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WO1997036606A1 - Peptides contraints a sequence de cd4 et procedes d'utilisation associes - Google Patents

Peptides contraints a sequence de cd4 et procedes d'utilisation associes Download PDF

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Publication number
WO1997036606A1
WO1997036606A1 PCT/US1997/004847 US9704847W WO9736606A1 WO 1997036606 A1 WO1997036606 A1 WO 1997036606A1 US 9704847 W US9704847 W US 9704847W WO 9736606 A1 WO9736606 A1 WO 9736606A1
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Prior art keywords
peptide
amino acid
peptides
cell
amino acids
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PCT/US1997/004847
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English (en)
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Mark I. Greene
Xin Zhang
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The Trustees Of The University Of Pennsylvania
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Application filed by The Trustees Of The University Of Pennsylvania filed Critical The Trustees Of The University Of Pennsylvania
Priority to AU25894/97A priority Critical patent/AU2589497A/en
Publication of WO1997036606A1 publication Critical patent/WO1997036606A1/fr

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    • 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
    • C07K14/70514—CD4
    • 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 aromatically modified exocyclic constrained peptides which include an active sequence derived from human CD4 and to methods of using such peptides to modulate CD4-associated protein-protein interactions.
  • the T cell lymphocyte surface protein, CD4 is a transmembrane glycoprotein that acts as an accessory molecule or co-receptor for T cell activation through association with the class II major histocompatibility complex (MHC II) antigens and T cell antigen receptors (TCR) .
  • MHC II major histocompatibility complex
  • TCR T cell antigen receptors
  • the immunoglobulin-like extracellular domains of CD4 contacts nonpolymorphic regions of the MHC II molecules, either in an adhesion interaction or as part of a ternary complex with the TCRs.
  • the cytopiasmic domain of CD4 associates with p56, a sarc-like tyrosine kinase, involved in T cell activation.
  • CD4 Although soluble monomeric CD4 has been unable to inhibit T cell responses, the oligomerization of CD4 may be relevant to T cell activation and may reflect dimerization of the T cell receptor assembly. A variety of studies have demonstrated that different domains and surfaces of CD4 are required for the formation of higher ordered complexes of the CD4 holoreceptor with MHC II molecules .
  • CDRs complementarity determining-like regions
  • AME aromatically modified exocyclic
  • the approach of creating novel synthetic antagonistic receptor complexes may represent a new receptor specific pharmaceutical approach to modulate biological function.
  • the present invention relates to aromatically modified constrained peptides which have an active sequence from human
  • Aromatically modified constrained peptides are constrained peptides which have free aromatic amino acid residues linked to the constrained peptide.
  • aromatically modified peptides of the invention comprise an amino acid sequence that consists of no more than 30 amino acid residues and has the formula:
  • R x is 1-6 amino acid residues, at least one of which is tyrosine or phenylalanine;
  • R 2 is a linking amino acid residue, preferably cysteine
  • R 3 is 0-13 amino acids
  • R 4 is an active sequence of 3-26 amino acids including human CD4 sequences ;
  • R s is 0-13 amino acids
  • R 6 is a linking amino acid residue, preferably cysteine
  • R 7 is 1-6 amino acid residues, at least one of which is tyrosine or phenylalanine; and wherein R 2 and R 6 are bound to each other, thereby forming a cyclic portion which includes R 2 , R 3 , R 4 , R 5 and R 6 with R x and R 7 forming exocyclic portions.
  • the present invention relates to pharmaceutical compositions which comprise peptides of the invention.
  • the present invention relates to methods of inhibiting the oligomerization of membrane bound CD4 in CD4+ cells.
  • the present invention relates to methods of inhibiting the T cell activation.
  • the present invention relates to methods of treating individuals with diseases, disorders and conditions whose causes and/or symptoms that are associated with and/or characterized by T cell activation.
  • U.S. Serial Number 08/257,783 filed June 10, 1994 filed June 10, 1994 is incorporated herein by reference in its entirety.
