[go: up one dir, main page]

WO1991004745A1 - Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation - Google Patents

Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation Download PDF

Info

Publication number
WO1991004745A1
WO1991004745A1 PCT/US1990/005105 US9005105W WO9104745A1 WO 1991004745 A1 WO1991004745 A1 WO 1991004745A1 US 9005105 W US9005105 W US 9005105W WO 9104745 A1 WO9104745 A1 WO 9104745A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
acid sequence
cadherin
cell
cell adhesion
Prior art date
Application number
PCT/US1990/005105
Other languages
English (en)
Inventor
Lee L. Rubin
Chen W. Liaw
Kevin J. Tomaselli
Original Assignee
Athena Neurosciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Athena Neurosciences, Inc. filed Critical Athena Neurosciences, Inc.
Publication of WO1991004745A1 publication Critical patent/WO1991004745A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compositions that transiently and reversibly dissociate the blood-brain barrier. More particularly, the invention relates to compositions that dissociate tight junctions between brain capillary endothelial cells that constitute the physiological barrier between the general circulation and the brain.
  • CNS central nervous system
  • the brain and spinal cord The entry of drugs from the blood stream to the central nervous system (CNS), i.e., the brain and spinal cord, is restricted by the presence of high resistance tight junctions between brain capillary cells and by the apparently low rate of transport across these endothelial cells (Betz, A.L., et al., Ann. Rev. Physiol., 48:241 (1986); Pardridge, W.M., Ann. Rev. Pharmacol. Toxicol., 28:25 (1988)).
  • the tight junctions of the blood brain barrier prevent diffusion of molecules and ions around the brain capillary endothelial cells.
  • the only substances that can readily pass from the luminal core of the capillary to the abluminal tissues that surround the capillary are those molecules for which selective transport systems exist in the endothelial cells, as well as those compounds that are lipophilic (i.e., hydrophobic).
  • drugs, peptides and other molecules that are neither lipophilic nor transported by specific carrier proteins are barred from entry into the brain, or their rates of entry are too low to be useful, thereby imposing a severe limitation upon the physician's ability to treat CNS disorders
  • the carrier-mediated transcellular transport system mentioned above may have limited usefulness for therapeutic modalities under some circumstances.
  • Transcytotic transport in general, involves, first, the binding of molecules to specific carrier proteins on the surface of endothelial cells, and, second, the delivery of such molecules across the endothelial cells.
  • Limitations on the usefulness of such a system for treatment of CNS disorders are based on the
  • physiological carrier proteins may not function efficiently, or at all, with non-physiological drugs; (2) even where function occurs, the rate of transport of therapeutic agents will be limited by the rate of transport of the
  • macromolecules may be simply too low to achieve
  • concentrated sugar solutions may not be innocuous, and might be expected to have undesirable side effects.
  • chemical agents may not be useful for the treatment of chronic neurological disease, their effects on tight junctions are not always reversible, and, as they all are
  • 7-fluorouracil is a powerful inhibitor of pyrimidine synthesis, and thus nucleic acid biosynthesis, in animals cells.
  • junctions of the BBB in order that administered drugs can reach the brain from the general circulation, and which have no undesirable side effects of their own in the subject.
  • CAM cell adhesion molecules
  • cadherin is the term applied to a family of glycoproteins found in most kinds of mammalian tissues and thought to be responsible for Ca 2+ - dependent cell-cell adhesion, (Takeichi, M.,
  • E-cadherin from epithelial tissues
  • P-cadherin from placental tissues
  • N-cadherin from neural tissues
  • the different cadherins exhibit distinct tissue distribution patterns (Takeichi, U., (1988) above). E-cadherin, which was found to be distributed
  • N-cadherin which is expressed in various neural tissues including astrocytes (Hatta, K., et al., Devel. Biol., 120:215 (1987); Matsunega, M., et al., Nature. 334:62 (1988); Tomaselli, K.J., Neuron, 1:33 (1988)), shows 92% amino acid sequence homology between
  • Placental P-cadherin has also been cloned, and the deduced amino acid sequence of this glycoprotein was found to exhibit about 58% homology with epithelial E-cadherin (Nose, A., et al., EMBO J., 12:3655 (1987)).
  • CAMs independent of Ca 2+ are also known, for example, the 125K glycoprotein of Urushihara et al. (Urushihara, H., et al., Cell, 20:363 (1980)); N-CAM (Rutishauser, U., Nature. Lond., 310:549 (1984));
  • Ng-CAM (Grunet, M. et al., Proc. Nat'l. Acad. Sci.
  • PECAM-1 CD 31
  • Ca 2+ -independent CAMs are known to exhibit certain properties of the Ca 2+ -dependent CAMs.
  • N-CAM and N-cadherin both promote retinal neurite outgrowth on astrocytes (Neugebauer, K.M., et al., J. Cell Biol., 107:1177 (1985)), and on Schwann cells (Bixby, J.L. et al., J. Cell Biol., 107:353 (1988)).
