initiation site at nucleotide positions 128-130 and ending at the stop codon at nucleotide positions 1259-1261 (Figure 74). The predicted poIypeptide precursor is 377 amino acids long (Figure 75). The full-length PR0853 protein shown in Figure 75 has an estimated molecular weight of about 40,849 daltons and a pI
of about 7.98. Important regions of the amino acid seguence of PR0853 include the signal peptide, corresponding to amino acids from about 1 to about 16 of SEQ ID N0:206, the glycosaminoglycan attachment site, corresponding to amino acids from about 46 to about 49 of SEQ ID N0:206, and two sequences typical of the short-chain alcohol dehydrogenase family, corresponding to amino acids from about 37 to about 49 and about 114 to about 124 of SEQ ID
N0:206, respectively. Clone UNQ419 (DNA48227-1350) has been deposited with ATCC and is assigned ATCC
deposit no. 209812.
EXAMPLE 34: Isolation of cDNA Clones Encoding Human PR0860 A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA38137. Based on the DNA38137 consensu sequence, oiigonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0860.
Forward and reverse PCR primers were synthesized:
forward PCR primer 5'-GAAGGGACCTACATGTGTGTGGCC-3' (SEQ ID N0:212) reverse PCR,pr_imer 5'-ACTGACCTTCCAGCTGAGCCACAC-3' (SEQ ID N0:2I3) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40654 sequence which had the following nucleotide sequence ~ybridization~robe 5'-AGGACTACACGGAGCCTGTGGAGCTTCTGGCTGTGCGAATTCAGCTGGAA-3' (SEQ ID N0:214) In order to screen several libraries for a source of a fiill-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0860 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for FR0860 (herein designated as UNQ421 (DNA41404-1352)] (SEQ 1D N0:210) and the derived protein sequence for PR0860.
The entire nucleotide sequence of UNQ421 {DNA41404-1352) is shown in Figures 76A-B (SEQ ID
N0:210). Clone UNQ421 (DNA41404-1352) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 58-60 and ending at the stop codon at nucleotide positions 3013-3015 (Figures 76A-B). The predicted polypeptide precursor is 985 amino acids long (Figure 77). The full-length PR0860 protein shown in Figure 77 has an estimated molecular weight of about 105,336 daltons and a pI of about 6.55. Important regions of the amino acid sequence. of PR0860 it>clude the transmembrane region corresponding to about amino acids 448-467, the extracellular domain, corresponding to amino acids about 1-447, several N-glycosylation sites, numerous N-myristoylation sites and a sequence typical of phosphotyrosine interaction domain proteins.. Clone UNQ421 (DNA41404-1352) has been deposited with ATCC and is assigned ATCC deposit na.
209844.
EXAMPLE 35: Isolation of~NA Clones Encoding Human PR0846 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39949. Based on the DNA39949 consensus sequence, oligonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0846.
Forward and reverse PCR primers were synthesized:
forward PCR~~imer 5'-CCCTGCAGTGCACCTACAGGGAAG-3' (SEQ ID N0:2I7) WO 99/d6281 PCTlUS99I05028 reverse PCR primer S'-CTGTCTTCCCCTGCTTGGCTGTGG-3' (SEQ ID N0:218) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39949 sequence which had the following nucleotide sequence hybridization probe S'-GGTGCAGGAAGGGTGGGATCCTCTTCTCTCGCTGCTCTGGCCACATC-3' S (SEQ iD NO:219) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0846 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal i6dney tissue (LI$227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR084b (herein designated as UNQ422 (DNA4419b-1353)] (SEQ 1D N0:21S) and the derived protein sequence for PRO846.
The entire nucleotide sequence of UNQ422 (DNA44196-1353) is shown in Figure 78 (SEQ.ID N0:21S).
Clone UNQ422 {DNA44196-i3S3) contains a single open reading frame with an apparent transiational initiation site at nucleotide positions 2S-27 and ending at the stop codon at nucleotide positions 1021-1023 (Figure 78). The 1S predicted polypeptide precursor is 332 amino acids long (Figure 79). The full-length PR0846 protein shown in Ftgure 79 has an estimated molecular weight of about 36,143 daltons and a p1 of about 5.89. Important regions of the amino acid sequence of PR084b include ttte signal peptide, the transmetnbrane domain, an N-glycosyIarion site, a scqt~e typical of fibrinogen beta and gamma chains C-terminal domain, and a sequence typical of Ig like V-type domain as shown in Fgure 79. Clone UNQ422 (DNA44196-1353) has been deposited with ATCC and is assigned ATCC deposit no. 209847. ' -EXAMPLE 36: Isolation of cDNA Clones Encoding Human PR0862 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA47370. Based on the DNA47370 consensus 2S sequertcc, oiigomtcleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0862.
Forward and reverse PCR primers were synthesized:
forward PCR pziLnrr S'GGGATCATGTTGT?'GGCCCTGGTC-3' (SEQ ID N0:222) reverse PCR primer S'-GCAAGGCAGACCCAGTCAGCCAG-3' (SEQ ID N0:223) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47370 sequence which had the following nucleotide aequence hybridization nnob"~
S'-CTGCCTGCTACCCTCCAAGTGAGGCCAAGCTCTACGGTCGTTGTG-3' (SEQ ID N0224) 3S in order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR at>lpIifrcation with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0862 gene using the probe oiigonucleotide and one of the PCR primers. RNA for consmtction of the cDNA libraries was isolated from human pancreas tissue (IdB55).
21i DNA sequetxing of the clones isolated as described above gave the full-length DNA sequence far PR0862 (herein designated as UNQ424 (DNA52187-1354)] (SFrQ ID N0:220) and the derived protein sequence for PR0862.
The entire nucleotide sequence of UNQ424 (DNA52187-1354) is shown in Figure 80 (SEQ ID N0:220).
Clone UNQ424 (DNA52187-1354) contains a single open reading frame with an apparent transiational initiation site at nucleotide positions 410-412 and ending at the stop codon at nucleotide positions 848-850 (Figure 80). The predicted polypeptide precursor is 146 amino acids long (Figure 81). The full-length PR0862 protein shown in Figure 81 has an estimated molecular weight of about 15,430 daltons and a pI
of about 5.05. Important regions of the amino acid sequence of PR0862 include the signal peptide, an N-myristoylation site, and sequences having similarity to region to Alpha-lactalbumin/lysozyme C proteins as shown in Figure 81. Clone UNQ424 (DNA52187-1354) has been deposited with the ATCC and is assigned ATCC deposit no.
209845.
I~XAM~LE 37: l~~on of cDNA Clones Encoditlg H_ uman PR08&i A consensus sequenre was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA40666. Based on the DNA40666 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0864.
Forward and reverse PCR primers were synthesized:
~rward PCR primer 5'-GCTGCAGCTGCAAATTCCACTGG-3' (SEQ ID N0:227) reverse PCR~rimr~ 5'-TGGTGGGAGACTGTTTAAATTATCGGCC-3' (SEQ ID N0:228) Additionally, a synthetic oligottucleotide hybridization probe was constructed from the consensus DNA40666 sequence which had the following nucleotide sequence ~yb~!'izauon probe 5'-TGCTTCGTCAAGT'GCCGGCAGTGCCAGCGGCTCGTGGAGTT-3' (SEQ ID N0:229) 1n order to screen several libraries for a source of a full-length clone, DNA
froth the libraries was screened by PCR amplification with ot>e of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0864 gene using the probe oligotrucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB153).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0864 [herein designated as UNQ42b (DNA48328-1355)] (SEQ ID N0:225) and the derived protein sequence for PR0864.
The entire nucleotide sequence of UNQ42b (DNA48328-1355) is shown in Figure 82 (SEQ ID N0:225).
Clone UNQ426 (DNA48328-1355) contains a single open reading frame with an apparent translationaI initiation site at ntxleotide positions 37-39 and ending at the stop codon at nucleotide positions 1090-1092 (Figure 82). The .
predicted polypeptide precursor is 351 amino acids long (Figure 83). The full-length PR0864 protein shown in Figure 83 has an estimated molecular weight of about 39,052 and a pI of about 8.97. Important regions of the amino acid sequence of PR08b4 include the signal peptide, two N-glycosylation sites, a Wnt-1 family signature sequence, and sequence regions homologous to Wnt-1 family proteins as shown in Figure 83. Clone UNQ426 (DNA48328-1355) has been deposited with ATCC and is assigned ATCC deposit no. 209843.

WO 99/4b28I PCT/US99/05028 EXAMPLE 38: Isolation o~cI~NA Clones Encg~iing~~n PR0792 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA38106, Based on the DNA38I06 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0792.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GCGAGAACTGTGTCATGATGCTGC-3' (SEQ ID N0:232) reverse PCR primer 5'-GTTTCTGAGACTCAGCAGCGGTGG-3' (SEQ ID N0:233) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA3810b sequence which had the following nucleotide sequence h,~r_ic i~ion probe 5'-CACCGTGTGACAGCGAGAAGGACGGCTGGATCTGTGAGAAAAGGCACAAC-3' (SEQ ID N0:234) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0792 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (L1B255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0792 jherein designated as UNQ431 (DNA56352-I358)] (SEQ ID N0:230) and the derived protein sequence far PR0792.
The entire nucleotide sequence of UNQ431 (DNA56352-1358) is shown in Figure 84 (SEQ ID N0:230).
Clone UNQ431 {DNA56352-1358) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 67-69 and ending at the stop codon at nucleotide positions 946-948 (Figure 84). The predicted polypeptide precursor is 293 amino acids long (Figure 8S). The full-length PR0792 protein shown in Figure 85 has an estimated molecular weight of about 32,562 daitons and a pI of about 6.53.
Analysis of the full-length PR0792 sequence shown in Figure 85 (SEQ ID N0:231) evidences the presence of the following: a type II transmembrane domain from about amino acid 31 to about amino acid 54, potential N-glycosylation sites from about amino acid 73 to about amino acid 76 and from about amino acid 159 to about amino acid 162, a leucine zipper amino acid sequence pattern from about amino acid 102 to about amino acid 123, potential N-myristolation sites from about amino acid 18 to about amino acid 23, from about amino acid 133 to about amino acid 138 and from about amino acid 242 to about amino acid 247 and a C-type lectin domain signature block from about amino acid 264 to about amino acid 287.
Clone UNQ431 (DNASb352-1358) has been deposited with ATCC on May 6, 1998 and is assigned ATCC deposit no.209846.
Analysis of the amino acid sequence of the full-length PR0792 poIypeptide suggests that it possesses significant sequence similarity to the CD23 protein, thereby indicating that PR0792 may be a novel CD23 hornolog.
More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0792 amino acid sequence and the following Dayhoff sequences, S34I98, A07100_l, AOS303~1, P 841689, P P82839, A10871_l, P R1279b, P 847199, A4b274 and P 832188.
EXAMPL 39: Isolation of cDNA Clones ,Fnco~i_rlg Human PR08b6 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA44708. Based on the DNA44708 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0866.
PCR primers (forward and reverse) were synthesized:
forward PCR-,primer 1 5'-CAGCACTGCCAGGGGAAGAGGG-3' (SEQ ID N0:237) forward PCR_primer 2 5'-CAGGACTCGCTACGTCCG-3' (SEQ ID N0:238) forward PCR prir.~r er 3 5'-CAGCCCCTTCTCCTCCTTTCTCCC-3' (SEQ ID N0:239) reverse PCR rid mer 1 5'-GCAGTTATCAGGGACGCACTCAGCC-3' (SEQ ID N0:240) reverse PCR yimer 2 5'-CCAGCGAGAGGCAGATAG-3' (SEQ 1D N0:241) reverse PCR primer 3 5'-CGGTCACCGTGTCCTGCGGGATG-3' (SEQ ID NO:242) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA44708 sequence which had the following nucleotide sequence hybridization probe 5'-CAGCCCCTTCTCCTCCTTTCTCCCACGTCCTATCTGCCTCTC-3' (SEQ ID N0:243) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0866 gene using the probe oIigonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0866 [herein designated as UNQ435 (DNA53971-1359)] (SEQ ID N0:235) and the derived protein sequence for PR0866.
The entire nucleotide sequence of UNQ435 (DNA53971-1359) is shown in Figure 86 (SEQ ID N0:235).
Clone UNQ435 t,'DNA53971-1359) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 275-277 and ending at the stop codon at nucleotide positions 1268-1270 {Figure 86). The predicted polypeptide precursor is 331 amino acids long (Figure 8?). The full-length PR0866 protein shown in Figure 87 has an estimated molecular weight of about 35,844 daltons and a pI
of about 5.45. Analysis of the full-length PR0866 sequence shown in Figure 87 (SEQ ID N0:236) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 26. Clone UNQ435 {DNA53971-1359) has been deposited with ATCC on April 7, 1998 and is assigned ATCC deposit no. 209750.
Analysis of the amino acid sequence of the full-length PR0866 polypeptide suggests that it possesses significant sequence similarity to the mindinlspondin family of proteins, thereby indicating that PR0866 may be a novel mindin homolog. More specifically, an analysis of the. Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0866 amino acid sequence and the following Dayhoff sequences,AB006085_l, AB006084_l, AB006486 1, AF017267_l, CWU42213_l, AC004160_l, CPMICRP'I, 549108, A48569 and I46687.
E~AMP~~~40: j~~glion of cDNA Clones Encoding, Human PR0871 A consensus sequence was obtained relative to a variety of EST sequences as described in Example l above, wherein the consensus sequence obtained is herein designated DNA40324. Based on the DNA40324 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of WO 99!46281 PCTIUS99l05028 interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR087I .
PCR primers (forward and reverse) were synthesized:
forward PCR grimer 1 5'-TGCGGAGATCCTACTGGCACAGGG-3' (SEQ ID N0:246) forward PCR,pri r 2 5'-CGAGTTAGTCAGAGCATG-3' (SEQ ID N0:247) forward PCR primer 3 5'-CAGATGGTGCTGTTGCCG-3' (SEQ ID N0:248) reverse PCR Qritner 1 5'-CAACTGGAACAGGAACTGAGATGTGGATC-3' (SEQ ID N0:249) reve,~se P_CR primer 2 5'-CTGGTTCAGCAGTGCAAGGGTCTG-3' (SEQ ID N0:250) reverse PCR primer, 5'-CCTCTCCGATTAAAACGC-3' (SEQ ID N0:251) Additionally, a synthetic oligonucleotide' hybridization probe was constructed from the consensus DNA40324 sequence which had the following nucleotide sequence hvbrj~diza_tiQn,probe ' 5'-GAGAGGACTGGTTGCCATGGCAAATGCTGGTTCTCATGATAATGG-3' (SEQ 1D N0:252) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0871 gene using the probe oligonucleotide and one of the PCR primers. RNA for IS construction of the cDNA libraries was isolated from human fetal kidney tissue (LI$227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence far PR0871 (herein designated as UNQ438 (DNA50919-136i)] (SEQ ID N0:244) and the derived protein sequence for PRO871.
The entire nucleotide sequence of UNQ438 (DNA50919-1361) is shown in Figure 88 (SEQ ID N0:244).
Clone UNQ438 (DNA50919-1361) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 19I-193 and ending at the stop codon at nucleotide positions 1607-1609 (Figure 88). The predicted polypeptide precursor is 472 amino acids long (Figure 89). The full-length PR0871 protein shown in Figure 89 has an estimated molecular weight of about 53,84? daltons and a p1 of about 5.75. Analysis of the full-length PR0871 sequence shown in Figure 89 (SEQ ID NO:245) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 21, potential N-glycosylation sites from about amino acid 109 to about amino acid 112 and from about amino acid 201 to about amino acid 204, a cyclophiIin-type peptidy-prolyl cis-traps isomerase signature sequence from about amino acid 49 to about amino acid 66 and regions that are homologous to cyciophilin-type peptidy-prolyl cis-traps isomerases from about amino acid 96 to about amino acid 140, from about amino acid 49 to about amino acid 89 and from about amino acid 22 to about amino acid 51. Clone UNQ438 (DNA50919-1361) has been deposited with ATCC on May 6, 1998 and is assigned ATCC deposit no.
209848.
Analysis of the amino acid sequence of the full-length PR087I polypeptide suggests that it possesses significant sequence similarity to the cyclophilin family of proteins, thereby indicating that PR0871 may be a navel cyclophilin protein family member. More specifically, an analysis of the Dayhoff database (version 35.4S SwissProt 35) evidenced significant homology between the PR087I amino acid sequence and the following Dayhoff sequences, SP$C16H5 5, 564705, YALS_SCHPO, CYP4 CAEEL, CELC34D4 7, CYPA CAEEL, HUMORF006 1, CYPI MYCTU, AF043b42 1 and HSSRCYP 1.
EXAMPLE 4i,: Violation of cDNA Clones Encoding~luman PR087~