  • U.S. Serial Number 08/257,783 describes aromatic modified exocyclic constrained peptides generally.
  • the disclosure in U.S. Serial Number 08/257,783 is meant to refer to aromatic modified exocyclic constrained peptides which include active regions derived from human CD4.
  • aromatic modified exocyclic constrained peptides are referred to U.S. Serial Number 08/257,783 for the purposes of this disclosure Applicants includes express description of such peptides having CD4 active regions.
  • Serial Number 08/257,783 is intended to be included in this disclosure and to describe the synthesis of peptides of the present invention. Similarly, the description of the peptides having various sizes in U.S. Serial Number 08/257,783 is intended to specifically describe peptides of the invention having such size limitations.
  • conformationally restricted peptides As used herein, the terms “conformationally restricted peptides”, “constrained peptides” and “conformationally constrained peptides” are used interchangeably and are meant to refer to peptides which, for example through intramolecular bonds, are conformationally stable and remain in a sufficiently constant conformation to maintain the peptide' s level of function and activity more consistently. Many conformationally restricted peptides whose structures are modeled upon the active region of a protein have been shown to have biological active similar to that of the protein.
  • aromatic amino acids and “aromatic amino acid residues” used interchangeably are meant to refer to phenylalanine and tyrosine.
  • exocyclic amino acid residue is meant to refer to amino acid residues which are linked to cyclicized peptide but which are not within the portion of the peptide that makes up the circularized structure.
  • exocyclic portions is meant to refer to an amino acid sequence having one or more amino acid residues which is linked to cyclicized peptide but which are not within the portion of the peptide that makes up the circularized structure.
  • linking amino acid residue is meant to refer to an amino acid residue in an amino acid sequence which when linked to a non-adjacent amino acid residue results in cyclicizing at least a portion of the peptide.
  • active sequence of human CD4 and “active region of human CD4" are used interchangeably and are meant to refer to the amino acid sequences of CDR3, specifically about amino acids 82-89 of the human CD4 molecule and may further include some additional amino acids on either side of the region such as about 80-91.
  • the active region of CD4 is directly involved in CD4 dimerization. In some embodiments, the active region of CD4 may refer to amino acids 45-50.
  • Constrained peptides according to the present invention comprise a cyclic portion which comprises a CD4 active region and which further comprise amino acid residues that have aromatic groups, specifically phenylalanine and tyrosine, linked to, but outside of, the cyclic portion.
  • the peptides of the present invention have the following features: 1) they consist of between 7 and 30 amino acids;
  • the cyclic portion includes a CD4 active sequence, preferably which consists of 3-18 amino acid residues;
  • the cyclic portion is linked to two exocyclic portions
  • each exocyclic portion consists of 1-6 amino acids residues and comprises at least one aromatic amino acid residue.
  • Constrained peptides are typically produced as linear peptides that are then cyclicized by non-peptide bonds, usually disulfide bonds between distally positioned cysteine residues, often N-terminal and C-terminal cysteines.
  • aromatic amino acid residues are provided as exocyclic amino acid residues in association with constrained peptides in order to provide increased interactions between the active sequence of the constrained peptide and other molecules.
  • aromatic amino acids are exocyclic; that is, they are linked to the constrained peptides but are not within the cyclicized portion of the molecule.
  • Peptides may be constrained by any of several well known means.
  • disulfide bonds between two non-adjacent cysteines cyclicize and thereby conformationally restrict the peptide.
  • the cyclization of linear peptides using disulfide bonds between non-adjacent cysteines is well known.
  • other non-adjacent amino acid residues may be linked to cyclicize a peptide sequence and the means to do so are similarly well known.
  • Other methods of cyclization include those described by Di Blasio, et al . , (1993) Biopolymers, 33:1037-1049; Wood, et al . , (1992) J. Pep . Prot . Res .