  • Monoclonal antibodies raised against epithelial E-type cadherins such as uvomorulin are known to disrupt the adhesion of several cell types, including embryo cells, cultured teratocarcinoma cells,
  • cadherins had not been found in brain capillary or other endothelial cells (see, Takeichi, et al. (1988), above). Further, the CAMs of microvascular endothelial cells had not yet been identified, nor had such molecules been localized specifically to brain capillary endothelial cells.
  • junctions between microvascular endothelial cells including those of the BBB, based upon an attack upon the CAM'S of such cells that are responsible for tight junction formation and maintenance.
  • CAR cell adhesion recognition
  • RGD which is found in laminin, fribronectin and other basement membrane components that are
  • cadherin cell adhesion molecules homologous to, and immunologically related to, cadherin cell adhesion molecules are present on brain and non- brain microvascular endothelial cells, such that
  • junctions between such endothelial cells can be reversibly opened so as to permit passage of
  • therapeutic drugs by the use of polypeptide and antibody compositions that compete with such cell adhesion molecules for binding to such cells.
  • Another object of this invention is to provide DNA sequences of genes, and plasmids containing same, coding for the expression of all or a cell-binding portion of microvascular endothelial cell adhesion molecules.
  • Yet another object of this invention is to provide means to identify those sequences of cell adhesion molecules responsible for the tight binding of
  • a further object is to provide therapeutic
  • compositions comprising polypeptides derived from cell adhesion molecules that reversibly disrupt cell-cell adhesion.
  • Still another object of this invention is to provide therapeutic compositions comprising polyclonal or monoclonal antibodies or fragments thereof directed against endothelial cell adhesion molecules, or against polypeptides representing cell binding regions thereof, that reversibly disrupt endothelial cell-cell adhesion.
  • Yet another object of this invention is to provide therapeutic formulations comprising therapeutic drugs conjugated with blood-brain barrier-disrupting
  • compositions of this invention that are capable of entering the central nervous system following
  • Figure 1 illustrates the partial cDNA sequence for bovine endothelial cell adhesion molecule homologous to chicken N-cadherin.
  • Figure 2 illustrates the partial cDNA sequence for bovine endothelial cell adhesion molecule homologous to mouse P-cadherin.
  • Figure 3 illustrates the cDNA sequence for the MDCK cell adhesion molecule homologous to mouse
  • Figure 4 illustrates the restriction sites in the bovine endothelial cell N- (4-1 to 4-5) and P-cadherin (4-6 to 4-8) cDNA sequences and in the MDCK E-cadherin (4-9 to 4-14) cDNA sequence.
  • Figure 5 shows the staining of a mouse brain thin section by an antibody raised against a fusion protein derived from amino acids 9-96 of MDCK E-cadherin containing an HAV region.
  • Figure 6 is a repeat of the experiment of Fig. 5, except that the antibody was raised against the entire E-cadherin molecule.
  • Figure 7 illustrates the effects of an 18-mer HAV- containing polypeptide on the resistance of tight junction monolayers of MDCK epithelial cells.
  • Figure 8 illustrates the effects of 11-mer and 18-mer HAV-containing polypeptides on the resistance of tight junction monolayers MDCK epithelial cells.
  • Figure 9 illustrates the effects of 11-mer and 18- mer HAV-containing polypeptides on the resistance of tight-junction monolayers of brain microvascular endothelial cells.
  • a polypeptide composition comprising cell binding domains of endothelial cell adhesion molecules may compete against such molecules for binding to such cells, such that by this means the junctions between such cells could be reversibly opened, thereby permitting penetration by therapeutic agents.
  • the present invention also discloses that polyclonal or monoclonal antibodies (or fragments thereof) raised against endothelial cell adhesion molecules or cell-binding domains thereof may also compete for endothelial cell surface binding sites, and, by this means, reversibly disrupt junctions between endothelial cells, thereby permitting entry into the central nervous system of therapeutic agents.
  • the endothelial cell cadherins disclosed herein exhibit one or more of several characteristics of E-, P- and N- cadherins, including: characteristics of a transmembrane integral protein, with cytoplasmic, hydrophobic plasma membrane, and extracellular regions; intraspecies DNA sequence homologies of greater than about 50% for the entire molecule; immunological cross- reactivity with antibodies raised against non- endothelial cell cadherins; and containing cell-binding domains. "Immunologically related to" means that these cadherin-like molecules cross-react with antibodies raised against non-endothelial cell cadherins.