_-WO 99146281 PCTlUS99/05028 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39621. Based on the DNA39621 consensus .
sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0873.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR-primer 5'-AGGTGCCTGCAGGAGTCCTGGGG-3' (SEQ ID N0:255) reverse PCR primer 5'- CCACCTCAGGAAGCCGAAGATGCC-3' (SEQ 1D N0:256) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39621 sequence which had the following nucleotide sequence:
hybridizatiQn probe . 5'-GAACGGTACAAGTGGCTGCGCTTCAGCGAGGACTGTCTGTACCTG-3' (SEQ ID N0:257) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0873 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0873 [herein designated as UNQ440 (DNA44179-1362)] (SEQ ID N0:253) and the derived protein sequence for PR0873.
The entire nucleotide sequence of UNQ440 (DNA44179-1362) is shown in Figure 90 (SEQ ID N0:253).
Clone UNQ440 (DNA44I79-1362) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 139-141 and ending at the stop codon at nucleotide positions 1774-1776 (Figure 90). The predicted polypeptide precursor is 545 amino acids long (Figure 91). The full-length PR08?3 protein shown in Figure 91 has an estimated molecular weight of about 58,934 daltons and a p1 of about 9.45. Analysis of the full-length PR0873 sequence shown in Figure 91 (SEQ ID N0:254) evidences the presence of the following features:
a signal peptide from about amino acid 1 to about amino acid 29; a carboxylesterase type-B serine active site at about amino acid 312 to about amino acid 327; a carboxylesterase type-B signature 2 motif at about amino acid 218 to about amino acid 228; and three potential N-glycosylation sites at about amino acid 318 to about amino acid 321, about amino acid 380 to about amino acid 383, and about atnitto acid 465 to about amino acid 468. Clone UNQ440 (DNA44179-13b2) has been deposited with ATCC on May 6, 1998 and is assigned ATCC deposit no. 209851.
Analysis of the amino acid sequence of the full-length PRO873 polypeptide suggests that it possesses significant sequence similarity to a human liver carboxylesterase, thereby indicating that PR0873 may be a novel carboxylesterase. Moze specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant hotnology _between the PR0873 amino acid sequence and the following Dayhoff sequences: ES 10 RAT, GEN12405, AB010633_l, EST4 RAT, A48809, SASE ANAPL, RNU41662_l, RNU22952 1, BAL RAT, GEN13522.
FJ~~3ViFLF~,42: ~ olazon of cI,~NA Clones Encodi~~iuman PR0940 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA47442. Based on the DNA47442 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0940.