  • the cyclized portion consists of 5 to 25 amino acid residues. In some preferred embodiments, the cyclized portion is 9 to 20 amino acid residues. In some preferred embodiments, the cyclized portion is 8 to 12 amino acid residues. In some preferred embodiments, the cyclized portion is 10 to 20 amino acid residues. In some preferred embodiments, the cyclized portion is 12 to 16 amino acid residues. It is contemplated that the active sequence of the cyclized portion consists of at least 3 amino acid residues. In some preferred embodiments, the active sequence of the cyclized portion is at least 4 to 12 amino acid residues. In some preferred embodiments, the active sequence of the active sequence of the cyclized portion is at least 6 to 10 amino acid residues. In some preferred embodiments, the active sequence of the cyclized portion is at least 6 to 8 amino acid residues.
  • each exocyclic portion is linked to two exocyclic portions.
  • each exocyclic portion is an amino acid sequence consisting of 1-6 aromatic amino acid residues linked to the cyclic portion but not within the cyclicized conformationally restricted peptide.
  • Each exocyclic portion extends out from the cyclic portion and comprises at least one aromatic amino acid residue.
  • each exocyclic portion consists of one amino acid residue.
  • one exocyclic portion consists of one amino acid residue and the other exocyclic portion consists of 1-6 amino acid residues.
  • one exocyclic portion consists of 1-3 amino acid residues and the other exocyclic portion consists of 1-6 amino acid residues.
  • each exocyclic portion consists of a single aromatic amino acid residue.
  • each exocyclic portion comprises a single aromatic amino acid residue. It is preferred that the exocyclic residues are linked to the residues furthest from the active sequence. In some embodiments, it is preferred that the exocyclic residues occupy the N- and C-terminal positions and that the bonds are formed between the second and penultimate residues which cyclicized the remainder of the peptide, providing the N- and C-terminal residues as exocyclic residues.
  • the second and penultimate residues are cysteines which are linked by disulfide bonds.
  • one of either the N- and C-terminal residues is phenylalanine and the other is tyrosine.
  • bonds which result in cyclization of a portion of the peptide are formed between one of the second, third, fourth, fifth, sixth or seventh residues and one of the penultimate, third to last, fourth to last, fifth to last, sixth to last residues or seventh to least residue.
  • the binding of non adjacent residues forms the cyclized portion of the constrained peptide which has two exocyclic sequences of exocyclic amino acid residues between 1 and 6 residues each, respectively.
  • Peptides can be synthesized by those having ordinary skill in the art using well known techniques and readily available starting materials.
  • references to synthesizing or constructing peptides is herein construed to refer to the production of peptides similar in sequence or structure to the corresponding regions identified by the method of the invention.
  • These peptides may be produced using any method known in the art, including, but not limited to, chemical synthesis as well as biological synthesis in an in vi tro or in vivo in a eukaryotic or prokaryotic expression system.
  • peptides of the invention are produced by solid phase synthesis techniques as taught by Merryfield, (1963) J. Am. Chem . Soc , 15:2149-2154 and J. Stuart and J.D. Young, Solid Phase Peptide Synthelia , Pierce Chemical Company, Rockford, IL (1984) , each of which is incorporated herein by reference.
  • the present invention relates to methods of using the aromatically modified exocyclic CD4 (AME-CD4) constrained peptides of the present invention.
  • AME-CD4 constrained peptides bind to CD4 on cells and prevent the CD4 molecules from interacting with other molecules.
  • the oligomerization of CD4 with other molecules is associated with activating CD4* cells. Accordingly, AME-CD4 constrained peptides may be administered to individuals in order to prevent or inhibit activation of CD4 + cells.
  • the present invention relates to methods of treating individuals with diseases, disorders and conditions whose causes and/or symptoms that are associated with and/or characterized by T cell activation.
  • Diseases, disorders and conditions which can be treated using the pharmaceutical compositions that comprise AME-CD4 constrained peptides of the invention include psoriasis, contact dermatitis, ocular inflammation, allogenic grafts, immunological suppression, and HIV treatment .