  • E-cadherin-like molecules were localized in brain by immunofluorescence. Cryostat sections of mouse brain were labeled with a rabbit antibody prepared against E-cadherin, and then with fluorescein
  • microvascular endothelial cell (BMEC) cadherins were cloned and sequenced as described below, and the partial sequence of N-cadherin and P-cadherin are disclosed herein in Figures 1 and 2, respectively.
  • MDCK dog kidney epithelial cells are known to employ E-cadherin to form high resistance tight junctions, and as the present invention discloses that brain capillary endothelial cell adhesion molecules include E-type cadherin, the DNA of this cadherin was also cloned; its complete DNA sequence is disclosed herein (Fig. 3).
  • N-, P- and E-cadherin-type clones described herein were deposited in the American Type Culture Collection on September 26, 1989, and were assigned the following accession numbers:
  • transmembrane glycoproteins the cytoplasmic domains of which are highly conserved, that is, are highly homologous.
  • 42-amino acid coding region in the cytoplasmic domain were selected to serve as primers for polymerase chain reaction (PCR) using either BMEC cDNA or MDCK cDNA as templates.
  • PCR polymerase chain reaction
  • BMEC cadherins are of two types - one homologous to chicken N-cadherin (neuronal type, see, e.g., Hatta, K., et al., J. Cell Biol., 106:873 (1988)) and the other homologous to mouse
  • P-cadherin placental type, see e.g., Nose, A., et al., (1987) above. It has also been found that there are two species of cadherins in MDCK cells - one homologous to mouse E-cadherin (see, e.g., Nagafuchi, A., et al., Nature, 329:341 (1987)) and the other homologous to mouse P-cadherin (Nose, et al. (1987), above).
  • PCR products were then used as probes to isolate the BMEC and MDCK cadherin cDNA clones as follows.
  • a cDNA library was constructed essentially according to Gubler et al . (Gubler, U. et al., Gene, 25:263 (1983), which is incorporated herein by
  • the partial restriction maps for each cDNA clone based on their sequences are shown in Fig. 4. Some of these restriction sites were confirmed by restriction enzyme digestions, including Hind III, Pst I, Kpn I, Bgl II for N-cadherin; Pvu II, Sac I and Pst I for P-cadherin; Pst I, Pvu II, BamH I, and Sac I for
  • E-cadherin cDNA contains all the information necessary for cadherin function
  • full-length E-cadherin cDNA joined to a suitable promoter may be introduced into mouse L-cells that have very little endogenous cadherin activity (Nagafuchi, et al. (1987), supra).
  • transfected L-cells may be tested for Ca 2+ -dependent aggregating activity. The extent of this aggregating activity should be closely correlated with the amount of E-cadherin expressed (Takeichi, M. (1988), supra).
  • L-cells may be first transfected as above with a cDNA of a size sufficient to cause Ca 2+ -mediated aggregation of transfectants.
  • a series of deletion mutants comprising truncated cDNA species missing different regions of the extracellular domain may be prepared by restriction enzyme digestion and proper end filling or exonuclease digestion to make the deletions in the proper coding frames. These deletion mutants can then be tested for their ability to express in L-cells a protein causing Ca 2+ -dependent aggregation. By correlating a loss of aggregation with deletion of particular fragments, the regions important for cell binding may be determined.
  • polypeptides corresponding to binding regions of cadherins may be synthesized chemically using an automated peptide synthesizer such as that of Applied Biosystems, Inc., Foster City, CA, or expressed by recombinant DNA methods.
  • Effective polypeptides may be of varying lengths, depending upon the natures of junctions being disrupted and the cell adhesion
  • sequences of cadherins may be analyzed to detect homologous regions.
  • this technique to bovine endothelial cell N- and P-cadherins and to epithelial cell E-cadherin, we have determined that, in the amino acid 80 region of each of these cadherins, there is conserved a triplet HAV (His-Ala-Val) region.
  • HAV His-Ala-Val
  • this HAV region may be a common cell adhesions recognition (CAR) sequence.
  • Polyclonal antibodies raised in rabbits and monoclonal antibodies derived from hybridomas may be generated against each of the chemically-synthesized polypeptides by standard methods. (Harlow, E., et al.,
  • recombinant antibodies may be prepared. Fragments of antibodies, e.g., Fc, Fab, F(ab)', may be prepared by standard methods.
  • CAM-derived polypeptides containing cell-binding domains, and the corresponding polyclonal and monoclonal antibodies, of the invention to disrupt tight junctions may be tested in in vitro and in vivo models of high resistance tight junctions and in animal models.
  • Monolayers of MDCK dog kidney epithelial cells, that are known to contain high resistance tight junctions (Gumbiner, B., J. Cell Biol., 102:457
  • Polyclonal antibodies prepared as described above may also be used in conjunction with Western blotting (Old, R.W., et al., Principles of Gene Manipulation, 3d ed., Blackwell, Oxford, 1985, p. 10) and a variety of tissue extracts in order to identify cell adhesion glycoproteins in such extracts.
