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WO1991018010A1 - Inhibition d'infection virale a l'aide de peptides analogues a la molecule-1 d'adhesion intercellulaire et/ou d'analogues de ces peptides - Google Patents

Inhibition d'infection virale a l'aide de peptides analogues a la molecule-1 d'adhesion intercellulaire et/ou d'analogues de ces peptides Download PDF

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Publication number
WO1991018010A1
WO1991018010A1 PCT/AU1991/000204 AU9100204W WO9118010A1 WO 1991018010 A1 WO1991018010 A1 WO 1991018010A1 AU 9100204 W AU9100204 W AU 9100204W WO 9118010 A1 WO9118010 A1 WO 9118010A1
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Prior art keywords
peptide
icam
analogue
amino acid
corresponds
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PCT/AU1991/000204
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English (en)
Inventor
John Vincent Fecondo
Andrew Wallace Boyd
Stephen Brian Henry Kent
Dale Alan Mcphee
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Swinburne Limited
The Walter And Eliza Hall Institute Of Medical Research
The California Institute Of Technology
Macfarlane Burnet Centre For Medical Research Limited
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Application filed by Swinburne Limited, The Walter And Eliza Hall Institute Of Medical Research, The California Institute Of Technology, Macfarlane Burnet Centre For Medical Research Limited filed Critical Swinburne Limited
Publication of WO1991018010A1 publication Critical patent/WO1991018010A1/fr

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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
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70525—ICAM molecules, e.g. CD50, CD54, CD102
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2821—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against ICAM molecules, e.g. CD50, CD54, CD102
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to Intercellular Adhesion Molecule-1-like peptides, analogues thereof and antibodies thereto, to pharmaceutical compositions comprising same and the use thereof to inhibit or reduce infection of mammalian cells by retroviruses, and in particular to inhibit or reduce infection of human cells by HIV or its variants.
  • ICAM-1 Leukocyte Function Associated antigen-1
  • LFA-1 Leukocyte Function Associated antigen-1
  • HIV human immunodeficiency virus
  • the infection process involves binding of infectious virus or virus-infected cells, through the surface glycoprotein involved in binding, to the CD4 receptor on susceptible cells. After binding, entry involves fusion of the virus or virus-infected cell to the susceptible cell at least via the HIV transmembrane glycoprotein (Kowalski et al., 1987), possibly with other molecules being involved.
  • HIV-induced cytopathology After infection "in vitro", two types of HIV-induced cytopathology are observed. The first involves fusion of the plasma membrane of an infected cell with the plasma membranes of other CD4+ cells. Multiple rounds of cell- cell fusion result in the formation of giant, multinucleated cells which are generally observed to be in some stage of "balloon" degeneration (Lifson et al. , 1986). This effect is called syncytium formation. The second type of HIV-induced cytopathology involves lysis of individual cells (Somasun mich and Robinson, 1988). Both of these mechanisms have been postulated to account for the loss of CD4+ cells "in vivo".
  • ICAM-1-like peptides are directed to ICAM-1-like peptides and to analogues thereof.
  • ICAM-like peptides as used in the specification and claims is meant a peptide, or a polypeptide, having an amino acid sequence substantially similar to, or identical with, a region of ICAM-1 and capable of reducing, inhibiting and/or interfering with retroviral replication in mammalian cells and in particular replication of HIV or its variants in human cells.
  • An amino acid sequence substantially similar to a region of ICAM-1 includes sequences having greater than 70% homology and preferably greater than 80% homology with the selected ICAM-1 region.
  • the ICAM-1-like peptides may have an amino acid sequence identical with the corresponding sequence in ICAM-1 or may contain single or multiple amino acid additions, deletions and/or substitutions compared to the amino acid sequence of the particular region of ICAM-1.
  • the peptides contemplated herein may be chemically synthesized such as by solid phase peptide synthesis or may be prepared by subjecting the ICAM-1 polypeptide to hydrolysis or other chemically disruptive processes whereby fragments of the molecule are produced. Alternatively, the peptides could be made in vitro or in vivo using recombinant DNA technology.
  • the peptides may need to be synthesized in combination with other proteins and then subsequently isolated by chemical cleavage or the peptides may be synthesized in multiple repeat units.
  • multiple antigen peptides could also be prepared according to Tarn (1988). The selection of a method of producing the subject peptides will depend on factors such as the required type, quantity and purity of the peptides as well as ease of production and convenience.
  • analogues extends to any functional chemical equivalent of an ICAM- 1-like peptide characterized by its increased stability and/or efficacy in vivo or in vitro in respect of the ability to reduce, inhibit and/or interfere with HIV replication.