  • compositions of the present invention may be administered by any means that enables the active agent to reach the agent's site of action in the body of a mammal.
  • Topical or parenteral administration i.e., intravenous, subcutaneous, intramuscular, ordinarily are used to optimize absorption.
  • pharmaceutical compositions which comprise the compounds of the present invention are administered topically or as a lavage for treatment of psoriasis, contact dermatitis or ocular inflammation.
  • pharmaceutical compositions which comprise the compounds of the present invention are administered systemically by parenteral administration for treatment of allogenic grafts, immunological suppression such as in the case of preventing organ or tissue rejection in transplantation procedures, and HIV infection.
  • compositions of the present invention may be administered either as individual therapeutic agents or in combination with other therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a daily dosage of active ingredient can be about 0.001 to 1 grams per kilogram of body weight, in some embodiments about 0.1 to 100 milligrams per kilogram of body weight.
  • ordinarily dosages are in the range of 0.5 to 50 milligrams per kilogram of body weight, and preferably 1 to 10 milligrams per kilogram per day.
  • the pharmaceutical compositions are given in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.
  • Dosage forms (composition) suitable for internal administration generally contain from about 1 milligram to about 500 milligrams of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95 by weight based on the total weight of the composition.
  • the compound can be formulated as a solution, suspension, emulsion or lyophilized powder in association with a pharmaceutically acceptable parenteral vehicle.
  • a pharmaceutically acceptable parenteral vehicle examples include water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used.
  • the vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives) .
  • the formulation is sterilized by commonly used techniques. Suitable pharmaceutical carriers are described in the most recent edition of Remington ' s Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
  • a parenteral composition suitable for administration by injection is prepared by dissolving 1.5% by weight of active ingredient in 0.9% sodium chloride solution.
  • the AME-CD4 constrained peptides may be administered to tissue of an individual by topically or by lavage.
  • the AME-CD4 constrained peptides may be formulated as a cream, ointment, salve, douche, suppository or solution for topical administration or irrigation. Formulations for such routes administration of pharmaceutical compositions are well known.
  • additives for isotonicity can include sodium chloride, dextrose, mannitol, sorbitol and lactose.
  • isotonic solutions such as phosphate buffered saline are used.
  • Stabilizers include gelatin and albumin.
  • a vasoconstriction agent is added to the formulation.
  • the pharmaceutical preparations according to the present invention are preferably provided sterile and pyrogen free.
  • a pharmaceutically acceptable formulation will provide the active ingredient (s) in proper physical form together with such excipients, diluents, stabilizers, preservatives and other ingredients as are appropriate to the nature and composition of the dosage form and the properties of the drug ingredient (s) in the formulation environment and drug delivery system.
  • the active ingredients can be formulated as a single phase or two-phase system, and in liquid, solid or semisolid dosage form, for example, cream, gel, emulsion, suspension, ointment, suppository, tablet.
  • the formulation vehicle may be aqueous, oleaginous, or an oil-in-water or water-in-oil emulsion, preferably water/oil.
  • the active ingredients may be formulated in sterile water or saline.
  • CD4 complementarity determining-like regions
  • Dl first domain of human CD4
  • the three CDR loops are juxtaposed along one surface of the molecule.
  • a new class of constrained forms of peptides was developed. The forms have been cyclized and constrained with cysteine disulfide bridges in order to preserve the predicted configuration of the adjacent CDR turn reversals, aromatic residues were added to the termini of the cyclic constructs to improve binding efficacy.
  • CDR3.AME(82-89) inhibits CD4 binding to MHC II ⁇ fragment (134- 148) .
  • competition binding assays were performed. Different species of the CD4.AME analogs were tested for their ability to inhibit the binding of the recombinant soluble 125 I-labeled human MHC II DR4 molecules produced in insect cells to immobilized recombinant soluble CD4 (sCD4) .