  • Another embodiment of the present invention is in drug delivery systems.
  • Conjugates between therapeutic drugs and agents that affect cell adhesion molecule function in brain capillary endothelial cells may be used to deliver therapeutic drugs to the CNS.
  • a polypeptide derived from a cell adhesion molecule that contains within its amino acid sequence a cell-binding domain, or antibodies thereto may be conjugated in biologically-active form to a therapeutic modality.
  • Such conjugates may have the dual effect of opening the BBB and delivering the therapeutic agent to the brain side of the BBB. Delivery of therapeutic drugs to the CNS, either alone or conjugated to agents that disrupt cell-cell adhesion, may be accomplished by administering such drugs to a subject either
  • modalities that may be delivered to the brain by the cell adhesion disruption compositions of this invention include Nerve Growth Factor, anti-Parkinsonian drugs, and brain enzymes known to be missing in
  • sphingolipidoses e.g., Tay-Sachs disease.
  • the integrity of the therapeutic agent is not compromised and such that the therapeutic agent is readily cleaved from the carrier by enzymes present on or within endothelial cells (e.g., amidases, esterases,
  • disulfide-cleaving enzymes are well known in the art. It is also apparent that these therapeutic conjugates may be delivered to endothelial cells in encapsulated form (e.g., in liposomes) or as microsuspensions stabilized by pharmacological excipients.
  • compositions that disrupt the junctions between the two tumors develop internal barriers, including high pressure zones and collapsed blood vessels, that make it difficult for blood-borne chemotherapeutic agents to reach the tumor's inner core.
  • the barrier problem is particularly troublesome with therapeutic products drawn from the human immune system, such as monoclonal antibodies conjugated with chemotherapeutic agents, interleukin-2, interferon and activated killer T-lymphocytes, because of their large size.
  • endothelial cells particularly the relatively small peptides that contain one or more cell-binding regions of cell adhesion macromolecules, may be used to enhance drug delivery to tumors with depressed blood flow.
  • compositions of this invention may also be used to provide penetration for chemotherapeutic agents of other well-known blood- tissue barriers, such as blood-testis barriers and blood-retina barriers.
  • the latter barrier is known to prevent the efficient transport of, for example, administered antibiotics to the retina from the general circulation.
  • the cell adhesion disrupting compositions of this invention may, thus, be used in conjunction with the administration of antibiotics to treat retinal infections.
  • the polypeptide was added to the cells either from the apical side (top) or basolateral side (bottom), as shown in the following sketch.
  • BASOLATERAL Figure 7 illustrates the effects of various concentrations of the aforementioned 18-mer polypeptide on resistance of MDCK epithelial cells. At the lowest concentration tested, 0.5 mg/ml, resistance was
  • the polypeptide was more effective when added from the basolateral side, but at high concentrations was quite effective even when added from the apical side. These data indicate that the 18-mer is effective in making tight junctions permeable. The 20-mer was similarly effective, and a 17-mer less effective.
  • Figure 9 illustrates the effect of 1 mg/ml of the 11-mer and 18-mer on high resistance monolayer cultures of brain endothelial cells (see copending United States Serial No. 07/413,332 for method of preparation).
  • the 11-mer (and the 6-mer) failed to reduce resistance values over a 48-hour period of observation.
  • the 18-mer (as well as the 20-mer) decreased resistance values markedly when added from either the basolateral or apical side, but the effect of the polypeptide was more rapid and more pronounced when it was added from the basolateral side; the 17-mer was less effective.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Sont présentées des compositions destinées à briser les jonctions étroites de cellules épithéliales et endothéliales, ainsi que leurs méthodes d'utilisation. De telles compositions comprennent des agents qui inhibent la liaison à des cellules des molécules d'adhérence cellulaire. De tels agents d'inhibition comprennent des molécules d'adhérence cellulaire, des fragments de molécules d'ahdérence cellulaire qui enferment un domaine de liaison cellulaire, comme la HAV, et des anticorps s'opposant aux molécules d'adhérence cellulaire et aux fragments de ces dernières. Sont également présentées des compositions libérant un médicament comprenant un médicament thérapeutique associé à un agent empêchant les jonctions serrées de cellules.
PCT/US1990/005105 1989-09-27 1990-09-13 Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation WO1991004745A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US41333289A 1989-09-27 1989-09-27
US413,332 1989-09-27
US57126790A 1990-08-23 1990-08-23
US571,267 1990-08-23