  • Analogues of ICAM-1-like peptides contemplated herein include, but are not limited to, modifications to side chains, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of crosslinkers and other methods which impose conformational constraints on the peptides or their analogues.
  • side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH ⁇ amidination with ethylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5'-phosphate followed by reduction with NaBH .
  • modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH ⁇ amidination with ethylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulphonic acid (TNBS);
  • the guanidino group of arginine residues may be modified by the formation of hetero ⁇ yclic condensation products with reagents such as 2, 3 butanedione, phenylglyoxal and glyoxal.
  • the carboxyl group may be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivatisation, for example, to a corresponding amide.
  • Sulphydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoa ⁇ etamide; performic acid oxidation to cysteic acid; formation of a mixed disulphide with other thiol compounds; reaction with maleimide, alaic anhydride or other substituted maleimide; formation of mercurial derivatives using 4- chloromercuribenzoate, 4-chloromercuriphenylsulphonic acid, phenylmercury chloride, 2-chloromercuric-4- nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH.
  • Tryptophan residues may be modified by, for example, oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides.
  • Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.
  • Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate.
  • Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4- amino-3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.
  • peptides could be conformationally constrained by, for example, incorporation of C ⁇ - and N ⁇ -methylamino acids, introduction of double bonds between C ⁇ and C p atoms of amino acids and of cyclic peptides or analogues by introducing covalent bonds such as forming an amide bond between the N and C termini, between two side chains or between a side chain and the N or C terminus.
  • the present invention extends to peptides and/or polypeptides and functional and/or chemical analogues corresponding to regions of ICAM-1 and which are capable of reducing, inhibiting and/or interfering with retroviral (e.g. HIV) replication.
  • ICAM-1-like peptide in the specification and claims herein is intended to include all such amino acid and chemical analogues of ICAM-1-like peptides broadly described above.
  • analogues include ICAM-1-like peptides in tandem or multiple repeats wherein each repeat is the same peptide or a different ICAM-1-like peptide. Such tandem or multiple repeat molecules may first need to be cleaved before becoming active.
  • the ICAM-1-like peptides may be a part of a larger molecule wherein the larger molecule may or may not be related to the native ICAM-1 polypeptide. Conveniently, however, larger fragments of ICAM-1 which include the preferred amino acid sequences are used.
  • the ICAM-like peptides correspond to amino acids in one or more of the amino acid regions 1 to 43, 460 to 507, 340 to 420 and/or 101 to 150 of ICAM-1. More preferably, the ICAM-like peptides correspond to amino acids in one or more of the amino acid regions 1 to 23, 367 to 394, 479 to 507 and/or 114 to 141 of ICAM-1.
  • the foregoing amino acid positions are according to Simmons et al. , (1988).
  • the present invention provides inter alia the following ICAM-1-like peptides:
  • JF7B having the amino acid sequence:
  • JF9 having the amino acid sequence:
  • JF10 having the amino acid sequence: GGAPRANLTWLLRGEKELKREPAVGEP and its amino acid and chemical analogues;
  • JFI3A having the amino acid sequence:
  • ICAM-1-like peptides inhibit HIV infection.
  • the subject peptides may act in one or more of the following ways:
  • ICAM-1-like peptide JF7B displayed the most marked effect on HIV infection and syncytia formation and, hence, indicates the importance of the amino terminus of the ICAM-1 molecule for HIV replication.
  • the amino terminus of ICAM-1 may, for example, interfere with fusion preventing LFA-1/HIV transmembrane glycoprotein interactions.
  • the present invention is also directed to ICAM-1-like peptides and/or their chemical analogues capable of interfering with HIV replication.
  • the subject ICAM-like peptides and/or their analogues may be useful in inhibiting, reducing and/or interfering with infection by pathogens via the entry process.
  • pathogens via the entry process.
  • One such example is the malaria parasite
  • Plasmodium falciparum extends to the use of ICAM-1-like peptides or their chemical analogues to inhibit or reduce infection by pathogens.
  • Amino acid analogues of JF7B contemplated herein include, but are not necessarily limited to, the following shown in Table 1:
  • AMINO ACID SEQUENCE ICAM-1 SEQUENCE POSITION ACCORDING TO SIMMONS et al. (1988)
  • Amino acid analogues of JF9 contemplated herein include, but are not necessarily limited to, the following shown in Table 2:
  • AMINO ACID SEQUENCE ICAM-1 SEQUENCE POSITION ACCORDING TO SIMMONS et al. (1988)
  • [X] is A or C - 11 -
  • Amino acid analogues of JFIO contemplated herein include, but are not necessarily limited to, the following shown in Table 3:
  • AMINO ACID SEQUENCE ICAM-1 SEQUENCE POSITION ACCORDING TO SIMMONS (1988)
  • Amino acid analogues of JF13A contemplated herein include, but are not necessarily limited to, the following shown in Table 4:
  • AMINO ACID SEQUENCE ICAM-1 SEQUENCE POSITION ACCORDING TO SIMMONS et al. (1988)
  • ICAM-1 represented by peptides such as JF7B
  • JF7B has no inhibitory effect upon adhesion in all systems so far tested and, hence, the effect of the ICAM-1-like peptides contemplated herein may be independent of the "normal" LFA-l/ICAM-1 interactions.