A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CAAAGCCTGCGCCTGGTCTGTG-3' (SEQ ID N0:260) reverse PCR primer 5' TTCTGGAGCCCAGAGGGTGCTGAG-3' (SEQ ID N0:261) Additionally, a synthetic oligonueleotide hybridization probe was corLStructed from the consensus DNA47442 sequence which had the following nucleotide sequence hybridization~robe 5'-GGAGCTGCCACCCATTCAAATGGAGCACGAAGGAGAGTTCACCTG-3' (SEQ ID N0:262) In order to screen xveral h-braries for a source of a full-lertgitt clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair idenlif:ed above. A positive library was then used to isolate clones encoding the PR0940 gene using the probe oiigonuclcotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LiB229).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0940 [herein designated as UNQ477 (DNA54002-1367)j (SEQ ID NO:258) and the derived protein sequence ;for PR0940.
The entire nucleotide sequence of UNQ477 (DNA54002-1367) is shown in Figure 92 (SEQ ID N0:258).
Clone UNQ477 (DNA54002-1367) contains a single open reading frame with an apparent ttansiational initiation site at nucleotide positions 46-48 and ending amhe stop colon at nucleotide positions 1678-1680 (Figure 92). The predicted polypepride precursor is S44 amino acids long (Figure 93). The full-length PR0940 protein shown in Figtue 93 has an estimated molecular weight of about 60,268 daltons and a p1 of about 9.53. Analysis of the full-iength PR0940 sequence shown in Figure 93 (SEQ ID N0:259) evidences the ptrsetxx of the following: a signal peptide from about amino acid 1 to about amino acid 15, potential N-glycosylation sites from about amino acid I00 to about amino acid 103, fret about amitw acid 297 to about amino acid 300 and from about amino acid 306 to about amino acid 309 and an immunoglobulin and major histocompatibility complez signature sequence block from about amino acid 365 to about amino acid 371. Clone UNQ477 (DNA54002-1367) has been deposited with ATCC on April 7, 1998 and is assigned ATCC deposit no. 209754.
Analysis of the amino acid sequence of the full-length PR0940 polypeptide suggesu that it possesses significant sequence similarity to CD33 and the OB binding protein-2. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0940 amino acid sequence and the following Dayhoff sequences, CD33 HUMAN, HSU71382_1, HSU71383_l, D86359 1, PGBM HUMAN.
MAGS MOUSE, D86983 I, C22B HUMAN, P W01002 and HW24116 l.
EXAMPLE 43: Isolation of cDNA Clone~ncoding Human PR094i A consauus seqtiertoe was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus seqt>euce obtained is herein designated DNA35941. An EST
sequence proprietary to h was employed iin the assembly and is herein designated DNA6415 (Figure 96;
SEQ ID N0:265). Based on the DNA35941 consensus xqucncc, oiigonuclcotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for rue as probes to isolate a clone of the full-length coding sequence for PR0941.
A pair of PCR prim~crs (forward and reverse) were syndtcsi2ed:
forward PCR primer 5'-CTTGACTGTCTCTGAATCTGCACCC-3' (SEQ ID N0:266) rcv~r a pCR n 'mer S'-AAGTGGTGGAAGCCTCCAGTGTGG-3' (SEQ ID N0:267) WO 99146281 PCTlUS99l05028 Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35941 sequence which had the following nucleotide sequence ~,ybridization probe 5'-CCACTACGGTATTAGAGCAAAAGTTAAAAACCATCATGGTTCCTGGAGCAGC-3' (SEQ ID N0:268) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screcned by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0941 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequer>cing of the clones isolated as described above gave the full-length DNA sequence for PR0941 (herein designated as UNQ478 (DNA53906-1368)] (SEQ ID N0:263) and the derived protein sequence for PR0941.
The entire nucleotide sequence of UNQ478 (DNA53906-1368) is shown in Figure 94 (SEQ ID N0:263).
Clone UNQ478 (DNA5390Cr1368) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 37-39 and ending at the stop codon at nucleotide positions 2353-2355 (Figure 94). The predicted polypeptide precursor is 772 amino acids long (Figure 95). The full-length PR0941 protein shown in Figure 95 has an estimated molecular weight of about 87,002 daltons and a pi of about 4.64. Analysis of the full-length PR0941 sequence shown in Figure 95 (SEQ ID N0:264) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 21, potential N-glycosylation sites from about amino acid 5?
to about amino acid 60, from about amino acid 74 to about amino acid 77, from about amino acid 419 to about amino acid 422, from about amino acid 437 to about amino acid 440, from about amino acid 508 to about amino acid 511, from about amino acid 515 to about amino acid 518, from about amino acid 516 to about amino acid 519 and from about amino acid 534 to about amino acid 537, and cadherin extracellular repeated domain signature sequences from about amino acid 136 to about amino acid 146 and from about amino acid 244 to about amino acid 254. Clone UNQ478 {DNA53906-1368) has been deposited with ATCC on Apri17, 1998 and is assigned ATCC deposit no.
209747.
Analysis of the amino acid sequence of the full-length PR0941 polypeptide suggests that it possesses significant sequence similarity to a cadheiin protein, thereby indicating that PR0941 may be a novel cadherin protein family member. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0941 amino acid sequence and the following Dayhoff sequences, I50180, CADA _CHICK, 150178, GEN12782, CADC HUMAN, P W25637, A38992, P 849731, D38992 and 6026?8.
EXAMPLE 44: Isolati~ of cDNA Clones Encoding~Human PR0944 A consensus sequetxx was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consetLStts sequence obtained is herein designated DNA47374. A
variety of proprietary Genentech EST
sequences were employed in the assembly and are shown in Figures 99-107. Based on the DNA47374 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0944.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR rrimer 5'-CGAGCGAGTCATGGCCAACGC-3' (SEQ ID N0:280) reverse PCR ~mer 5'-GTGTCACACGTAGTCTTTCCCGCTGG-3' (SEQ ID N0:281) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47374 sequence which had the following nucleotide sequence hybridization probe 5'-CTGCAGCTGTTGGGCTTCATTCTCGCCTTCCTGGGATGGATCG-3' (SEQ ID N0:282) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0944 gene using the probe oligontieleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0944 jherein designated as UNQ481 (DNA52I85-1370)] (SEQ ID N0:269) and the derived protein sequence for PR0944.
The eraire nucleotide sequence of UNQ481 (DNA52185-1370) is shown in Figure 97 (SEQ ID N0:269).
Clone UNQ481 (DNA52185-1370) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 219-221 and ending at the stop codon at nucleotide positions 852-854 (Figure 97). The predicted polypeptide precursor is 211 amino acids long (Figtore 98). The full-length PR0944 protein shown in Figure 98 has an estimated molecular weight of about 22,744 daltons and a pI
of about 8.51. Analysis of the full-length PR0944 sequence shown in Figure 98 (SEQ ID N0:270) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 21, transmembrane domains from about amino acid 82 to about amino acid 102, from about amino acid 118 to about amino acid 142 and from about amino acid 161 to about amino mid 187, a potential N-glycosylation site from about amino acid 72 to about amino acid 75, a sequence block having homology to PMP-22IEMPlMP20 family of proteins from about amino acid 70 to about amino acid I I1 and a sequence block having homology to ABC-2 type transport system integral membrane protein from about amino acid 119 to about amino acid 133. Clone UNQ481 (DNA52185-1370) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209861.
Analysis of the amino acid sequence of the full-length PR0944 polypeptide suggests that it possesses significant sequence similarity to the CPE-R protein, thereby indicating that PR0944 may be a novel CPE-R
homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0944 amino acid sequence and the following Dayhoff sequences, AB000713_l, AB000714~1, AF0358Ia I, AF000959 1, HSU8991ti I, EMP2_HUMAN, JC5732, CELF53B3 6, PM22 MOUSE
and CGU49797 1.
FXA P 4 : Isolation of cDNA Clones Encoding ~iuman PRO983 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA474?3. Various proprietary Genentech EST
sequences were employed in the assembly, wherein those EST sequences are shown in Figures 1 i0-116. Based on the DNA47473 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that con2aained the sequence of interest, and 2) far use as probes to isolate a clone of the full-length coding sequence for PR0983.
A pair of PCR primers (forward and reverse) were synthesized:
forward R 'mer 5'-GCACCACCGTAGGTACTTGTGTGAGGC-3' (SEQ ID N0:292) reverse PCR r~'t et, 5'-AACCACCAGAGCCAAGAGCCGGG -3' (SEQ ID N0:293) Zz9 Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47473 sequence which had the following nucleotide sequence h_yhridization probe 5'-CAGCGGAATCATCGATGCAGGGGCCTCAATTAATGTATCTGTGATGTTAC-3' (SEQ ID N0:294) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the FCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0983 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow (LIB256).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0983 [herein designated as UNQ484 (DNA53977-1371)] (SEQ ID N0:283) and the derived protein sequence for PR0983.
The entire nucleotide sequence of UNQ484 (DNA53977-1371) is shown in Figure 108 (SEQ ID N0:283).
Clone UNQ484 (DNA53977-1371) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 234-236 and ending at the stop codon at nucleotide positions 963-965 (Figure 108). The predicted golypeptide precursor is 243 amino acids long (Figure 109). The full-length PR0983 protein shown in Figure 109 has an estimated molecular weight of about 27,228 daltons and a p1 of about 7.43. Analysis of the full-length PR0983 sequence shown in Figure I09 (SEQ ID N0:284) evidences the presence of the following features:
a putative transmembrane domain from about amino acid 224 to about amino acid 239; a potential N-glycosylation site from about amino acid 68 lo about amino acid 71; and three potential N-myristoylation sites from about amino acid 59 to about amino acid 64, from about amino acid 64 to about amino acid 69, and from about amino acid 235 to about amino acid 240. Clone UNQ484 (DNA53977-1371) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209862.
Analysis of the amino acid sequence of the full-length PR0983 polypeptide suggests that it possesses significant sequence similarity to the vesicle-associated protein, VAP-33, thereby indicating that PRO983 may be a novel vesicle associated membrane protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0983 amino acid sequence and the following Dayhoff sequences: VP33 APLCA, CELF33D11~12, CELF42G2 2, S50623, YDFC~SCHPO, CELF54H5 2, CELZC196 8, CEF57A10 3, MSP3 GLORO, CEC15H11_l.
EXAMPLE 46: Isolation of cDNA Clones Encoding Human PR01057 A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained'is herein designated DNA49808. Based on the DNA49808 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR01057.
PCR primers {forward and reverse) were synthesized:
forward PSR primer 5'-GCATCTGCAGGAGAGAGCGAAGGG-3' (SEQ ID N0:297) reverse PCRprjmer 5'-CATCGTTCCCGTGAATCCAGAGGC-3' (SEQ ID N0:298) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA49808 sequence which had the following nucleotide sequence hy~ri ization probe 5'-GAAGGGAGGCCTTCCTTTCAGTGGACCCGGGTCAAGAATACCCAC-3' (SEQ ID N0:299) t In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01057 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01057 [herein designated as UNQ522 (DNA57253-1382)] (SEQ ID N0:295) and the derived protein sequence for PR01057.
The entire nucleotide sequence of UNQ522 (DNA57253-1382) is shown in Figure 117 (SEQ ID NO:295).
Clone UNQ522 (DNA57253-1382) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 275-277 and ending at the stop colon at nucleotide positions 1514-1516 (Figure 117). The predicted polypeptide precursor is 413 amino acids long (Figure I 18). The full-length PR01057 protein shown in I0 Figure 118 has an estimated molecular weight of about 47,070 daltons and a p1 of about 9.92. Analysis of the full-length PR01057 sequence shown in Figure 118 (SEQ ID N0:296) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid Ib, potential N-glycosylation sites from about amino acid 90 to about amino acid 93, from about amino acid I 10 to about amino acid 113 and from about amino acid 193 to about amino acid 19b, a glycosaminogiycan attachment site from about amino acid 236 to about amino acid 239 and a serine protease histidine-containing active site from about amino acid 165 to about amino acid 170. Clone UNQ522 (DNA57253-1382) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209867.
Analysis of the amino acid sequence of the full-length PR01057 polypeptide suggests that it possesses significant sequence similarity to various protease proteins, thereby indicating that PR01057 may be a novel protease.
More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR01057 amino acid sequence and the following Dayhoff sequences,TRYE DROER, P 814159, A69bb0, EBNl EBV, S65494, GEN12688, A51084 1, P 899571, A575I4 and AF003200,1.
EXAMPLE 47: Isolation of cDNA Cones ~ncod'~ng Human PR0,~071 A consensus sequence was obtained relative to a variety of EST sequences as described in Example I above, wherein the consensus sequence obtained is herein designated DNA53035. Based on the DNA53035 consensus sequence, it was determined that that consensus sequence shared significant sequence identity with Incyte EST clone no. 2872569, a clone that upon review appeared to encode a full length protein. As such, Incyte EST clone no.
2872569 was purchased and its insert was obtained and sequenced so as to confirm the proper sequence. This sequence is herein designated UNQ528 or DNA58847-1383.
DNA sequencing of the clone isolated as described above gave the full-length DNA sequence for PR0107I
[herein designated as UNQ528 (DNA58847-1383)] (SEQ ID N0:300) and the derived protein sequence for PR01071.
The entire nucleotide sequence of UNQ528 (DNA58847-1383) is shown in Figure 119 (SEQ ID N0:300).
Clone UNQ528 (DNA58848-1383) contains a single open reading frame with an apparent transiational initiation site at nucleotide positions 133-135 and ending at the stop colon at nucleotide positions 1708-1710 (Figure 119). The predicted polypeptide precursor is 525 amino acids long (Figure 120). The full-length PR01071 protein shown in Figure 120 has an estimated molecular weight of about 58,416 daltons and a pI
of about 6.62. Analysis of the full-length PR01071 sequence shown in Figure 120 (SEQ ID N0;301) evidences the presence of the following; a signal peptide from about amino acid 1 to about amino acid 25, a potential N-glycosylation site from about amino acid 251 to about amino acid 254, a thrombospondin-1 homology block from about amino acid 385 to about amino acid 399 WO 99146281 PCT/US99l05028 and von Willibrands factor type C homology blocks from about amino acid 38S to about amino acid 399, from about amino acid 445 to about amino acid 459 and from about amino acid 42 to about amino acid 56. Clone UNQ528 (DNA58847-1383) has been deposited with ATCC on May 20, 1998 and is assigned ATCC deposit no. 209879.
Analysis o'f the amino acid sequence of the full-length PR01071 polypeptide suggests that it possesses significant sequence similarity to the thrombospondin protein, thereby indicating that PROI071 may be a novel thrombospondin homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR01071 amino acid sequence and the following Dayhoff sequences, AB002364_1, D67076 1, BTPCINPGN_l, CET13H10_l, CEF25H8 5, CEF53B6 2, CEC26C6~b, HSSEMG_l;
CET2IB6 4 and BTY08561 1.
EXAMPLE 48: Isolation of cDNA Clones Encoding Human PR01072 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA53125. Based on the DNA53125 consensus sequence, aligonucleotides were synthesized: I) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR01072.
PCR primers (forward and reverse) were synthesized:
forward PC$,primer 5'-CCAGGAAATGCTCCAGGAAGAGCC-3' (SEQ ID N0:305) _rgverse PCR primer 5'-GCCCATGACACCAAATTGAAGAGTGG-3' (SEQ ID N0:306) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA5312S
sequence which had the following nucleotide sequence hybridization_probe 5'-AACGCAGGGATCTTCCAGTGCCCTTACATGAAGACTGAAGATGGG-3' (SEQ ID NO:307) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01072 gene using the probe oligonucleoude and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LiB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01072 [herein designated as UNQ529 (DNA58747-1384)] (SEQ ID N0:302) and the derived protein sequence for PR01072.
The entire nucleotide sequence of UNQ529 (DNA58747-1384) is shown in Figure 121 (SEQ ID N0:302).
Clone UNQ529 (DNA58747-1384) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 65-67 and ending. at the stop codon at nucleotide positions 1073-1075 (Figure 121). The predicted poIypeptide precursor is 336 amino acids long (Figure,122). The full-length PR01072 protein shown in Figure 122 has an estimated molecular weight of about 36,865 daltons and a pI
of about 9.15. Analysis of the full-length PR01072 sequence shown in Figure 122 (SEQ ID N0:303) evidences the presence of the following: a signal peptide from about amino acid l to about amino acid 21, short-chain alcohol dehydrogettase protein homology blocks from about amino acid 134 to about amino acid 144, from about amino acid 44 to about amino acid 56 and from about amino acid 239 to about amino acid 248 and potential N-glycosylation sites from about amino acid 212 to about amino acid 215 and from about amino acid 239 to about amino acid 242. Clone UNQ529 (DNA58747-1384) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209868.