Publications (1)

Publication Number Publication Date
WO1991004745A1 true WO1991004745A1 (fr) 1991-04-18

Family

ID=27022149

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/005105 WO1991004745A1 (fr) 1989-09-27 1990-09-13 Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation

Country Status (4)

Country Link
EP (1) EP0494175A4 (fr)
JP (1) JPH05500504A (fr)
CA (1) CA2067183A1 (fr)
WO (1) WO1991004745A1 (fr)

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011401A1 (fr) * 1992-11-17 1994-05-26 Yale University Homologue humain du gene de la cadherine e et procedes d'utilisation
WO1994014960A3 (fr) * 1992-12-29 1994-08-18 Doheny Eye Inst Protocaherines, leurs anticorps et emplois
US5340800A (en) * 1990-08-27 1994-08-23 Liu David Y Peptide medicaments for the treatment of disease
EP0493444A4 (en) * 1989-09-27 1994-11-09 Athena Neurosciences Inc Blood-brain barrier model
WO1995013820A1 (fr) * 1993-11-19 1995-05-26 Eisai Co., Ltd. Utilisation d'un agent modulateur de la phosphorylation par la tyrosine, afin de moduler la permeabilite d'une barriere physiologique
US5597725A (en) * 1992-04-17 1997-01-28 Doheny Eye Institute Cadherin-specific antibodies and hybridoma cell lines
US5639634A (en) * 1992-04-17 1997-06-17 Doheny Eye Institute Cadherin polynucleotides
US5646250A (en) * 1992-04-17 1997-07-08 Doheny Eye Institute Cadherin polypeptides
US5708143A (en) * 1992-12-29 1998-01-13 Doheny Eye Institute Protocadherin materials and methods
WO1998002452A3 (fr) * 1996-07-12 1998-03-05 Univ Mcgill Composes et procedes pour la modulation de l'adherence cellulaire
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
WO1998045319A3 (fr) * 1997-04-10 1998-12-17 Univ Mcgill COMPOSES ET PROCEDES PERMETTANT D'INHIBER L'INTERACTION ENTRE L'α-CATENINE ET LA β-CATENINE
WO1999016791A3 (fr) * 1997-09-29 1999-05-20 Adherex Inc Composes et procedes de regulation d'adherence cellulaire
WO1999033875A1 (fr) * 1997-12-23 1999-07-08 Mcgill University Composes et procedes servant a moduler la stabilite synaptique
WO1999057149A3 (fr) * 1998-05-05 2000-03-02 Adherex Technologies Inc Composes et procedes servant a moduler des fonctions etablies par l'intermediaire de cadherine non classique
US6033665A (en) * 1989-09-27 2000-03-07 Elan Pharmaceuticals, Inc. Compositions and methods for modulating leukocyte adhesion to brain endothelial cells
WO2000002917A3 (fr) * 1998-07-10 2000-05-04 Adherex Technologies Inc Composes permettant de moduler des fonctions induites par la cadherine et techniques afferentes
WO2000062815A3 (fr) * 1999-04-15 2001-02-08 Glaxo Group Ltd Nouvelle composition pharmaceutique utilisable en therapie genique
US6207639B1 (en) 1996-07-12 2001-03-27 Mcgill University Compounds and methods for modulating neurite outgrowth
US6333307B1 (en) * 1996-07-12 2001-12-25 Mcgill University Compounds and method for modulating neurite outgrowth
US6339060B1 (en) 1990-11-01 2002-01-15 Oregon Health & Science University Conjugate of biologically active compound and polar lipid conjugated to a microparticle for biological targeting
US6346512B1 (en) 1996-07-12 2002-02-12 Mcgill University Compounds and methods for modulating cell adhesion
US6358920B1 (en) 1998-05-05 2002-03-19 Adherex Technologies Compounds and methods for modulating nonclassical cadherin-mediated functions
US6417325B1 (en) 1996-07-12 2002-07-09 Mcgill University Compounds and methods for cancer therapy
WO2001092543A3 (fr) * 2000-05-30 2002-09-12 Ich Productions Ltd Procede ameliore de transfection
US6465427B1 (en) 1996-07-12 2002-10-15 Mcgill University Compounds and methods for modulating cell adhesion
US6465007B1 (en) 1998-07-02 2002-10-15 Genzyme Corporation Transgene expression in polarized cells
US6562786B1 (en) 1996-07-12 2003-05-13 Mcgill University Compounds and methods for modulating apoptosis
US6593297B2 (en) 1998-05-05 2003-07-15 Adherex Technologies, Inc. Compounds and methods for inhibiting cancer metastasis
US6610821B1 (en) 1996-07-12 2003-08-26 Mcgill University Compounds and methods for modulating endothelial cell adhesion
US6638911B1 (en) 1998-05-05 2003-10-28 Adherex Technologies Inc. Compounds and methods for modulating desmosomal cadherin-mediated functions
US7122623B2 (en) 1996-07-12 2006-10-17 Adherex Technologies, Inc. Compounds and methods for modulating cell adhesion
US7244764B2 (en) 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7268115B2 (en) 2000-01-24 2007-09-11 Adherex Technologies, Inc. Peptidomimetic modulators of cell adhesion
WO2006088491A3 (fr) * 2004-06-29 2007-09-27 Massachusetts Inst Technology Procedes et compositions concernant la modulation de jonctions intercellulaires
US7414076B2 (en) 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7452537B2 (en) 2005-04-26 2008-11-18 Agouron Pharmaceuticals, Inc. P-cadherin antibodies
US7476509B2 (en) 2002-11-14 2009-01-13 Adherex Technologies Inc. Compounds and methods for modulating functions of nonclassical cadherins
US7481999B2 (en) 1998-05-05 2009-01-27 Adherex Technologies, Inc. Compounds and methods for modulating OB-cadherin-mediated function
WO2010035261A2 (fr) 2008-09-29 2010-04-01 Ben Gurion University Of The Negev Research And Development Authority Beta-peptides amyloides et procédés d'utilisation associés
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US9688727B2 (en) 2013-09-24 2017-06-27 University Of Washington Desmoglein 2 (DSG2) binding proteins and uses therefor
WO2018081454A1 (fr) * 2016-10-26 2018-05-03 Duke Universtiy Biomarqueurs et traitements destinés au cancer métastatique
WO2018226992A1 (fr) 2017-06-07 2018-12-13 Adrx, Inc. Inhibiteur d'agrégation de tau
WO2019036725A2 (fr) 2017-08-18 2019-02-21 Adrx, Inc. Inhibiteurs peptidiques d'agrégation de tau

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4671958A (en) * 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4866042A (en) * 1987-11-18 1989-09-12 Neuwelt Edward A Method for the delivery of genetic material across the blood brain barrier