  • the constrained exocyclic forms of both CDR3.AME(82-89) and CDR2.AME(45-50) inhibited 50 percent of 125 I human MHC DR4 binding to immobilized sCD4 at 4 uM and 62 uM, respectively.
  • CDR3-like compound CDR3.AME (82-89) inhibited CD4 binding in a dose dependent manner.
  • CDR3.AME (30-55) and CDR3.AME (85-91) could not inhibit CD4 interaction with the MHC II peptide. Therefore our studies have shown that the CDR3 region of CD4 plays an important role in the interaction with the 134-148 fragment of the MHC II molecule.
  • CDR3.AME (82-89) inhibited 85% of the IL-2 production by CD4 + DOU.IO cells at lOuM.
  • CDR3-like analog was the most effective inhibitor.
  • CDR3.AME (82-89) specifically binds to the CD4 receptor.
  • CDR3.AME (82-89) does not bind to non-lymphoid L-cells. Independently, it was verified that none of these cell lines expresses MHC II molecules excluding the possibility of promiscuous binding of the CD4 AMEs. These data indicate that CDR3.AME (82-89) binds specifically to the CD4 molecules on the CD4 + T cells, and O 97/36606 PC17US97/04847
  • CDR3.AME (82-89) forms heteromers with the cell surface CD4 molecule.
  • the heteromers appear to be responsible for interference with IL-2 production and T cell activation. It is likely that the CDR3.AME (82-89) /CD4 heteromer prevents ordered and specific binding to MHC class II polypeptides.
  • Residues 86-96 of the CDR3 surface as well as other distal residues of CD4 have been shown to be permissive for binding of a CD4 IgG chimeric immunoadhesin to CD4 linear peptides.
  • a constrained CDR3 peptide derived from murine CD4 was found to inhibit some T cell activities in vitro and in vivo at high concentrations.
  • the murine peptide' s binding pattern could not be established and its mode of action was thought to affect T cell signal transduction.
  • the murine peptide could not affect CD4-MHCII interactions.
  • the present invention conclusively demonstrate that the CDR3 region of CD4 is relevant to binding MCHII molecules.
  • CDR3.AME (82-89) can directly bind to the 134-148 MHC ⁇ chain residues, it is apparent that other CDR-like regions of CD4 are also involved in MHC II binding. While the intact CD4 holoreceptor may be able to make contact with different parts of MHC class II, clearly interference of the CDR3 site of attachment appears sufficient for inhibiting T cell activation.
  • FCSIQFHWCY SEQ ID NO:2 CDR2.AME (39-44) YCNQGSFLCY SEQ ID NO:3 CDR2.AME (45-50) FCTKGPSKCY SEQ ID NO:4 CDR2.AME (50-55) FCKLNDRACY SEQ ID NO:5 CDR3.AME (82-89) FCYLCEVEDQCY SEQ ID NO: 6 CDR3.AME (85-91) FCEVECQKECY SEQ ID NO:7 CDR3.LIN (82-89) FCYICEVEDQCY SEQ ID NO: 8 CDR3.LIN (85-91) FCEVEDQKECY
  • peptides were synthesized by solid-phase methods at the Protein Chemistry Laboratory at the Department of Pathology and Laboratory Medicine of the University of Pennsylvania, deprotected, and released from the resin utilizing anhydrous HE. Peptides were lyophilized and further purified by High Performance Liquid Chromatography (HPLC) utilizing Delta-Park C16 column and then lyophilized. Peptide was more than 95% pure by HPLC analysis and mass spectrometry. The peptides containing internal cysteine residues were refolded and oxidized by dissolving them at 0.1-0.3 mg/ml in distilled water pH 8.0 and stirring them for 3 days exposed to the air at 4°C.