'a i WO 991x6281 PCT/US99105028 Analysis of the amino acid sequence of the full-length PR01072 polypeptide suggests that it possesses significant sequence similarity to the reductase family of proteins, thereby indicating that PR01072 may be a novel reductase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR01072 amino acid sequence and the following Dayhoff sequences, P W03198, P W15759, P 860800, MTV037 3, CEC15H11 6, ATAC00234314, MTV022_I3, SCU43704_l, OXIR
STRAT AND
CELCOI G8 3.
EXAMPLE 49: Violation of cDNA C~ne~ Encoding Human PR01~0?5 A consensus sequence was obtained relative to a variety, of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA34363. >lased on the DNA34363 sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR01075.
PCR primers (forward and reverse) were synthesized;
forward PCR pri~neF 5'-TGAGAGGCCTCTCTGGAAGTTG-3' (SEQ ID NO:312) ,~,rward PCR,primer 5'-GTCAGCGATCAGTGAAAGC-3' (SEQ ID N0:313) forward PCR.primer 5'-CCAGAATGAAGTAGCTCGGC-3' (SEQ ID N0:314) forward PAR primer 5'-CCGACTCAAAATGCATTGTC-3' (SEQ ID N0:315) brward PCR pr~ner 5'-CATTTGGCAGGAATTGTCC-3' (SEQ ID N0:316) brward PCR grimer 5'-GGTGCTATAGGCCAAGGG-3' (SEQ ID N0:317) reverse PCR primer 5'-CTGTATCTCTGGGCTATGTCAGAG-3' (SEQ ID N0:318) revere PCR primer 5'-CTACATATAATGGCACATGTCAGCC-3' (SEQ ID N0:319) Additionally, a synthetic oIigonucleotide hybridization probe was constructed from the consensus DNA34363 sequence which had the following nucleotide sequence hybridization probe 5'-CGTCTTCCTATCCTTACCCGACCTCAGATGCTCCCTTCTGCTCCTG-3' (SEQ ID N0:320) 1n order to screen several libraries for a source of a full-length clone; DNA
from the libraries was screened by PCR amplifica>ion with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01075 getx using the probe oligonucieotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human slats tumor tissue (LIB324).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01075 [herein designated as UNQ532 (DNA576$9-1385)] (SEQ 1D N0:308) and the derived protein sequence for PR01075.
The entire nucleotide sequence of UNQ532 (DNA57b89-1385) is shown in Figure 124 (SEQ ID N0:308).
Clone UNQ532 (DNA57689-1385) contains a single open reading frame with an apparent translationat initiation site at nucleotide positions 137-139 and ending at the stop codon at nucleotide positions 1355-1357 (Figure 124). The predicted polypeptide precursor is 406 amino acids long (Figure 125). The full-length PR01075 protein shown in Figure 125 has an estimated molecular weight of about 46,927 daltons and a p1 of about 5 ~1. Analysis of the full-length PR01075 sequence shown in Figure I25 (SEQ ID N0:309) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 29, an endoplasmic reticulum targeting sequence from about amino acid 403 to about amino acid 406, a tyrosit~ ldnase phosphorylation site from about a~tino acid 203 to about amino acid 211 and a sequence block having homology to the thioredoxin family of proteins from about amino acid WO 9914b281 PCT/US99I05028 50 to about amino acid 66. Clone UNQ532 tDNA57689-1385) has been deposited with ATCC on May I4, 1998 and is assigned ATCC deposit no. 209869.
Analysis of the amino acid sequence of the foil-length PR01075 polypeptide suggests that it possesses significant sequence similarity to protein disulfide isomerase, thereby indicating that PR01075 may be a novel protein disulfide isomerase. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR01075 amino acid sequence and the following Dayhoff sequences, CELC30H7 2, CELC06A6 3, CELF42G8 3, S57942, ER72 CREEL, CELC07A12 3, CEH06001 4 and P 851696.
EXAMPLE 50: Isolation of cDNA Clones Encoding Human PRO181 A cDNA sequence isolated in the amylase screen described in Example 2 above was found, by BLAST and FastA sequence alignment, to have sequence homology to a nucleotide sequence encoding the cornichon protein. This cDNA sequence is herein designated DNA13242 (Figure 130; SEQ ID N0:323). Based on the sequence homology, oligonucleotide probes were generated from the sequence of the DNAI3242 molecule and used to screen a human placenta t2IB89) library prepared as described in paragraph 1 of Example 2 above, The cloning vector was pRKSB
(pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Hoimes et al., cien e, ~:I278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
The oligonucleotide probes employed included:
forward FCR primer 5'-GTGCAGCAGAGTGGCTTACA-3' (SEQ ID N0:326) reverse PCR primer 5'-ACTGGACCAATTCTTCTGTG-3' (SEQ ID NO:327) h~bridizationprobe S'-GATATTCTAGCATATTGTCAGAAGGAAGGATGGTGCAAATTAGCT-3' (SEQ ID N0:328) A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 14-16 and ending at the stop codon found at nucleotide positions 446-448 (Figure 128; SEQ ID N0:321). The predicted polypeptide precursor is 144 amino acids long, has a calculated molecular weight of approximately 16,699 daltons and an estimated pI of approximately 5.6. Analysis of the full-length PR0181 sequence shown in Figure 129 (SEQ ID N0:322) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20, a putative type II transmembrane domain frora about amino acid 11 to about amino acid 31 and other transtnembrane domains from about amino acid 57 to about amino acid 77 and from about amino acid 123 to about amino acid 143. Clone UNQ155 ('DNA23330-1390) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no. 209775.
Analysis of the amino acid sequence of the full-length PR0181 polypeptide suggests that it possesses significant sequence similarity to the cornichon protein, thereby indicating that PRO 181 may be a novel cornichon homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PRO18I amino acid sequence and the following Dayhoff sequences, AF022811_l, CET09E8 _3, S64058, YGF4 YEAST, YB60_YEAST, EBU89455_1, SIU36383 3 and PH1371.
EXAMPLE SI: ~ol~ion of cDNA Clones Encodin~Human P~0195 A cDNA sequence was isolated in the amylase screen described in Example 2 above and is herein designated DNAI3199 (Figure 134; SEQ ID N0:332). The DNA13199 sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) to identify existing homologies. The homology search was performed using the computer program BLAST
or BLAST2 (Altshul et aL, Methods in Enzy om Io_QV, ~fb :460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode lqtown proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Washington;
http:/tbozeman.mbt.washington.edulphrap.docslphrap.htlrtl). The consensus sequence obtained therefrom is herein designated as DNA22778.
Based on the DNA22778 sequence, oligonucIeotide probes were generated and used to screen a human placenta library ()~B89) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB
(pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., cie e, 2~:I278-1280 IO (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
forward PCR vrimer S'-ACAAGCTGAGCTGCTGTGACAG-3' (SEQ ID N0:333) reverse PCR primer 5'-TGATTCTGGCAACCAAGATGGC-3' (SEQ ID N0:334) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA22778 sequence which had the following nucleotide sequence hybridization probe S'-ATGGCCTTGGCCGGAGGTTCGGGGACCGCTTCGGCTGAAG-3' (SEQ ID N0:335) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR019S gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 70-72 and ending at the stop codon found at nucleotide positions 1039-1041 (Figure 132; SEQ ID N0:330). The predicted polypeptide precursor is 323 amino acids long, has a calculated molecular weight of approximately 36,223 daltons and an estimated pI of approximately 5.06. Analysis of the full-length PR0195 sequence shown in Figure 132 (SEQ ID N0:330) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 3l, a transmembrane domain from about amino acid 241 to about amino acid 260 and a potential N-glycosylation site from about amino acid 90 to about amino acid 93. Clone UNQ169 (DNA26847-1395) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no.
209772.
Analysis of the amino acid sequence of the full-length PR0195 polypepride suggests that it possesses no significant sequence similarity to any known protein. However, an analysis of the Dayhoff database (version 35.45 SwissProt 3S) evidenced some degree of homology between the PROI9S amino acid sequence and the following Dayhoff sequences, P P91380, AF035118 I, HUMTROPCS 1, NUOD SALTY and E70002.
EXAMPLE S2: Isolation of cDNA Ones Encodin,E Human P1~0865 A cDNA sequence isolated is the amylase screen descn'bed in Example 2 above was herein designated DNA37642 (Figure 137, SEQ 1D N0:338). The DNA37b42 sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA
database (ISFESEQ"'', Incyte Pharmaceuticals, Palo Alto, CA) to identify homologies therebetween. The homology zzs search was performed using the computer program BLAST or BLAST2 {Altshul et aL, Methods in Enzymology 26:460-480 (1996))_ Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA
sequences with the program "phrap"
( P h t 1 Greew, University of Washington, Seattle, Washington;
http:Ilbozeman.mbt.washington.edulphrap.docslphrap.html). The consensus sequence obtained is herein designated DNA48615.
Based on the DNA48615 consensus sequence, probes were generated and used to screen a human fetal kidney (L18227) library prepared as described in paragraph I of Example 2 above. The cloning vector was pRKSB
(pRKSB is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., Science, x:1278-1280 (1991)}, and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 1 5'-AAGCTGCCGGAGCTGCAATG-3' (SEQ ID N0:339) forward PCR primer 2 5'-TTGCTTCTTAATCCTGAGCGC-3' (SEQ ID N0:340) forward PCR primer 3 5'-AAAGGAGGACTTTCGACTGC-3' (SEQ ID N0:34I) reverse PCR primer I 5'-AGAGATTCATCCACTGCTCCAAGTCG-3' (SEQ ID N0:342) reverse~CR primer 2 5'-TGTCCAGAAACAGGCACATATCAGC-3' (SEQ ID N0:343) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA48615 sequence which had the following nucleotide sequence hybridization probe 5'-AGACAGCGGCACAGAGGTGCTTCTGCCAGGTTAGTGGTTACTTGGATGAT-3' (SEQ ID N0:344) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PR0865 gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 173-175 and ending at the stop codon found at nucleotide positions 1577-1579 (Figure 135; SEQ ID N0:336). The predicted polypeptide precursor is 468 amino acids long, has a calculated molecular weight of approximately 54,393 daltons and an estimated pI of approximately 5.63. Analysis of the full-length PR0865 sequence shown in Figure 136 (SEQ ID N0:33?) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 23, potential N-glycosylation sites from about amino acid 280 to about amino acid 283 and from about amino acid 384 to about amino acid 387, a potentiat amidation site from about amino acid 94 to about amino acid 97, glycosaminoglycan attachment sites from about amino acid 20 to about amino acid 23 and from about amino acid 223 to about amino acid 226, an aminotransferase class-V pyridoxyl-phosphate amino acid sequence block from about amino acid 216 to about amino acid 222 and an amino acid sequence block similar to that found in the interleukin-7 protein from about amino acid 338 to about amino acid 343. Clone UNQ434 (DNA53974-1401) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no.
209774.
Analysis of the amino acid sequence of the full-length PR0865 polypeptide suggests that it possesses no signi5cant sequence similarity to any known protein. However, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced some degree of homology between the PR0865 amino acid sequence and the following Dayhoff sequences, YMNO YEAST, ATFCA4 43, 544168, P W 14549 and RABTCRG4_1.

~XAMPI~ 53: Violation of cDNA Clones Encodipg Human PR0827 A cDNA sequence isolated in the amylase screen described in Example 2 above was found, by BLAST and.
FaStA sequence alignment, to have sequence homology to nucleotide sequences encoding various integrin proteins.
This cDNA sequence is herein designated DNA47751 (see Figure 140; SEQ ID
N0:347). Based on the sequence homology, probes were generated from the sequence of the DNA47751 molecule and used to screen a human fetal pigment epithelium library {LIB113) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB is a precursor of pRKSD chat does not contain the SfiI site;
see, Holmes et al., c'enc , 2:1278-1280 (1991)), and the cDNA size cut was less than 2800 bp.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-AGGGACAGAGGCCAGAGGACTTC-3' (SEQ ID N0:348) reverse PCR primer 5'-CAGGTGCATATTCACAGCAGGATG-3' (SEQ 1D N0:349) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47751 sequence which had the following nucleotide sequence h~rbridization p;Qbe 5'-GGAACTCCCCTTCGTCACTCACCTGTTCTTGCCCCTGGTGTTCCT-3' (SEQ iD
N0:350) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0827 gene using the probe oligonucleotide and one of the PCR
primers.
A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 134-136 and ending at the stop codon found at nucleotide positions 506-508 (Figure 138; SEQ ID N0:345). The predicted polypeptide precursor is 124 amino acids long, has a calculated molecular weight of approximately 13,352 daitons and an estimated pI of approximately 5:99. Analysis of the full-length PR0827 sequence shown in Figure 139 (SEQ ID N0:346) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 22, a cell attachment sequence from about amino acid 70 to about amino acid 72, a potential N-giycosylation site .from about amino acid 98 to about amino acid 101 and an itnegrin alpha chain protein homology sequence from about amino acid 67 fo about amino acid 81. Clone UNQ468 (DNA57039-1402) has been deposited with ATCC on April 14, 1998 and is assigned ATCC deposit no. 209777.
Analysis of the amino acid sequence of the full-length PR0827 polypeptide suggests that it possesses significatu sequence similarity to the VLA-2 integrin protein and various other integrin proteins, thereby indicating that PR0827 may be a novel integrin or splice variant thereof. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PRO240 amino acid sequence and the following Dayhoff sequences, S44142, ITA2 HUMAN, ITAl RAT, ITAl HUMAN, ITA4 HUMAN, ITA9 HUMAN, AF032108 1, ITAM MOUSE, ITA8 CHICK and TTA6 CHICK.
EXAMPLE 54: Isolation of eDNA Clones Eqeo~in$ Human PRO! l 14 A cDNA seQue~e isolated in the amylase screen described in Example 2 was found, by the WU-BLAST2 sequence alignment computer program, to have certain sequence identity to other lrnown interferon receptors. This cDNA sequence is herein designated DNA48466 (Figure 143; SEQ ID N0:352). Based on the sequence identity, probes were ger~rated from the sequence of the DNA4846ti molecule and used to screen a human breast carconoma WO 99146281 PCTlUS99/05028 library (LIBI35) prepared as described in paragraph 1 of Example 2 above. The cloning vector was pRKSB (pRKSB
is a precursor of pRKSD that does not contain the SfiI site; see, Holmes et al., Science, 25:12?8-1280 (1991)), and the cDNA size cut was less than 2800 bp.
The oligonucleotide probes employed were as follows:
forward PCR primer 5'-AGGCTTCGCTGCGACTAGACCTC-3' {SEQ ID N0:354) reverse PCR Pfizer 5'-CCAGGTCGGGTAAGGATGGTTGAG-3' (SEQ ID N0:355) hybridization Rrobe 5'-TTTCTACGCATTGATTCCATGTTTGCTCACAGATGAAGTGGCCATTCTGC-3' (SEQ ID N0:356) A full length clone was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 250-252,. and a stop signal at nucleotide positions 1183-1185 (Figure 141, SEQ
ID N0:351). The predicted polypeptide precursor is 311 amino acids long, has a calculated molecular weight of approximately 35,076 daltons and an estimated pI of approximately 5.04.
Analysis of the full-length PR01114 interferon receptor sequence shown in Figure I42 (SEQ ID N0:352) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 29, a transmembrane domain from about amino acid 230 to about amino acid 255, potential N-glycosylation sites from about amino acid 40 to about amino acid 43 and from about amino acid 134 to about amino acid 137, an amino acid sequence block having homology to tissue factor proteins from about amino acid 92 to about amino acid 119 and an amino acid sequence block having homology to integrin alpha chain proteins from about amino acid 232 to about amino acid 262. Clone UNQ557 (DNA57033-1403) has been deposited with ATCC on May 27, 1998 and is assigned ATCC deposit no.
209905.
An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in Figure I42 (SEQ ID N0:352), evidenced significant homology between the PR01114 interferon receptor amino acid sequence and the following Dayhoff sequences: G014I8, INRl MOUSE, P R?1035, INGS HUMAN, A26595,1, A26593_l, I56215 and TF HUMAN.
EXAMPLE 55: Isolation of cDNA Clones Encodine Human PR0237 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30905. Based on the DNA30905 consensus sequence, oligorntcleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO237.
PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-TCTGCTGAGGTGCAGCTCATTCAC-3' (SEQ ID N0:359) ~v_grse PAR primer 5'-GAGGCTCTGGAAGATCTGAGATGG-3' (SEQ ID N0:360) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30905 sequence which had the following nucleotide sequence hybridization probe 5'-GCCTCTTTGTCAACGTTGCCAGTACCTCTAACCCATTCCTCAGTCGCCTC-3'. (SEQ ID N0:361) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0237 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB153).

~1 DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0237 [l~rein designated as UNQ211 t'DNA34353-1428)] (SEQ ID N0:357) and the derived protein sequence for PR0237.
The entire nucleotide sequence of UNQ21 l (DNA34353-1428) is shown in Figure 144 (SEQ ID N0:357).
Clone UNQ211 (DNA34353-1428) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 586-588 and ending at the stop codon at nucleotide positions 1570-1572 (Figure 144). The predicted polypeptide precursor is 328 amino acids long (Figure 145). The full-length PR0237 protein shown in Figure 145 has an estimated molecular weight of about 36,238 daltons and a pI
of about 9.90. Analysis of the full-length PR0237 sequence shown in Figure I45 (SEQ ID N0:358) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 23, a transmembrane domain from about amino acid 177 to about amino acid 199, potential N-glycosyiation sites from about amino acid 118 to about amino acid 121, from about amino acid 170 to about amino acid 173 and from about amino acid 260 to about amino acid 263 and eukaryotic-type carbonic anhydrase sequence homology blocks from about amino acid 222 to about amino acid 270, from about amino acid 128 to about amino acid 164 and from about amino acid 45 to about amino acid 92. Clone UNQ21I
(DNA34353-1428) has been deposited with ATCC on May I2, 1998 and is assigned ATCC deposit no. 209855.
Analysis of the amino acid sequence of the full-length PR0237 polypeptide suggests that it possesses IS significant sequence similarity to the carbonic anhydrase protein. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0237 amino acid sequence and the following Dayhoff sequences, AF050106 1, OACALP 1, CELD1022 8, CAH2'HUMAN, ICAO, CAHS HUMAN, CAHP HUMAN, CAH3 HUMAN, CAH1'HUMAN and 2CAB.
>AMPLE 56: isolation of c~NA Clones Ert,~oditlg Human PR0541 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42259. Based on the DNA42259 consensus sequence, oiigonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0541.
PCR primers {forward and reverse) were synthesized:
forward PCR p~r~m_e~ S'-GGACAGAATTTGGGAGCACACTGG-3' (SEQ ID N0:364) forward PCR,primer 5'-CCAAGAGTATACTGTCCTCG-3' (SEQ ID N0:365) reverse PCR primer 5'-AGCACAGATTTTCTCTACAGCCCCC-3' (SEQ ID N0:366) reverse PCR primer 5'-AACCACTCCAGCATGTACTGCTGC-3' {SEQ ID N0:367) Additionally, a synthetic oiigonucleotide hybridization probe was constructed from the consensus DNA42259 sequence which had the following nucleotide sequence hybridization robe S'-CCATTCAGGTGTTCTGGCCCTGTATGTACACATTATACACAGGTCGTGTG-3' (SEQ ID N0:368) In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was sczeened by PCR amplification with one of the PCR primer pairs identified above. A
positive library was then used to isolate clones encoding the PR0541 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue {LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0541 [herein designated as UNQ342 (DNA45417-1432)] (SEQ ID N(~:362) and the derived protein sequence for PR054I .