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4671958A (en) * 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Development Biology, Volume 139, No. 1, issued May 1990, O.W. BLASCHUK et al., "Identification of a Cadherin Cell Adhesion Recognition Sequence", pp 227-229, see the entire Document. *
Development, Volume 102, issued April 1988, M. TAKEICHI, "The Cadherins: Cell-cell Adhesion Molecules controlling Animal Morphogenesis", pp. 639-655 see the Summary and pages 643, 645 and 651. *
See also references of EP0494175A4 *
The EMBO Journal, Volume 4, No. 13A, issued December 1985, VESTWEBEN et al., "Identification of a Putative Cell Adhesion Domain of Uvomorulin", pp. 3393-3398. See the Abstract and Discussion. *
The EMBO Journal, Volume 6, No. 12, issued 1987, M. RINGWALD et al., "The Structure of Cell Adhesion Molecule Uvomorulin Insights into the Molecular Mechanism of Ca---dependent Cell Adhesion", pp 3347-3353, see page 3647-3648. *
The Journal of Cell Biology, Volume 107, issued October 1988, B. GUMBINER et al., "The Role of the Cell Adhesion Molecule Uvomorulin in the Formation and Maintenance of the Epithelial Junctional Complex", pp. 1575-1587 see the Abstract. *

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6033665A (en) * 1989-09-27 2000-03-07 Elan Pharmaceuticals, Inc. Compositions and methods for modulating leukocyte adhesion to brain endothelial cells
EP0493444A4 (en) * 1989-09-27 1994-11-09 Athena Neurosciences Inc Blood-brain barrier model
US5340800A (en) * 1990-08-27 1994-08-23 Liu David Y Peptide medicaments for the treatment of disease
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6024977A (en) * 1990-11-01 2000-02-15 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6339060B1 (en) 1990-11-01 2002-01-15 Oregon Health & Science University Conjugate of biologically active compound and polar lipid conjugated to a microparticle for biological targeting
US6436437B1 (en) 1990-11-01 2002-08-20 Oregon Health And Science University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6858582B2 (en) 1990-11-01 2005-02-22 Oregon Health And Sciences University Composition containing porous microparticle impregnated with biologically-active compound for treatment of infection
US5597725A (en) * 1992-04-17 1997-01-28 Doheny Eye Institute Cadherin-specific antibodies and hybridoma cell lines
US5646250A (en) * 1992-04-17 1997-07-08 Doheny Eye Institute Cadherin polypeptides
US5639634A (en) * 1992-04-17 1997-06-17 Doheny Eye Institute Cadherin polynucleotides
EP2325203A2 (fr) 1992-04-17 2011-05-25 Doheny Eye Institute Eléments et procédés permettant la production de cadherines
WO1994011401A1 (fr) * 1992-11-17 1994-05-26 Yale University Homologue humain du gene de la cadherine e et procedes d'utilisation
US5798224A (en) * 1992-12-29 1998-08-25 Doheny Eye Institute Nucleic acids encoding protocadherin
US5708143A (en) * 1992-12-29 1998-01-13 Doheny Eye Institute Protocadherin materials and methods
US5891706A (en) * 1992-12-29 1999-04-06 Doheny Eye Institute Human protocadherin-43 antibodies
US6262237B1 (en) 1992-12-29 2001-07-17 Doheny Eye Institute Methods of antagonizing the binding of protocadherin-42
WO1994014960A3 (fr) * 1992-12-29 1994-08-18 Doheny Eye Inst Protocaherines, leurs anticorps et emplois
WO1995013820A1 (fr) * 1993-11-19 1995-05-26 Eisai Co., Ltd. Utilisation d'un agent modulateur de la phosphorylation par la tyrosine, afin de moduler la permeabilite d'une barriere physiologique
US6312686B1 (en) 1993-11-19 2001-11-06 Eisai Co., Ltd. Modulating the permeability of a physiological barrier with an agent that modulates tyrosine phosphorylation
US7423010B2 (en) 1994-05-19 2008-09-09 Oregon Health & Science University Nonporous microparticle-prodrug conjugates for treatment of infection
US6169071B1 (en) 1996-07-12 2001-01-02 Mcgill University Compounds and methods for modulating cell adhesion
US6417325B1 (en) 1996-07-12 2002-07-09 Mcgill University Compounds and methods for cancer therapy
US6207639B1 (en) 1996-07-12 2001-03-27 Mcgill University Compounds and methods for modulating neurite outgrowth
WO1998002452A3 (fr) * 1996-07-12 1998-03-05 Univ Mcgill Composes et procedes pour la modulation de l'adherence cellulaire
US7138369B2 (en) 1996-07-12 2006-11-21 Mcgill University Compounds and methods for modulating apoptosis
US6610821B1 (en) 1996-07-12 2003-08-26 Mcgill University Compounds and methods for modulating endothelial cell adhesion
US6326352B1 (en) 1996-07-12 2001-12-04 Mcgill University Compounds and methods for modulating cell adhesion
US6333307B1 (en) * 1996-07-12 2001-12-25 Mcgill University Compounds and method for modulating neurite outgrowth
US6562786B1 (en) 1996-07-12 2003-05-13 Mcgill University Compounds and methods for modulating apoptosis
US6346512B1 (en) 1996-07-12 2002-02-12 Mcgill University Compounds and methods for modulating cell adhesion
US7122623B2 (en) 1996-07-12 2006-10-17 Adherex Technologies, Inc. Compounds and methods for modulating cell adhesion
US6780845B2 (en) 1996-07-12 2004-08-24 Mcgill University Compounds and methods for cancer therapy
US6914044B2 (en) 1996-07-12 2005-07-05 Mcgill University Compounds and methods for modulating cell adhesion
US6465427B1 (en) 1996-07-12 2002-10-15 Mcgill University Compounds and methods for modulating cell adhesion
US6967238B2 (en) 1996-07-12 2005-11-22 Mcgill University Compounds and methods for modulating cell adhesion
US7063842B2 (en) 1997-04-10 2006-06-20 Mcgill University Compounds and methods for inhibiting the interaction between α-catenin and β-catenin
WO1998045319A3 (fr) * 1997-04-10 1998-12-17 Univ Mcgill COMPOSES ET PROCEDES PERMETTANT D'INHIBER L'INTERACTION ENTRE L'α-CATENINE ET LA β-CATENINE