  • the present invention also contemplates a method of inhibiting infection of cells by a retrovirus in a mammal comprising administering to said mammal an effective amount of an ICAM-1-like peptide or analogue thereof for a time and under conditions sufficient to inhibit, reduce and/or interfere with the retrovirus replication.
  • the mammal is a human and the retrovirus is HIV or its variants.
  • the HIV may be HIV-1 or HIV-2.
  • Reference hereinafter to "HIV” includes all relevant retroviruses.
  • inhibiting HIV infection includes complete, substantially complete or only partial inhibition of infection. The term may apply to prophylaxis, i.e.
  • HIV infection is applied herein in relation to replication of the virus and syncytia formation since these parameters, up to the present time, represent the most convenient means to monitor infection. It is not the intention, however, to limit the definition of HIV infection to only these parameters since other indicators of infection may be substituted by one skilled in the art without departing from the scope of the present invention.
  • the method of administration will vary depending on the circumstances. Examples of such administration would include intravenous injection or infusion. Depending on the particular ICAM-1-like peptide or analogue used, administration by other routes, such as intranasal, oral, intraperitoneal, sub-cutaneous, rectal, topical or by any means whereby the active molecules can be put in contact with target cells and/or viruses may be possible. In these cases, the peptides or analogues may have to be modified to or co-administered with other molecules to prevent their breakdown or to prolong their half life or to facilitate entry into the bloodstream or target area.
  • the effective amount of ICAM-1-like peptide or its analogue will be that required to reduce, inhibit or interfere with HIV replication and must not be at cytotoxic levels or at least cause only clinically acceptable cytotoxicity.
  • concentration selected will vary depending on the exigencies of the clinical situation but will generally be greater than 0.005 ⁇ M and preferably in the range 0.005-200 ⁇ M.
  • the inclusion of agonists to the ICAM-1-like peptides or their analogues in any therapeutic programme or the inclusion of other molecules having activity against HIV or in promoting the immune system may result in less ICAM-1-like peptide or analogue being required. In such a case, 5nM to lOO ⁇ M may be sufficient.
  • another active agent may be co-administered or sequentially administered to facilitate the treatment and/or activity of the ICAM-1- like peptides or analogues.
  • Such other active agents include anti-viral agents, immune response stimulating agents, cytokines and analogues of ICAM-1-like peptides.
  • the present invention extends to mixtures of two or more different ICAM-1-like peptides and/or their analogues.
  • microorganisms such as normal flora organisms may be engineered to express appropriate amounts of peptide or analogue either as single molecules or as tandem or multiple repeats as discussed above.
  • An example of a suitable microorganism is Escherichia coli.
  • Such organisms and their use in administering the active peptides are encompassed by the present invention.
  • compositions comprising an ICAM-1-like peptide and/or analogue and one or more pharmaceutically acceptable carriers and/or diluents.
  • suitable carrier vehicles and their formulation inclusive of other human proteins, eg. human serum albumin, is described in Remington's Pharmaceutical Sciences 17th ed., Mack Publishing Co., edited by Osol et al. , which is hereby incorporated by reference.
  • compositions may also include additional molecules to stabilize the active agent or which act as agonists or otherwise assist the ICAM-1- peptide and/or its analogue to perform the desired function.
  • the present invention extends to the use of ICAM-1-like peptides and/or its analogues in the manufacture of a medicament for the treatment or prevention of HIV infection in humans.
  • the ICAM-1-peptide and/or its analogue may be in combination with another active agent which will also act against HIV or against the symptoms caused by infection of HIV.
  • ICAM-1-like peptides and/or analogues thereof may be used in combination with soluble CD4 or its derivatives or any other molecule capable of binding, associating and/or otherwise interacting with the HIV surface glycoprotein and/or transmembrane glycoprotein.
  • the ICAM-1-like peptides and/or their analogues may be used in combination with HIV anti-viral compounds and/or a molecule capable of stimulating the immune system.