The entire nucleotide sequence of UNQ342 (DNA45417-1432) is shown in Figure 146 (SEQ ID N0:362).
Clone UNQ342 (DNA45417-1432) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 469-471 and ending at the stop codon at nucleotide positions 1969-1971 (Figure 146). The predicted polypeptide precursor is S00 amino acids long (Figure 147). The full-length PR054I protein shown in Figure 147 has an estimated molecular weight of about 56,888 daltons and a p1 of about 8.53. Analysis of the full-length PR0541 sequence shown in Figure 147 (SEQ ID N0:363) evidences the presence of the following: a signal peptide from about amino acid I to about amino acid 20, amino acid sequence blocks having homology to extraceliular proteins SCPITpx-i/AgSIPR-11Sc7 from about amino acid 165 to about amino acid 186, from about amino acid 196 to about amino acid 218, from about amino acid 13$ to about amino acid 146, from about amino acid 96 to about amino acid 108 and from about amino acid 58 to about amino acid 77 and a potential N-glycosyiation site from about amino acid 28 to about amino acid 31. Clone UNQ342 (DNA45417-1432) has been deposited with ATCC
on May 27, 1998 and is assigned ATCC deposit no. 209910.
Analysis of the amino acid sequence of the full-length PR054i polypeptide suggests that it possesses significant sequence similarity to a trypsin inhibitor protein, thereby indicating that PR0541 may be a novel trypsin inhibitor. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PR0541 amino acid sequence and the following Dayhoff sequences, D45027_l, AB009609li, JC5308, CRS3 HORSE, TPXl HUMAN, HELD HELHO, GEN14351, A28112_l, CET05A10 4 and P W11485.
EXAMPLE 57: Isolation of cDNA Clones Encoding Human PR0273 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA36465. Based on the DNA3b465 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0273.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CAGCGCCCTCCCCATGTCCCTG-3' (SEQ ID N0:371) reverse PCR primer 5'-TCCCAACTGGTTTGGAGTTTTCCC-3' (SEQ ID N0:372) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA3fi465 sequence which had the following nucleotide sequence lybridization probe 5'-CTCCGGTCAGCATGAGGCTCCTGGCGGCCGCTGCTCCTGCTGCTG-3' (SEQ ID NO:373) In order to screen several libraries for a source of a fall-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above.- A positive library was then used to isolate clones encoding the PR0273 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0273 jherein designated as UNQ240 (DNA39523-I 192)] (SEQ ID N0:369) and the derived protein sequence for PR0273.
The entire nucleotide sequence of UNQ240 (DNA39523-1192) is shown in Figure 148 (SEQ ID N0:369).
Clone UNQ240 (DNA39523-l I92) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 167-169 and ending at the stop codon~at nucleotide positions 500-502 (Figure 148). The predicted polypeptide precursor is 111 amino acids long (Figure i49). Clone UNQ240 (DNA39523-1192) has been deposited with the ATCC. It is understood that the deposited clone contains the actual sequence and that the sequences provided herein are merely representative based on current sequencing techniques. Moreover, given the sequences provided herein and knowledge of the universal genetic code, the corresponding nucleotides for any given amino acid can be routinely identified and vice versa.
Analysis of the amino acid sequence of the full-length PR0273 polypeptide suggests that portions of it possess sequence identity with human macrophage inflammatory protein-2, cytokine-induced neutrophil ctiemoattractant 2, and neutrophil chemotactic factor 2-beta, thereby indicating that PR0273 is a novel chemokine.
As discussed further below, the cDNA was subcloned into a baculovirus vector and expressed in insect cells as a C-terminally tagged 1gG fusion protein. N-terminal sequencing of the resultant protein identified the signal sequence cleavage site, yielding a mature poiypeptide of 77 amino acids. The mature sequence, showing 31-40%
identity to other human CXC chemokines, includes the four canonical cysteine residues but lacks the ELR motif.
Northern analysis demonstrates expression at least in the small intestine, colon, spleen, lymph node and kidney. By in situ hybridization, also described in detail below, mRNA is localized to the lamina propria of intestinal villi and to renal tubules.
EXAMPLE 58: Isolation of cDNA Clones Encoding Human PR0701 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39848. Based on the DNA39848 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0741.
A pair of PCR primers (forward and reverse) were synthesized:
forward PAR primer 5'-GGCAAGCTACGGAAACGTCATCGTG-3' (SEQ ID N0:376) reverse PCR primer 5'-AACCCCCGAGCCAAAAGATGGTCAC-3' (SEQ ID N0:377) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA39848 sequence which had the following nucleotide sequence:
hybridization lobe 5'-GTACCGGTGACCAGGCAGCAAAAGGCAACTATGGGCTCCTGGATCAG-3' (SEQ ID N0:378).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR ampli5cation with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0701 gene using the probe oligonucieotide and one of the PCR
primers. RNA for construction of tht cDNA libraries was isolated from human fetal Iadney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0701 [hey designated as UNQ365 (DNA44205-1285)] (SEQ ID N0:374) and the derived protein sequence for PR0701.
The entire nucleotide sequence of UNQ365 (DNA44205-1285) is shown in Figure 150 (SEQ 1D N0:374).
Clone UNQ365 (DNA44205-1285) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 50-52 and ending at the stop codon at nucleotide positions 2498-3000 (Figure 150). The predicted polypeptide precursor is 81b amino acids long (Figure 151). The full-length PR0701 protein shown in Figure 151 has an estimated molecular weight of about 91,794 daltons, a p1 of about 5.88 anti NX(SIT) being 4.
Clone UNQ365 (DNA44205-1285) has been deposited with the ATCC on March 31, 1998. It is understood that the clone was the correct and actual sequence, wherein the sequences provided herein are represernative based on sequencing techniques.
Still regarding the amino acid sequence shown in Figure 151, there is a potential signal peptide cleavage site at about amino acid 25. There are potential N-glycosylation sites at about amino acid positions 83, 511, 716 and 803.
The carboxylesterases type-B signature 2 sequence is at about residues 125 to 135. Regions homologous with carboxylesterase type-B are also at about residues 54-74, 197-212 and 221-261.
A potential transmembrane region corresponds approximately to amino acids 671 through about 700. The corresponding nucleic acids can be routinely determined from the sequences provided herein.
Analysis of the amino acid sequence of the full-length PR0701 polypeptide suggests that it possess significant homology to the neuroligins from rattus norvegicus indicating that PR0701 may be a novel human neuroligin.
EXAMPLE 59: I~ol~io~ of cDNA Clones Encoding Human PR0704 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43033. Based on the DNA43033 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0704.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CCTTGGGTCGTGGCAGCAGTGG-3' (SEQ ID N0:381);
reverse PCR primer 5'-CACTCTCCAGGCTGCATGCTCAGG-3' (SEQ ID N0:382).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA43033 consensus sequence which had the following nucleotide sequence:
hybridization probe 5'-GTCAAACGTTCGAGTACTTGAAACGGGAGCACTCGCTGTCGAAGC-3' (SEQ ID N0:383).
In order to screen several libraries for a source of a full-length clone, DNA
from the Libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0704 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0704 (herein designated as UNQ368_ (DNA50911-1288)) (SEQ ID N0:379) and the derived protein sequence for PR0704.
The entire nucleotide sequence of UNQ368 (DNA50911-1288) is shown in Figure 152 (SEQ ID N0:379).
Clone UNQ368 (DNA509I1-1288) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 8-10 and ending at the stop codon at nucleotide positions 1052-1054 (Figure 152). The predicted polypeptide precursor is 348 amino acids long (Figure 153). The full-length PR0704 protein shown in Figure 153 has an estimated molecular weight of about 39,711 and a p1 of about 8.7. Clone UNQ368 (DNA50911-1288) has been deposited with the ATCC on March 31, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0704 polypeptide suggests that portions of it possess significant homology to the vesicular integral membrane protein 36, thereby indicating that PR0704 may be a novel vesicular integral membrane protein.

I
WO 99!46281 PCT/US99105028 StiII analyzing the amino acid sequence of SEQ ID N0:380, the putative signal peptide is at about amino acids 1-39 of SEQ ID N0:380. The transmembrane domain is at anuno acids 310-335 of SEQ ID N0:380. A
potential N-glycosylation site is at about amino acids 180-183 of SEQ ID
N0:380. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE C~O: Isolation of eDNA Clones ~,~c_oding Human PR0706 A consensus sequence was obtained relative to a variety of F.ST sequences as described in Example l above, whezein the consensus sequence obtained is herein designated DNA40669. Based on the DNA40669 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0706.
A pair of PCR primers (forward and reverse) were synthesized:
forward PAR primer 5'-CCAAGCAGCTTAGAGCTCCAGACC-3' (SEQ ID N0:386) reverse PCR primer 5'-TTCCCTATGCTCTGTATTGGCATGG-3' (SEQ 1D N0:387) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40669 sequence which had the following nucleotide sequence IS h~ridazation probe 5'-GCCACTTCTGCCACAATGTCAGCTTTCCCTGTACCAGAAATGGCTGTGTT-3' (SEQ ID N0:388) In order to screen several libraries for a source of a full-length clone; DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0706 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the eDNA 1'braries was isolated from human fetal braintissue (LIB153).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0706 [herein designated as UNQ370 (DNA48329-1290)] (SEQ ID N0:384) and the derived protein sequence for PR0706.
It is understood that the deposited clone contains the actual sequence, and that the sequences provided herein are representative based on current sequencing techniques.
The entire nucleotide sequence of UNQ370 (DNA48329-1290) is shown in Figure 154 (SEQ ID N0:384).
Clone UNQ370 (DNA48329-1290) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 279-281 and ending at the stop colon at nucleotide positions 1719-1721 (Figure 154). The predicted polypeptide precursor is 480 amino acids long (Figure I55). The full-length PR0706 protein shown in Figure 155 has an estimated molecular weight of about 55,239 daltons and a pI
of about 9.30. Clone UNQ370 (DNA48329-1290) has been deposited with the ATCC on April 21, 1998.
Still regarding the amitw acid sequetxe shown in Figure i55, there is a patential signal peptide cleavage site at about amino acid i9. There are potential N-glycosylation sites at about amino acid positions 305 and 354. There is a potential tyrosine Idnase phosphorylation site at about amino acid position 333. A region homologous with histidine acid phosphatase is at about residues 87-102. The corresponding nucleic acid regions can be routinely determined given the provided sequences, l.c., the colons can be determined from the specifically named amino acids given.
Analysis of the amino acid sequence of the full-length PR0706 polypeptide suggests that portions of it possess signi5cant homology to the human prostatic acid phosphatase precursor thereby indicating that PR0706 may WO 99146281 PCTJUS99l05028 be a novel human prastatic acid phosphatase.
EXAMPLE 61: Isolation of cDNA Clones Encoding Human PR0707 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42775. Based on DNA42775, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for P.RO?07.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-TCCGTCTCTGTGAACCGCCCCAC-3' (SEQ ID N0:391};
reverse PCR primer 5'-CTCGGGCGCATTGTCGTTCTGGTC-3' (SEQ ID N0:392).
; Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA42775 sequence which had the following nucleotide sequence:
hybridization probe 5'-CCGACTGTGAAAGAGAACGCCCCAGATCCACTTATTCCCC-3' (SEQ 1D N0:393).
In order to screen several h'braries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO707 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0707 [herein designated as UNQ371 (DNA48306-1291}] (SEQ ID N0:389) and the derived protein sequence for PR0707.
The entire nucleotide sequence of UNQ371 (DNA48306-1291) is shown in Figure 156 (SEQ ID N0:389).
Clone UNQ3?1 (DNA48306-I291) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 371-373 and ending at the stop colon at nucleotide positions 3119-3121 of SEQ ID N0:389.
The predicted polypeptide precursor is 916 amino acids long (Figure 15?). The full-length PR070? protein shown in Figtwe 157 has an estimated molecular weight of about 100,204 daltons and a pI of about 4.92. Clone UNQ371 tDNA4830b-1291) has been deposited with ATCC on May 2?, 1998. It is understood that the clone UNQ371 which is deposited is that which encodes PR0707, and that the sequences herein are merely representations based on known sequencing techniques which may be subject to minor errors.
Regarding analysis of the amino acid sequence, the signal sequence appears to be at about 1 through 30 of SEQ ID N0:390. Cadherins extraceIlular repeated domain signature sequence is at about amino acids 121-131, 230-240, 335-345, 440-450, and 550-560 of SEQ ID NO:390. Tyrosine kinase phosphorylation sites are at about amino acids 124-132 and 580-586 of SEQ ID N0:390. A potential transmernbrane domain is at about amino acids 682-715 t 5. The nucleic acid positions can be derived by referring to the corresponding colon for the named amino acid.
Analysis of the amino acid sequence of the full-length PR0707 polypeptide suggests that portions of it possess significant homology to the cadherin FIB3 protein, expressed in human fibroblasts, thereby indicating that PR0707 may be a novel cadherin.