US6551994B1 (en) 1997-04-10 2003-04-22 Mcgill University Compounds and methods for inhibiting the interaction between α-catenin and β-catenin
WO1999016791A3 (fr) * 1997-09-29 1999-05-20 Adherex Inc Composes et procedes de regulation d'adherence cellulaire
US6203788B1 (en) 1997-09-29 2001-03-20 Adherex Inc. Compounds and methods for regulating cell adhesion
US7326686B2 (en) 1997-09-29 2008-02-05 Adherex Inc. Compounds and methods for regulating cell adhesion
WO1999033875A1 (fr) * 1997-12-23 1999-07-08 Mcgill University Composes et procedes servant a moduler la stabilite synaptique
US6569996B1 (en) 1998-05-05 2003-05-27 Adherex Technologies, Inc. Antibody that specifically binds to the cadherin-5 cell adhesion recognition sequence
US6358920B1 (en) 1998-05-05 2002-03-19 Adherex Technologies Compounds and methods for modulating nonclassical cadherin-mediated functions
US6638911B1 (en) 1998-05-05 2003-10-28 Adherex Technologies Inc. Compounds and methods for modulating desmosomal cadherin-mediated functions
US6680175B2 (en) 1998-05-05 2004-01-20 Adherex Technologies, Inc. Methods for diagnosing and evaluating cancer
US6682901B2 (en) 1998-05-05 2004-01-27 Adherex Technologies, Inc. Methods for diagnosing and evaluating cancer
US6472367B1 (en) 1998-05-05 2002-10-29 Adherex Technologies, Inc. Compounds and methods for modulating OB-cadherin mediated cell adhesion
US7481999B2 (en) 1998-05-05 2009-01-27 Adherex Technologies, Inc. Compounds and methods for modulating OB-cadherin-mediated function
US6593297B2 (en) 1998-05-05 2003-07-15 Adherex Technologies, Inc. Compounds and methods for inhibiting cancer metastasis
US6962969B2 (en) 1998-05-05 2005-11-08 Adherex Technologies, Inc. Compounds and methods for modulating nonclassical cadherin-mediated functions
WO1999057149A3 (fr) * 1998-05-05 2000-03-02 Adherex Technologies Inc Composes et procedes servant a moduler des fonctions etablies par l'intermediaire de cadherine non classique
US6433149B1 (en) 1998-05-05 2002-08-13 Adherex Technologies, Inc. Compounds and methods for inhibiting cancer metastasis
US6465007B1 (en) 1998-07-02 2002-10-15 Genzyme Corporation Transgene expression in polarized cells
US6277824B1 (en) 1998-07-10 2001-08-21 Adherex Technologies Compounds and methods for modulating adhesion molecule function
US6806255B2 (en) 1998-07-10 2004-10-19 Adherex Technologies, Inc. Compounds and methods for modulating adhesion molecule function
US6472368B1 (en) 1998-07-10 2002-10-29 Adherex Technologies, Inc. Compounds and methods for modulating adhesion molecule function
WO2000002917A3 (fr) * 1998-07-10 2000-05-04 Adherex Technologies Inc Composes permettant de moduler des fonctions induites par la cadherine et techniques afferentes
WO2000062815A3 (fr) * 1999-04-15 2001-02-08 Glaxo Group Ltd Nouvelle composition pharmaceutique utilisable en therapie genique
US7446120B2 (en) 2000-01-24 2008-11-04 Adherex Technologies, Inc. Peptidomimetic modulators of cell adhesion
US7268115B2 (en) 2000-01-24 2007-09-11 Adherex Technologies, Inc. Peptidomimetic modulators of cell adhesion
WO2001092543A3 (fr) * 2000-05-30 2002-09-12 Ich Productions Ltd Procede ameliore de transfection
US7476509B2 (en) 2002-11-14 2009-01-13 Adherex Technologies Inc. Compounds and methods for modulating functions of nonclassical cadherins
US7414076B2 (en) 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7244764B2 (en) 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7598269B2 (en) 2003-06-23 2009-10-06 Bellus Health (International) Limited Methods and compositions for treating amyloid-related diseases
WO2006088491A3 (fr) * 2004-06-29 2007-09-27 Massachusetts Inst Technology Procedes et compositions concernant la modulation de jonctions intercellulaires
US8529889B2 (en) 2004-06-29 2013-09-10 Massachusetts Institute Of Technology Methods and compositions related to the modulation of intercellular junctions
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US7452537B2 (en) 2005-04-26 2008-11-18 Agouron Pharmaceuticals, Inc. P-cadherin antibodies
US8974781B2 (en) 2005-04-26 2015-03-10 Pfizer Inc. P-cadherin antibodies
US7928214B2 (en) 2005-04-26 2011-04-19 Agouron Pharmaceuticals, Inc. P-cadherin antibodies
US10238611B2 (en) 2006-10-12 2019-03-26 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10857109B2 (en) 2006-10-12 2020-12-08 Bellus Health, Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US11020360B2 (en) 2006-10-12 2021-06-01 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
WO2010035261A2 (fr) 2008-09-29 2010-04-01 Ben Gurion University Of The Negev Research And Development Authority Beta-peptides amyloides et procédés d'utilisation associés
US9688727B2 (en) 2013-09-24 2017-06-27 University Of Washington Desmoglein 2 (DSG2) binding proteins and uses therefor
US10150798B2 (en) 2013-09-24 2018-12-11 University Of Washington Through Its Center For Commercialization Desmoglein 2 (DSG2) binding proteins and uses therefor
US10611803B2 (en) 2013-09-24 2020-04-07 University Of Washington Through Its Center For Commercialization Desmoglein 2 (DSG2) binding proteins and uses therefor
US11248028B2 (en) 2013-09-24 2022-02-15 University Of Washington Through Its Center For Commercialization Desmoglein 2 (DSG2) binding proteins and uses therefor
US11820795B2 (en) 2013-09-24 2023-11-21 University Of Washington Desmoglein 2 (DSG2) binding proteins and uses therefor
WO2018081454A1 (fr) * 2016-10-26 2018-05-03 Duke Universtiy Biomarqueurs et traitements destinés au cancer métastatique
WO2018226992A1 (fr) 2017-06-07 2018-12-13 Adrx, Inc. Inhibiteur d'agrégation de tau
WO2019036725A2 (fr) 2017-08-18 2019-02-21 Adrx, Inc. Inhibiteurs peptidiques d'agrégation de tau