  • the present invention also extends to the use of ICAM-1- like peptides and/or analogues thereof to quantitatively or qualitatively detect or screen for LFA-1 receptors on cells in the blood stream or other body fluids.
  • a range of techniques are available which could use the above molecules directly or indirectly via antibodies to same, such as an ELISA or radioimmunoassay.
  • the ICAM-1-like peptide and/or its analogue may also be used in immobilized form to isolate specific LFA-1 expressing cells.
  • the present invention therefore, also extends to monoclonal or polyclonal antibodies to the ICAM-1-like peptides or their analogues.
  • FIG. 1 Analysis of the surface expression of LFA-1 (a and b) and ICAM-1 (c and d) on CEM (a and c) and MT-2 (b and d) cells. Classed matched control antibodies are shown by the dotted line.
  • Figure 3 Inhibition of virus antigen production from CEM/HTLV-III B (a, b and c) or MT-2/228200 (d, e and f) virus-infected cells or mock-infected cells (stripe) in the presence of peptides JF7B (a and d), JF9 (b and e) and JF13A (c and f) at 0 (blank), 10 (cross-hatch) or 100 (black) ⁇ g/ml.
  • Figure 4 Cell morphology of mock-infected (b) and HIV isolate 228200 infected (a and c) MT-2 cells at 8 days post-infection.
  • Panel c is infected cells in the presence of lO ⁇ g/ml peptide JF7B. Magnification in all panels is x200.
  • Figure 5 Inhibition of virus antigen production from HIV isolate 228200 infected MT-2 cells in the presence of W- CAM-1 monoclonal antibody (lO ⁇ g/ml) pre- (heavy stripe), post- (cross-hatch) and pre- and post-infection (black) compared to positive (blank), negative (heavy stiple) and antibody (heavy cross-hatch) controls.
  • the HTLV-I transformed cell line, MT-2 was established by Miyoshi et al. (1981), by the co-cultivation of cells from a patient with adult T-cell leukaemia with normal cord lymphocytes, and provided by Dr. Y. Hinuma, Institute for Virus Research, Kyoto University, Japan.
  • CEM cells are a lymphoblastoid cell line derived by Foley et al. (1965) from an individual with acute lymphoblastic leukaemia.
  • the prototype virus HTLV-III B was obtained from Dr R Gallo, Laboratory of Tumour Cell Biology, National Cancer Institute, Bethesda, U.S.A. and isolate 228200 from a patient attending Fairfield Hospital. The characteristics of the local isolate are described elsewhere (Kiernan et al. , 1990).
  • Peptides were synthesized on an Applied Biosystems automated peptide synthesizer using highly optimized solid phase t-Boc chemistry protocols (Clark-Lewis and Kent, 1989). The peptides were deprotected and cleaved from the resin by S N 1-S N 2 acidolysis in HF according to the methods described by Tarn et al. (1983). Peptides were purified to >95% by preparative reverse phase HPLC using an Aquapore C8 100 x 10 mm 20 micron Prep 10 cartridge column and analysed on Aquapore RP-300 30 x 4.6 mm 7 micron cartridge columns (Applied Biosystems Inc., Santa Clara, CA).
  • Flow Cytometry For flow cytometry cells were incubated with anti-LFA-1 or Fluorescein isothiocyanate (FITC) labelled anti-ICAM-1 MAb followed by FITC-conjugated second antibody for the anti-LFA-1 MAb and analysed by flow cytometry.
  • FITC Fluorescein isothiocyanate
  • Purified peptides were solubilized in distilled water at 10 mg/ml and diluted in RPMI 1640 medium containing 29.2 ⁇ g/ml glutamine, 100 ⁇ g/ml streptomycin, 100 U/ml penicillin, 2 ⁇ g/ml polybrene (polybrene used only for CEM cells) and 10% (v/v) heat inactivated foetal calf serum (RF-10) to working dilution.
  • Cells (4 x 10 5 in 1ml) were pretreated for 1 hour at 37°C with peptide, followed by 1ml of virus at 1000 pfu (Kiernan et al.
  • Flow cytometric analyses of uninfected and HIV-infected CEM/HTLV-III B and MT-2/228200 cells revealed CEM cells to have high expression of LFA-1 (Fig. la) opposed to MT-2 cells which had relatively low expression (Fig. lb).
  • LFA-1 surface expression of ICAM-1 was very low for CEM cells (Fig. lc) compared to MT-2 cells (Fig. Id) where over 90% of cells expressed ICAM-1.
  • the number of cells expressing ICAM-1 increased substantially (13 to 37%) after infection for CEM cells but did not change substantially for MT-2 cells as it was already at a very high level. The levels of expression were similar if different HIV isolates were used.