EXAMPLE 62: Isgiation of cDNA hones Encoding Human PR03~2 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA48336. Based on the DNA48336 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0322.
S A pair of PCR primers (forward and reverse) were synthesized:
forward P_CR primer 5'-CAGCCTACAGAATAAAGATGGCCC-3' (SEQ 1D N0:396) reve a PCR ,primer 5'-GGTGCAATGATCTGCCAGGCTGAT-3' (SEQ 1D N0:397) Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA48336 consensus sequence which had the following nucleotide sequence:
hy~ridization~robe 5'-AGAAATACCTGTGGTTCAGTCCATCCCAAACCCCTGCTACAACAGCAG-3' (SEQ ID N0:398).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0322 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0322 [herein designated as UNQ283 (DNA48336-1309)] (SEQ ID N0:394) and the derived protein sequence for PR0322.
It is understood that UNQ283 (DNA48336-1309) in fact encodes PR0322, and that SEQ ID N0:394 is a representation of the sequence based on sequencing techniques known in the art.
The entire nucleotide sequence of UNQ283 (DNA48336-1309) is shown in Figure I58 (SEQ ID N0:394).
Cloy UNQ283 (DNA4833b-1309) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 166-168 and ending at the stop colon at nucleotide positions 946-948 (Figure 158). The predicted potypeptide precursor is 260 amino acids long (Figure 159). The full-length PRO322 protein shown in Figure 159 has an estimated molecular weight of about 28,028 daltons and a pI
of about 7:87. Clone UNQ283 (DNA48336-1309) has been deposited with ATCC and is assigned ATCC. deposit no.
209669.
Regarding the amino acid sequence of Figure 159, a potential N-giycosylation site is at amino acid 110 of SEQ ID N0:395. Tlx seriue proteases, trypsin family and histidine active site is identified at amino acids 69 through 74 of SEQ ID N0:395 and the consensus sequence is identified at amino acids 207 through 217 of SEQ ID N0:395.
The kringle domain proteins motif is identified at amino acids 205 through 217 of SEQ ID N0:395. The putative signal peptide is encoded at about amino acids 1-23.
Analysis of the amino acid sequence of the full-length PR0322 polypeptide suggests that portions of it possess significatu homology to neuropsin and other serine proteases, thereby indicating that PR0322 is a novel serine protease related to neuropsin.
EXAMp F 6 ; Isolation of DNA Clones Encoding_I3u~~n PR0526 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39626. Based on the DNA39626 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO526.

A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-TGGCTGCCCTGCAGTACCTCTACC-3' (SEQ ID N0:401);
reverse PCR primer ~'-CCCTGCAGGTCATTGGCAGCTAGG-3' (SEQ ID N0:402).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA39626 consensus sequence which had the following nucleotide sequence:
hybridization~robe 5'-AGGCACTGCCTGATGACACCTTCCGCGACCTGGGCAACCTCACAC-3' (SEQ ID N0:403).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0526 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of : the cDNA libraries was isolated from human fetal liver tissue (LIB228).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0526 [herein designated as UNQ330 (DNA44184-I319)1 (SEQ ID N0:399) and the derived protein sequence for PR0526.
The entire nucleotide sequence of UNQ330 (DNA44184-1319) is shown in Figure 160 (SEQ ID N0:399).
Clone UNQ330 (DNA44184-1319) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 514-516 and ending at the stop codon at nucleotide positions 1933-1935 (Figure 160). The predicted polypeptide precursor is 473 amino acids long (Figure 161), The full-length PR0526 protein shown in Figure 161 has an estimated molecular weight of about 50,708 daltons and a pI
of about 9.28. Clone UNQ330 (DNA44184-1319) has been deposited with the ATCC on March 26, 1998. It is understood that the clone contains the actual sequence, whereas the sequences presented herein are representative based on current sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0526 polypeptide suggests that portions of it possess significant homology to the leucine repeat rich proteins including ALS, SLIT, carboxypeptidase and platelet glycoprotein V thereby indicating that PR0526 is a novel protein which is involved in protein-protein interactions.
Still aralyzing SEQ ID NO:400, the signal peptide sequence is at about amino acids 1-26. A leucine zipper pattern is at about amino acids 135-156. A glycosaminoglycan attachment is at about amino acids 436-439. N-glycosylation sites are at about amino acids 82-85, 179-182, 237-240 and 423-426. A von WiIlebrand factor (VWF) type C domains) is found at about amino acids 411-425. The skilled artisan can understand which nucleotides correspond to these amino acids based on the sequences provided herein.
~~MPL.E 64: Isolation of cDNA Clones Encoding Human PR0531 An ECD database was searched and an expressed sequetxe tag (EST) from LIFESEQT"", Incyte Pharmaceuticals, Palo Alto, CA was identified which showed homology to protocadherin 3. Based on this sequence, a search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in En~yr~olog~y 2,x:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence.
Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap° (Phil Green, University of Washington, Seattle, Washington;
http:/lbowman.mbt.washington.edu/phrap.docslphrap.html).
A consensus DNA sequence was assembled relative to other EST sequences using phrap. Based on the consensus sequence obtained, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained A

the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0531.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CTGAGAACGCGCCTGAAACTGTG-3' (SEQ ID N0:406);
reverse PCR primer 5'-AGCGTTGTCATTGACATCGGCG-3' (SEQ ID N0:407).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA sequence which had the following nucleotide sequence:
hybridization vrobe 5'-TTAGTTGCTCCATTCAGGAGGATCTACCCTTCCTCCTGAAATCCGCGGAA-3' (SEQ ID N0:408).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones IO encoding the PR0531 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal braitz tissue (L1BI53). -The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA. The cDNA was primed with oligo dT containing a NotI
site, /inked with blunt to Sall hemikitiased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined IS orientation into a suitable cloning vector (such as pRKB or pRKD; pRKSB is a precursor of pRKSD that does not comain the Sfil site; see, Holmes et al., Science, .~S :1278-1280 (1991)) in the unique XhoI and Notl sites.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PROS31 (herein designated as UNQ332 (DNA48314-1320)] (SEQ ID N0:404) and the derived protein sequence for PR0531.
Ttte entire representative nucleotide sequence of UNQ332 (DNA48314-1320) is shown in Figure 162 (SEQ
20 ID N0:404). It is understood that the actual sequence is that within the clone deposited with the ATCC as DNA48314-1320. Clone UNQ332 (DNA483I4-1320) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 171-I73 and ending at the stop codon at nucleotide positions 2565 2567 (Figure 162). The predicted polypeptide precursor is 789 amino acids long (Figure 163). The full-length PR0531 protein shown in Figure 163 has an estimated molecular weight of about 87,552 dollops and a pI of about 25 4.84. Clone UNQ332 (DNA483I4-1320) has been deposited with the ATCC on March 26, 1998.
Analysis of the amino acid sequence of the full-length PR053I polypeptide suggests that portions of it possess significant homology to protocadherin 3. Moreover, PR0531 is found in the brain, like other protocadherins, thereby indicating that PR0531 is a novel member of he cadherin superfatnily.
Still analyzing the amino acid sequence of SEQ ID N0:405, the cadherin extracellular repeated domain 30 signature is found at about amino acids 122-I32, 231-241, 336-346, 439-449 and 549-559 of SEQ ID N0:405. An ATPIGTP-binding site motif A (P loop) is found at about amino acids 285-292 of SEQ ID N0:405. N-glycosylation sites are found at least at about amino acids 567-570, 786-790, 418-421 and 336-339 of SEQ ID N0:405. The signal peptide is at about amino acids 1-26, and the transmembrane domain is at about amino acids 685-7I2 of SEQ ID
N0:405.
EXAMPLE 65: Isolation of cDN A Clones Enco,~gp~man PRt~SZd A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43038. Based on the 43048 consensus sequence, oiigonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0534.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR~rimer 5'-CACAGAGCCAGAAGTGGCGGAATC-3' (SEQ ID N0:411);
reverse PCR primer 5'-CCACATGTTCCTGCTCTTGTCCTGG-3' (SEQ ID N0:412).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43038 sequence which had the following nucleotide sequence:
l~bridization probe 5'-CGGTAGTGACTGTACTCTAGTCCTGTTTT'ACACCCCGTGGTGCCG-3' {SEQ ID N0:413).
In order to screen several 3ibraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0534 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB26).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0534 [herein designated as UNQ335 (DNA48333-1321)] (SEQ ID N0:409) and the derived protein sequence for PR0534.
The entire nucleotide sequence of UNQ335 (DNA48333-1321) is shown in Figure 164 (SEQ ID N0:409).
Clone UNQ335 (DNA48333-132I) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 87-89 and ending at the stop codon at nucleotide positions 1167-1169 (Figure 164}. The predicted polypeptide precursor is 360 amino acids long (Figure 165}. The full-length PR0534 protein shown in Figure 165 has an estimated molecular weight of about 39,885 daltons and a pI
of about 4.79. Clone UNQ335 (DNA48333-1321) has been deposited with ATCC on March 26, 1998. It is understood that the deposited clone contains the actual sequence, and that the sequences provided herein are representative based an current sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0534 polypeptide suggests that portions of it possess significant sequence identity with the protein disulfide isomerase, therehy indicating that PR0534 may be a novel disulfide isotnerase.
Still analyzing the amino acid sequence of PR0534, the signal peptides is at about amino acids 1-25 of SEQ
ID N0:410. The iransmembrane domain is at about amino acids 321-340 of SEQ ID
N0:410. The disulfide isomerase corresponding region is at amino acids 212-302 of SEQ ID N0:410. The thioredoxin domain is at amino acids 211-227 of SEQ ID N0:410. N-glycosylation sites are at: 165-168, 18I-184, 187-190, 194-197, 206-209, 278-281, and 293-296 of SEQ ID N0:410. The corresponding nucleotides can routinely be determined from the sequences provided herein. PR0534 has a transmembrane domain rather than an ER
retention peptide like other protcin disulfide isomerases. Additionally, PR0534 may have an inuon at the 5 prime end.
SAMPLE 66: I ola tQn of cDNA Clones Encode ~j~ RF 0697 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43052. Based on this consensus sequence, oligortucleotides were synthesized: I) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0697.
A pair of PCR primers (forward and reverse) were synthesized:
forwar gCR primer 5'-CCTGGCTCGCTGCTGCTGCTC-3' (SEQ ID NO:416);