Also Published As

Publication number Publication date
EP0494175A1 (fr) 1992-07-15
CA2067183A1 (fr) 1991-03-28
EP0494175A4 (en) 1993-05-05
JPH05500504A (ja) 1993-02-04

Similar Documents

Publication Publication Date Title
WO1991004745A1 (fr) Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation
Escribano et al. cDNA from human ocular ciliary epithelium homologous to βig‐h3 is preferentially expressed as an extracellular protein in the corneal epithelium
JP3520272B2 (ja) リンパ球機能関連抗原３のｃｄ２結合ドメイン
JP3253064B2 (ja) ウイルスの感染性を阻止するヒトライノウイルス受容体タンパク質
KR100586202B1 (ko) ανβ6 길항제로의 급성 폐 상해 및 섬유증의 치료방법
EP1297013B1 (fr) Taci utilisee en tant qu'agent antitumoral
JPH04502859A (ja) 内皮細胞―白血球付着分子（ｅｌａｍ）および白血球付着に関与する分子（ｍｉｌａ）
JPH09505725A (ja) セマホリン遺伝子群
JP2011135886A (ja) Ｎｏｔｃｈタンパク質およびＤｅｌｔａタンパク質中の結合ドメイン
KR100543730B1 (ko) 종양 괴사 인자 관련 리간드
JPH11500128A (ja) 抗トランスフォーミング増殖因子β遺伝子治療
IL96907A (en) Proteins produced by human lymphocytes a dna sequence coding for said proteins and their pharmaceutical and biological application
JP2003159088A (ja) 組換えトロンビンレセプターおよびそれに関連した薬剤
JP2010065045A (ja) Ｒｇｍおよびそのモジュレーターの用途
JPH05508308A (ja) 血小板細胞付着分子とその変種
CA2156395A1 (fr) Regions regulatrices des proteines g
US20190008897A1 (en) Compositions and methods for producing pro-inflammatory macrophages
Finnemann et al. Cadherin transfection of Xenopus XTC cells downregulates expression of substrate adhesion molecules
CA2247067C (fr) Meltrines
JP2003531120A (ja) 内皮細胞接着を調節するための組成物および方法
US20030087811A1 (en) Compounds and methods for cancer therapy
JPH07502495A (ja) 特定種のｌｆａ−３またはｃｄ２結合蛋白質を投与することによる同種移植または異種移植の寛容性を改善するための方法
KR100335348B1 (ko) 종양 혈관신생 억제기능을 가지는 살모신을 유효성분으로 함유하는 항암제
WO1998016241A1 (fr) Procede servant a perturber l'adhesion cellulaire
WO1998016241A9 (fr) Procede servant a perturber l'adhesion cellulaire

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 2067183

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1990913684

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1990913684

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1990913684

Country of ref document: EP