  • ICAM-like peptides were tested for their effect on HIV replication (Table 4). Three of these (JF7B, JF9 and JF13A) had an effect on HIV replication, with the concentrations tested (10 and 100 ⁇ g/ml), as observed by measuring antigen production in the supernatant over an 8 day period (Fig. 3.) Peptide JF7B showed the most marked inhibition with reduction in antigen production of 94% at 10 ⁇ g/ml and 99% at 100 ⁇ g/ml over the 8 day period tested with isolate 228200 infected MT-2 cells (Fig. 3d). Both peptides JF7B and JF9 showed consistent inhibition of HIV antigen production in both cell lines used with inhibition being dose dependent.
  • JFll PIGESVTVTRDLEGTYLCRARSTQG
  • JF13A PIGESVTVTRDLEGTYLCRARSTQG

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Abstract

La présente invention concerne des peptides analogues à la Molécule-1 d'Adhésion Intercellulaire, des analogues et des anticorps de ces peptides, ainsi que des compositions pharmaceutiques comprenant ces mêmes peptides et leur utilisation pour inhiber ou réduire l'infection de cellules mammifères par des rétrovirus et en particulier pour inhiber ou réduire l'infection de cellules humaines par le VIH ou ses variantes.
PCT/AU1991/000204 1990-05-15 1991-05-14 Inhibition d'infection virale a l'aide de peptides analogues a la molecule-1 d'adhesion intercellulaire et/ou d'analogues de ces peptides WO1991018010A1 (fr)

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US5525487A (en) * 1992-01-27 1996-06-11 Icos Corporation DNA encoding I-CAM related protein
US5532127A (en) * 1992-01-27 1996-07-02 Icos Corporation Assay for 1-CAM related protein expression
US5589453A (en) * 1988-09-01 1996-12-31 Molecular Therapeutics, Inc. Human rhinovirus receptor protein (ICAM-1) that inhibits rhinovirus attachment and infectivity
US5663293A (en) * 1992-01-27 1997-09-02 Icos Corporation ICAM-related protein
WO1997032596A1 (fr) * 1996-03-06 1997-09-12 Boehringer Ingelheim Pharmaceuticals, Inc. Formulation en poudre de molecules a adhesion intracellulaire
US5674982A (en) * 1990-07-20 1997-10-07 Bayer Corporation Multimeric form of human rhinovirus receptor protein
US5686582A (en) * 1990-07-20 1997-11-11 Bayer Corporation Multimeric forms of human rhinovirus receptor protein
US5770686A (en) * 1992-01-27 1998-06-23 Icos Corporation ICAM-related protein fragments
US5773218A (en) * 1992-01-27 1998-06-30 Icos Corporation Method to identify compounds which modulate ICAM-related protein interactions
US5837822A (en) * 1992-01-27 1998-11-17 Icos Corporation Humanized antibodies specific for ICAM related protein
US5843885A (en) * 1994-04-19 1998-12-01 The University Of Kansas ICAM-1/LFA-1 short-chain peptides and method of using same
US5891841A (en) * 1991-06-11 1999-04-06 The Center For Blood Research, Inc. Methods of using intercellular adhesion molecule-3 (ICAM-3), antibodies thereto, and soluble fragments thereof
US5989843A (en) * 1992-01-27 1999-11-23 Icos Corporation Methods for identifying modulators of protein kinase C phosphorylation of ICAM-related protein
US6040176A (en) * 1992-01-27 2000-03-21 Icos Corporation Antibodies to ICAM-related protein
US6075004A (en) * 1996-04-26 2000-06-13 The University Of Kansas Peptide compositions which induce immune tolerance and methods of use
US6107461A (en) * 1990-07-20 2000-08-22 Bayer Corporation Multimeric forms of human rhinovirus receptor and fragments thereof, and method of use
US6566095B1 (en) 1999-06-24 2003-05-20 Johns Hopkins University Compositions and methods for preventing transepithelial transmission of HIV
US6649746B1 (en) 1999-05-07 2003-11-18 University Of Virginia Patent Foundation Biological production of stable glutamine, poly-glutamine derivatives in transgenic organisms and their use for therapeutic purposes
US6818743B1 (en) 1992-01-27 2004-11-16 Icos Corporation I-CAM related protein
WO2004108938A3 (fr) * 2003-06-06 2005-05-12 Ich Productions Ltd Ligands peptidiques
US7132395B1 (en) 1988-09-01 2006-11-07 Bayer Pharmaceuticals Corporation Antiviral methods using human rhinovirus receptor (ICAM-1)
WO2009039990A3 (fr) * 2007-09-11 2009-07-16 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique

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