WO 99/x6281 PCTIUS99105028 reverse PCR p3imer 5'-CCTCACAGGTGCACTGCAAGCTGTC-3' (SEQ ID N0:417).
Additionally, a synthetic oiigonucIeotide hybridization probe was constructed from the DNA43052 consensus sequence which had the following nucleotide sequence:
hybridization ~rob~
5'-CTCTTCCTCTTTGGCCAGCCCGACTTCTCCTACAAGCGCAGAATTGC-3' (SEQ ID N0:418}, In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0697 gene using the probe oiigonucieotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LI13227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0697 (herein designated as UNQ361 (DNA50920-1325}] (SEQ ID N0:414) and the derived protein sequence for PRO697.
The entire nucleotide sequence of UNQ36I (DNA50920-1325) is shown in Figure 166 (SEQ ID N0:4I4).
Clone UNQ361 (DNA50920-1325) contains a single open reading frame with an apparent uanslational initiation site at nucleotide positions 44-46 and ending at the stop codon at nucleotide positions 929-931 (Figure 166}. The predicted polypeptide precursor is 295 amino acids long (Figure I67). The full-length PR0697 protein shown in Figure 167 has an estimated molecular weight of about 33,518 daltons and a pI
of about 7.74. Clone UNQ361 (DNA50920-1325) was deposited with the ATCC on March 26, 1998. It is understood that the deposited clone contains the actual sequence, and that the sequences provided herein are representative based an current sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0697 polypeptide suggests that portions of it possess significant sequence identity with sFRPs, thezeby indicating that PR0697 may be a novel sFRP family member.
Still analyzing the amino acid sequence of PR0697, the signal peptides is at about amino acids I-20 of SEQ
ID N0:415. The cystein rich domain, having identity with the frizzled N-terminus, is at about amino acids 6-153 of SEQ ID N0:415. The corresponding nucleotides can routinely be determined from the sequences provided herein.
EXAMPLE 67: solo ion of cD A Clones Encoding, Human PR0717 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA42829. Based on the DNA42829 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and Z) for use as probes to isolate a clone of the full-length coding sequence for PRO?17.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR,primer 5'-AGCTTCTCAGCCCTCCTGGAGCAG-3" (SEQ ID N0:421);
reverse PCR primer 5'-CGGGTCAATAAACCTGGACGCTTGG-3' (SEQ ID N0:422).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA42829 consensus sequence which had the following nucleotide sequence:
h bridizgtion probe 5'-TATGTGGACCGGACCAAGCACTTCACTGAGGCCACCAAGATTG-3' (SEQ ID N0:423).
In order to screen several h'braries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones ~i encoding the PR0717 gene using the probe oIigonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).
DNA sequencing of.the clones isolated as described above gave the full-length DNA sequence for PR0717 [herein designated as UNQ385 (DNA50988-1326)] (SEQ ID N0:419) and the derived protein sequence for PR0717.
The entire nucleotide sequence of UNQ385 (DNA50988-1326) is shown in Figure 168 (SEQ ID N0:419).
Clone UNQ385 (DNA5U988-1326) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 17-19 and ending at the stop codon at nucleotide positions 1697-1699 (Figure 168). The predicted polypeptide precursor is 560 amino acids long (Figure 169). The full-length PR0717 protein shown in Figure 169 has an estimated molecular weight of about 58,427 dahons and a pI
of about 6.86. Clone UNQ385 (DNA50988-1326) has been deposited with the ATCC on April 28, 1998. Regarding the sequence, it is understood ~ that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0717 polypeptide suggests that PR0717 may be a novel 12 transmembrane receptor. The reverse complement strand of DNA50988 has a stretch that matches identically with human regulatory myosin light strand.
Still analyzing the amino acid sequence of SEQ ID N0:420, transmembrane domains are at about amino acids 30-50, 61-79, 98-1 i2, 126-146, 169-182, 201215, 248-268, 280-300, 318-337, 341=357, 375-387, and 420-441 of SEQ ID N0:420. N-glycosylation sites are at about amino acids 40-43 and 43-46 of SEQ ID N0:420. A
glycosaminoglycan attachment site is at about amino acids 468-471 of SEQ 1D
N0:420. The corresponding nucleotides can be routinely deternuned given the sequences provided herein.
EXAMPLE 68: Isolation of cDNA Clones Encoding_Human PRO731 A database was used to search expressed sequence tag (EST) databases. The EST
database used herein was the proprietary EST DNA database LIFESEQ7"', of Incyte Pharmaceuticals, Palo Alto, CA. Incyte clone 2581326 was herein identified and teamed DNA42801. Based on the DNA42801 sequence, oligonucleotides were synthesized:
1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0731.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GTAAGCACATGCCTCCAGAGGTGC-3' (SEQ ID N0:426);
reverse P,QRSrimer S'-GTGACGTGGATGCTTGGGATGTTG-3' (SEQ ID N0:427).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA42801 sequence which had the following nucleotide sequence:
hybridization probe 5'-TGGACACCTTCAGTATTGATGCCAAGACAGGCCAGGTCATTCTGCGTCGA-3' (SEQ ID N0:428).
In order to screen several libzaries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0731 gene using the probe oiigonucleotide and one ofthe PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue {LIB25f). The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA. The cDNA was primed with oligo dT containing a Notl site, linked with blunt to Salt hemikinased adaptors, cleaved with Nod, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRICB or pRICD; pRKSB is a precursor of pRKSD that does not contain the Sfil site; see, Holmes et al., Sc' ce; 2~:1278-1280 (1991)) in the unique XhoI and Notl sites.
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0731 [herein designated as UNQ395 (DNA48331-1329)) (SEQ ID NU:424) and the derived protein sequence for PR0731.
The entire nucleotide sequence of UNQ395 (DNA48331-1329) is shown in Figures 170A-B (SEQ ID
N0:424). Clone UNQ395 (DNA4833I-I329) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 329-331 and ending at the stop codon at nucleotide positions 3881-3883 (Figures 170A-B). The predicted polypeptide precursor is 1184 amino acids long (Figure 171 ). The full-length PR0731 protein shown in Figure 171 has an estimated molecular weight of about 129,022 daltons and a pI of about 5.2. Clone UNQ395 (DNA48331-1329) was deposited with the ATCC on March 31, 1998.
Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0731 polypeptide suggests that portions of it possess significant identity and similarity to members of the protacadherin family, thereby indicating that PR0731 may be a novel protocadherin.
Still analyzing the amino acid sequence of SEQ ID N0:425, the putative signal peptide is at about amino acids 1-13 of SEQ ID N0:425. The transmembrane domain is at amino acids 719-739 of SEQ ID N0:425. The N-glycosylation of SEQ ID N0:425 are as follows: 415-418, 582-586, 659-662, 662-665, and 857-860. The cadherin extracellular repeated domain signantres are at about amino acids (of SEQ ID
N0:425): I23-133, 232-242, 340-350, 448-458, and 553-563. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 69: Isolation of cDNA Cl~es Encoding Human PR0218 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA17411. Two proprietary Genentech EST
sequences were employed in the consensus assembly and are shown in Figure 174 and 175. Based on the DNA174I I
consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0218.
A pair of PCR primers (forward.and reverse) were synthesized:
forward PCR primer 5'-AAGTGGAGCCGGAGCCTTCC-3' (SEQ ID N0:433);
rrwerse P $ grimer 5'-TCGTTGTTTATGCAGTAGTCGG-3' (SEQ ID N0:434).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA17411 sequence which had the following nucleotide sequence:
hybridization probe 5'-ATTGTTTAAAGACTATGAGATACGTCAGTATGTTGTACAGG-3' (SEQ ID N0:435).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0218 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB28).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0218 [herein designated as UNQ192 (DNA30867-1335)] (SEQ ID N0:429) and the derived protein sequence for PR0218.
The entire nucleotide sequence of UNQ192 (DNA30867-1335) is shown in Figure 172 (SEQ ID N0:429).
Clone UNQ192 (DNA30867-1335) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 150-152 and ending at the stop codon at nucleotide positions 1515-1517 (Figure 172). The predicted polypeptide precursor is 455 amino acids long {Figure 173). The full-length PR0218 protein shown in Figure I73 has an estimated molecular weight of about 52,917 daltons and a p1 of about 9.5. Clone UNQ192 (DNA30867-1335) has been deposited with the ATCC on April 28, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0218 polypeptide suggests that PR0218 may be a novel transmembrane protein.
Still analyzing the amino acid sequence of SEQ ID N0:4~30, the putative signal peptide is at about amino acids 1 through 23 of SEQ 1D N0:430. Transmembrane domains are potentially at about amino acids 37-55, 81-102, 150-168, 288-311, 338-356, 375-398, and 425-444 of SEQ ID N0:430. N-glycosylation sites are at about amino acids 67, 180, and 243 of SEQ ID N0:430. Eukaryotic cobalamin-binding protein is at about amino acids 151-160 of SEQ ID N0:430. The corresponding nucleotides can be routinely determined given the sequences provided herein.
F:XAMPj..E 70: Isolation of cDNA Clone, Encoding Human PR0768 A consensus seguence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43448. Based on the DNA43448 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0768.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-GGCTGACACCGCAGTGCTCTTCAG-3' (SEQ ID N0:438);
reverse PCR primer 5'-GCTGCTGGGGACTGCAATGTAGCTG-3' (SEQ ID N0:439).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA43448 consensus sequence which had the following nucleotide sequence:
hybridization probe 5'-CATCCTCCATGTCTCCCATGAGGTCTCTATTGCTCCACGAAGCATC-3' (SEQ ID N0:440).
In order to scmxn several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0768 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0768 (herein designated as UNQ406 (DNA55737-1345)] (SEQ ID 1V0:436) and the derived protein sequence for PR0768.
The entire nucleotide sequence of UNQ406 (DNA55737-1345) is shown in Figures 176A-B (SEQ ID
N0:436). Clone UNQ406 (DNA55737-1345) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 20-22 and ending at the stop codon at nucleotide positions 3443-3445 (Figures WO 99/46281 PCTltlS99/05028 176A-B). The predicted polypeptide precursor is T 141 amino acids long (Figure 177). The full-length PR0768 protein shown in Figure 177 has an estimated molecular weight of about 124,671 daltons and a pI of about 5.82.
Clone UNQ406 (DNA55737-1345) has been deposited with the ATCC on April 6, I998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0768 polypeptide suggests that portions of it possess significant sequence identity and similarity with integrin 7.
Still analyzing the amino acid sequence of SEQ ID N0:437, the putative signal peptide is at about amino acids I-33 of SEQ ID N0:437. The transmembrane domain is at amino acids 1039-1064 of SEQ ID N0:437. N-glycosylation sites are at amino acids: 86-89, 746-749, 949-952, 985-988 and 1005-1008 of SEQ ID N0:437.
Integrin alpha chain protein domains are identified at about amino acids: 1064-1071, 384-409, 1041-I07I, 317-346, 443-465, 385-407, 215-224, 634-647, 85-99, 322-346, 470-479, 442-466, 379-408 and 1031-1047 of SEQ ID
N0:437. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 71: Isolation of cDNA CI nes Encoding Human PR0771 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA43330. Based on the DNA43330 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0771.
A pair of PCR primers (forward and reverse) were synthesized:
forward PC$, rimer5'-CAGCAATATTCAGAAGCGGCAAGGG-3' (SEQ ID N0:443);
reverse PCR~~r 5'-CATCATGGTCATCACCACCATCATCATC-3' (SEQ ID N0:444).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA43330 consensus sequence which had the following nucleotide sequence:
hylhridization probe 5'-GGTTACTACAAGCCAACACAATGTCATGGCAGTGTTGGACAGTGC?'GG-3' (SEQ ID N0:445).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones et>cx~iag the PR0771, gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB28).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0771 [herein desigmted as UNQ409 (DNA49829-1346)] (SEQ ID N0:441) and the derived protein sequence for PR0771.
The ettare nucleotide sequence of UNQ409 (DNA49829-1346) is shown in Figure I78 (SEQ ID NO:441).
Clone UNQ409 (DNA49829-1346) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 134-136 and ending at the stop codon at nucleotide positions 1442-1444 (Figure 178). The predicted polypeptit3e precursor is 436 amino acids long (Figure 179). The full-length PR0771 protein shown in Figure I79 has an estimated molecular weight of about 49,429 daltons and a p1 of about 4.8. Clone UNQ409 (DNA49829-1346) has been deposited with the ATCC on April ?, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on lrnown sequencing techniques.

Analysis of the amino acid sequence of the full-length PR0771 polypeptide suggests that portions of it possess significant homology to the testican protein, thereby indicating that PR0771 may be a novel testican homologue.
Still analyzing the amino acid sequence of SEQ 1D N0:442, the putative signal peptide, leucine zipper pattern, N-myristoylation sites, and thyroglobulin type-1 repeats are also shown in Figure 179. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 72: Isolation of cDNA Cloned Encodine Human PR0733 A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained, is herein designated DNA45600. Based on the DNA45600 consensus sequence, oligonucleotides were synthesized: 1 ) to identify by PCR a cDNA
library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0733.
A pair of PCR primers (forward and reverse) were synthesized:
forward PCR primer 5'-CCCAGCAGGGATGGGCGACAAGA-3' (SEQ ID N0:448);
revere PCR primer 5'-GTCTTCCAGTTTCATATCCAATA-3' (SEQ ID N0:449).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA45600 consensus sequence which had the following nucleotide sequence:
hybridization probe 5'-CCAGAAGGAGCACGGGGAAGGGCAGCCAGATCTTGTCGCCCAT-3' (SEQ ID N0:450).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR0733 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human bone marrow tissue {LI8255).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0733 [herein designated as UNQ411 (DNA52196-1348)] (SEQ ID N0:446) and the derived protein sequence for PR0733.
The entire nucleotide sequence of UNQ411 (DNA52196-1348) is shown in Figures 180A-B (SEQ ID
N0:446). Clone UNQ411 (DNA52196-1348) contains a single open reading frame with an apparent translational itutiation site at nucleotide positions 106-108 and ending at the stop codon at nucleotide positions 793-795 (Figures 180A-B). The predicted polypeptide precursor is 229 amino acids long (Figure 18I). The full-length PR0733 protein shown in Figure 181 has an estimated molecular weight of about 26,017 daltons and a pI of about 4.73. Clone UNQ411 (DNA52196-1348) has been deposited with the ATCC on April 7, 1998.
Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on laaown sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0733 polypeptide suggests that portions of it possess significant sequence identity and similarity to the Tl/ST2 receptor binding protein precursor and therefore tray have a similar function in cell signaling. If it is a cytoltine, it may be useful in the treatment of inflammation and cancer.
Still analyzing the amino acid sequence of SEQ 1D N0:447, the putative signal peptide, transmembrane domain, N-myristoylation site, and tyrosine Idnase site are also shown in Figure 181. The corresponding nucleotides can be routinely determined given the sequences provided herein.

EXAMPL)r 73: Isolation of cDNA Clones Encoding Numa~ PR0162 An expressed sequence tag (EST) DNA database (MerckIWashington University) was searched and an EST
AA397543 was identified which showed homology to human pancreatitis-associated protein. The EST AA397543 Cole was purchased and its insert obtained and sequenced and the sequence obtained is shown in Figure 182 (SEQ
ID N0:451).
The entire nucleotide sequence of PR0162 is shown in Figure 182 (SEQ ID
N0:451). DNA sequencing of the clorre gave the full-length DNA sequence for PROl62 [herein designated as UNQ429 (DNA56965-1356)] (SEQ
ID N0:451) and the derived protein sequence for PR0162. Clone UNQ429 (DNA56965-I356) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 86-88 and ending at the stop codon at nucleotide positions 611-613 (Figure 182). The predicted polypeptide precursor is I75 amino acids long (Figure 183). The full-length PR0162 protein shown in Figure 183 has an estimated molecular weight of about 19,330 daltons and a pI of about 7.25. Clone UNQ429 (DNA5G965-1356) has been deposited with the ATCC. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR0162 polypeptide suggests that portions of it possess significant homology to the human pancreatitis-associated protein, thereby indicating that PROi62 may be a novel pancreatitis-associated protein.
Still analyzing the amino acid sequence of SEQ ID N0:452, the putative signal peptide is at about amino acids 1-26 of SEQ ID N0:452. A C-type lectin domain signature is at about amino acids 146-171 of SEQ ID
N0:452. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 74: Isolation of cDNA Clones Eneod~rlg_Huma~t PR0788 A consensus DNA sequence (designated herein as DNA49308) was assembled relative to other EST
sequetxes using phrap as described in Example I above. Based upon an observed homology between the DNA49308 consensus sequence and the Incyte EST clo0ne no, 2?77282, the Incyte EST clone no. 2777282 was purchased and its insert obtained and sequenced, which gave the full-length DNA sequence for PR0788 (herein designated as UNQ430 (DNA56405-1357)] (SEQ ID N0:453) and the derived protein sequence for PRU788.
Clone UNQ430 (DNA56405-1357) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 84-86 and ending at the stop codon at nucleotide positions 459-461 (Figure 184).
The predicted poiypeptide precursor is 125 amino acids: long (Figure 185). The full-lengtb PR0788 protein shown in Figure 185 has an estimated molecular weight of about 13,115 daltons and a pI of about 5.90: Clone UNQ430 (DNA56405-1357) has been deposited with the ATCC. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on irnown sequencing techniques.
Sa71 analyzing Figure 185, a signal peptide is shown at about amino acids I-17 of SEQ ID N0:454. An N-glycosylation site is at about amino acids 46-49 of SEQ ID N0:454.
FXA; Isolation of cDNA Clones Encoding Hs~an_ PROlpnB
A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example I above. This consensus sequence is herein designated as DNA49804. An EST proprietary to Genentech was employed in the consensus assembly and is herein designated as DNA16508 (Figure 188; SEQ ID N0:457).

Based upon an observed homology between the DNA49804 sequence and Merck EST
clone no. AA143670, the Merck EST clone no. AA143670 was purchased and its insert obtained and sequenced. That sequence is shown herein in Figure 186 (SEQ ID N0:455).
Sequencing gave the full length sequence for PR01008 [herein designated as UNQ492 (DNA57530-13?5)]
(SEQ ID N0:455) and the derived protein sequence for PR01008 were identified.
The entire nucleotide sequence of UNQ492 (DNA57530-1375) is shown in Figure 186 (SEQ ID N0:455).
Clone UNQ492 (DNA57530-1375) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 138-140 and ending at the stop codon at nucleotide positions 936-938 (Figure 186). The predicted polypeptide precursor is 266 amino acids long (Figure 187). The full-length PR01008 protein shown in Figure 187 has an estimated molecular weight of about 28,672 daltons and a pI
of about 8.85. Clone UNQ492 : (DNA57530-1375) has been deposited with the ATCC on May 20, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR01008 polypeptide suggests that portions of it possess significant sequence identity andlor similarity with mdkk-1, thereby indicating that PR01008 may be a novel member of this family and have head inducing activity.
Still analyzing the amino acid sequence of SEQ ID N0:456, the putative signal peptide is at about amino acids 1-23 of SEQ ID N0:456. The N-glycosylation site is at about amino acids 256-259 of SEQ ID N0:456, and the fungal zn-{2~cys(6) binuclear cluster domain is at about amino acids 1I0-I26 of SEQ ID N0:456. The corresponding nucleotides can of all the amino acids can be routinely determined given the sequences provided herein.
EXAMPLE 76: Isolation of cDNA Cloned Encoding,Human P~tOl0I2 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above, wherein the consensus sequence is herein designated DNA49313.
Based on the DNA49313 consensus sequence, oligonucleotides were synthesized: I) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR01012.
A pair of PCR primers (forward and reverse) were synthesized:
forward.PCR primer 5'-ACTCCCCAGGCTGTTCACACTGCC-3' (SEQ ID N0:460);
zeverse PCR urimer 5'-GATCAGCCAGCCAATACCAGCAGC-3' (SEQ ID N0:461).
Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA49313 consensus sequence which had the following nucleotide sequence:
hybridization probe 5'-GTGGTGATGATAGAATGCTTTGCCGAATGAAAGGAGTCAACAGCTATCCC-3' (SEQ ID N0:462).
In order to screen several libraries for a source of a full-length clone, DNA
from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PR01012 gene using the probe oligonucleotide and one of the PCR
primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).
DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR01012 [herein designated as UNQ495 (DNA56439-I37b)] (SEQ ID N0:458) and the derived protein sequence for PR01012.

The entire nucleotide sequence of UNQ49S (DNAS6439-1376) is shown in Figures 189A-B (SEQ 1D
N0:4S8). Clone UNQ495 (DNA56439-1376) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 404406 and ending at the stop codon at nucleotide positions 2645-2647 (Figures 189A-B). The predicted polypeptide precursor is 747 amino acids long (Figure 190). The full-length PR01012 protein shown in Figure 190 has an estimated molecular weight of about 86127 daltons and a pI of about 7.46. Clone S UNQ49S (DNA56439-1376) has been deposited with ATCC on May 14, 1998.
Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on Irnown sequencing techniques.
Analysis of the amino acid sequence .of the full-length PR01012 polypeptide suggests that portions of it possess sequence identity with disulfide isomerase thereby indicating that PR01012 may be a novel disulfide isomerase related protein.
Still analyzing the amino acid sequence of SEQ ID N0:459, the cytochrome C
family heme-binding site signature is at about amino acids 158-163 of SEQ ID N0:459. The Nt-DNAJ domain signature is at about amino acids ?7-96 of SEQ ID N0:4S9. An N-glycosylation site is at about amino acids 484-487 of SEQ ID N0:4S9. The ER targeting sequence is at about amino acids 744-747 of SEQ ID N0:459: 1t is understood that the polypeptide and nucleic acids disclosed can be routinely formed with or without, these portions as desired, in alternative embodiments.
For example, it may be desirable to produce PR01012 without the ER targeting sequence. The corresponding nucleotides can be routinely determined given the sequences provided herein.
EXAMPLE 77: Isolation of cDN~Clones Encodin~a Human PROi014 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 abobe, wherein the consensus sequence obtained is herein designated DNA49811. Based upon an observed homology between the DNA49811 sequence and lncyte EST clone no:
2612207, Incyte EST clone no:
2612207 was purchased and its insert was obtained and sequenced, wherein the sequence obtained is shown in Figure 191 (SEQ OD N0:463).
2S DNA sequencing gave the full-length DNA sequence for PR01014 [herein designated as UNQ497 (DNAS6409-1377)] (SEQ ID N0:463) and the derived protein sequence for PR01014.
The entire nucleotide sequence of UNQ497 (DNAS6409-1377) is shown in Figure 191 (SEQ ID N0:463).
CIone UNQ497 (DNA56409-137?) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 66-68 and ending at the stop codon at nucleotide positions 966-968 (Figure 191). The predicted polypeptide precursor is 300 amino acids long (Figure 192). The full-length PR01014 protein shown in Figure 192 has an estimated molecular weight of about 33,655 daltons and a pI
of about 9.31. Clone UNQ497 (DNA56409-1377) has been deposited with the ATCC on May 20, 1998. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on lrnown sequencing techniques.
3S Analysis of the amino acid sequence of the full-length PR01014 polypeptide suggests that portions of it possess sequence identity with reductase, thereby indicating that PR01014 may be a novel member of the reductase family.
Still analy2ing the amino acid sequence of SEQ iD N0:4b4, the putative signal peptide is at about amino acids 1-19 of SEQ ID N0:464. The cAMP and cGMP dependent protein ltinase phosphorylation sites are at about amino acids 30-33 and 58-61 of SEQ ID N0:464. Short chain alcohol dehydrogenase family proteins are at about an>ino acids 165-202, 3?-49, 112-122 and 210-219 of SEQ ID N0:464. The corresponding nucleotides of these domains and any other amino acids provided herein can be routinely determined given the sequences provided herein.
EXAMPLE 78. Isolation of cDNA Clones Encodi~ Human PR01017 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example I above, wherein that consensus DNA sequence is herein designated DNA53235. Based upon an observed homology between the DNA53235 consensus sequence and the Merck EST clone no.
AA243086, the Merck EST
clone no. AA243086 was purchased and its insert obtained and sequenced, wherein the sequence obtained is shown in Figure 193 (SEQ ID N0:465). DNA sequencing gave the full-length DNA
sequence for PR01017 (herein designated as UNQ500 (DNA561I2-I379)J (SEQ ID N0:465) and the derived protein sequence for PR01017, The entire nucleotide sequence of UNQ500 (DNA56112-1379) is shown in Figure 193 (SEQ ID N0:465).
Clone UNQ500 (DNA56112-1379) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 128-130 and ending at the stop codon at nucleotide positions 1370-1372 (Figure 193). The predicted polypeptide precursor is 4I4 amino acids long (Figure 194). The full-length PR01017 protein shown in Figure 194 has an estimated molecular weight of about 48,414 daltons and a pt of about 9.54. Clone UNQ500 (DNA56112-1379) has been deposited with the ATCC. Regarding the sequence, it is understood that the deposited clone contains the correct sequence, and the sequences provided herein are based on known sequencing techniques.
Analysis of the amino acid sequence of the full-length PR01017 polypeptide suggests that portions of it possess sequence identity with HNK-1 sulfotransferase, thereby indicating that PROl0I7 may be a novel sulfotransferase.
Still analyzing the amino acid sequence of SEQ ID N0:466, the putative signal peptide is at about amino acids 1 31 of SEQ ID N0:466. N-glycosylation sites are at about amino acids 134-137, 209-212, 280-283 and 370-273 of SEQ ID N0:466. The TNFR/NGFR family cystein-rich region protein is at about amino acids 329-332 of SEQ ID N0:466. The corresponding nucleotides can be routinely determined given the sequences provided herein.
The protein can be secreted.
EXAMPLE 79: ~.g~~i~ of cDNA Clones Encoding Human PR0474 A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA49818. Based upon an observed homology between the DNA49818 consensus sequence,and the Merck EST
clone no. H77889, the Merck EST clone no. H77889 was purchased and its insert obtained and sequenced, wherein the sequence obtained is herein shown in Figure 195 (SEQ ID N0:467). DNA sequencing gave the full-length DNA
sequence for PR0474 [herein designated as UNQ502 (DNA56045-1380)) (SEQ ID N0:467) and the derived protein sequence for PR0474.
The entire nucleotide sequence of UNQ502 (DNA56045-1380) is shown in Figure 195 (SEQ ID N0:467).
Clone UNQ502 (DNA56045-1380) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 106-108 and ending at the stop codon at nucleotide positions 916-918 (Figure 195). The predicted polypeptide precursor is 270 amino acids long (Figure 196). The full-length PR0474 protein shown in Figure 196 has an estimated molecular weight of about 28,317 daltons and a pI
of about 6Ø Clone UNQ502 I)EMAN~ES OU BREVETS VOLUMINEUX
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Claims

1. Isolated nucleic acid having at least 80% sequence identity to a nucleotide sequence that encodes a polypeptide comprising the amino acid sequence shown in Figure 85 (SEQ ID NO:231).

2. The nucleic acid of Claim 1, wherein said nucleotide sequence comprises the nucleotide sequence shown in Figure 84 (SEQ ID NO:230).

3. The nucleic acid of Claim 1 or Claim 2, wherein said nucleotide sequence comprises the full-length coding sequence from within the sequence shown in Figure 84 (SEQ ID
NO:230).

4. The nucleic acid of Claim 1 which comprises the full-length coding sequence of the DNA deposited under accession number ATCC 209846.

5. Isolated nucleic acid having a nucleotide sequence that encodes a polypeptide comprising the amino acid sequence shown in Figure 85 (SEQ ID NO:231).

6. The nucleic acid of Claim 5, wherein said nucleotide sequence comprises the nucleotide sequence shown in Figure 84 (SEQ ID NO:230).

7. The nucleic acid of Claim 5 or Claim 6, wherein said nucleotide sequence comprises the full-length coding sequence from within the sequence shown in Figure 84 (SEQ ID
NO:230).

8. The nucleic acid of Claim 5 which comprises the full-length coding sequence of the DNA deposited under accession number ATCC 209846.

9. A vector comprising the nucleic acid of any one of claims Claim 1 to 8.

10. The vector of Claim 9 wherein said nucleic acid is operably linked to control sequences recognized by a host cell transformed with the vector.

11. A host cell comprising the vector of Claim 9 or Claim 10.

12 The host cell of Claim 11 wherein said cell is a CHO cell, an E. coli or a yeast cell.

13. A process for producing a polypeptide comprising culturing the host cell of Claim 11 or Claim 12 under conditions suitable for expression of said polypeptide and recovering said polypeptide from the cell culture.

14. Isolated polypeptide comprising a sequence having at least 80% sequence identity to the amino acid sequence shown in Figure 85 (SEQ ID NO:231).

15. Isolated polypeptide comprising a sequence having at least 80% sequence identity to the amino acid sequence encoded by the nucleotide deposited under accession number ATCC
209846.

16. Isolated polypeptide comprising a sequence having the amino acid sequence shown in Figure 85 (SEQ ID NO:231).

17. Isolated polypeptide comprising a sequence having the amino acid sequence encoded by the nucleotide deposited under accession number ATCC 209846.

18. A chimeric molecule comprising a polypeptide according to any one of Claims 14 to 17, fused to a heterologous amino acid sequence.

19. The chimeric molecule of Claim 18 wherein said heterologous amino acid sequence is an epitope tag sequence.

20. The chimeric molecule of Claim 18 wherein said heterologous amino acid sequence is a Fc region of an immunoglobulin.

21. An antibody which specifically binds to a polypeptide according to any one of Claims 14 to 17.

22. The antibody of Claim 21 wherein said antibody is a humanised antibody.

23. The antibody of Claim 21 wherein said antibody is a monoclonal antibody.

24. The antibody of Claim 23 wherein said antibody is a chimeric antibody.

25 A composition comprising an antibody according to any one of Claims 21 to inadmixture with a pharmaceutically acceptable corner.