  • HPLC High Performance Liquid Chromatography
  • RPMI 1640 containing 10% fetal calf serum, 2mM L- glutamine (GIBCO, Grand Island, NY) , 0. ImM nonessential amino acids, ImM sodium pyruvate, lOmM Hepes, 50 uM 2-
  • the IL-2 dependent T cell line, HT-2 was maintained in RPMI 1640 medium containing 10 units/ml (Sigma) mouse recombinant IL-2.
  • the antigen presenting cell line, RT3.3H6 cell lines (provided by Dr. Ronald Germain from NIH) is a transfected line of mouse L cells expressing cell surface murine MHC class II (I-Ad) and was grown in DMEM (GIBCO) at lx HAT (Sigma) .
  • IL-2 assay RT2.3H6 cells were bred in 0.025% glutaraldehyde
  • DR4 molecules were purified by affinity chromatography from insect cells coinfected with HLA-DR2-and ⁇ -DAF recombinant baculoviruses (a gift of P. Sinigaglia and J. Guardiola, Roche Milano Ricerche, Milan, Italy) .
  • Purified recombinant soluble CD4 (sCD4) kindly provided by A. Traunecker (Base) Institute For Immunology, Basel, Switzerland), was a chimeric molecule comprising the CD4 domains 1, domain 2 and part of the human IgG3 heavy chain sCD4 was obtained from R. Sweet (SmithKline Beecham Pharmaceuticals, Philadelphia) . Protein labeling and solid phase radioimmunoassays
  • DR4 was iodinated with lmCi Na 15 I (Amersham) according to the choramine T method. Specific activities was 10 ⁇ Ci/ ⁇ g.
  • Purified CD4 molecule (1 to 3 ⁇ g/ml) diluted in 50 ⁇ l PBS was immobilized onto immulon removestrips (Dynatech, Billingshurst, U.K.) by an incubation for 2 hours at 37°C. After 3 washes with PBS containing 0.1% Tween 20 (PBS-Tw) , coated wells were saturated overnight at 4°C with PBS containing 1% bovine serum albumin.
  • Antibodies (IgG) or peptides which were fluorescene- labeled by using FITC kit from Boehringer Mannheim were incubated with cells on ice in the dark in 150 ⁇ l binding buffer (Ca ++ and Mg ++ free Hanks' balanced salt solution 0.5% bovine serum albumin 0.05% sodium ozide, pH 7.4) for 30 minutes. The cells were washed twice and then resuspended in 0.5 ml binding buffer. FITC-conjugated anti-mlgG antibody was used to detect the primary antibody. The mean channel fluorescene of different cells were determined by FACScan IV analyzer (Becton Dickinson) . Data was acquired while gating on the live cell population.

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Abstract

Cette invention concerne des peptides contraints comportant une séquence d'acides aminés constituée d'au plus 30 résidus d'acides aminés. Ces peptides comporte une séquence de CD4 d'origine humaine à l'intérieur d'une partie cyclique ainsi que deux parties exocycliques comportant chacune un résidu d'acide aminé aromatique. Cette invention concerne également des compositions pharmaceutiques contenant ledit peptide ainsi que des procédés permettant d'inhiber l'oligomérisation de CD4 lié à la membrane dans une cellule de CD4+ et consistant à mettre en contact la cellule avec un peptide. L'invention concerne en outre des procédés permettant d'inhiber l'activation d'un lymphocyte T ainsi que des procédés de traitement d'individus souffrant de maladies, de troubles ou d'états pathologiques dont les causes ou les symptômes sont liés à (et/ou caractérisés par) l'activation des lymphocytes T.
PCT/US1997/004847 1996-03-29 1997-03-25 Peptides contraints a sequence de cd4 et procedes d'utilisation associes WO1997036606A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010891A3 (fr) * 1999-08-05 2001-08-16 Res Corp Technologies Inc Antagonistes d'il-16
US6638962B2 (en) 2001-01-18 2003-10-28 Les Laboratoires Servier Cycloheptene compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589458A (en) * 1992-11-13 1996-12-31 Thomas Jefferson University Compounds that inhibit T cell proliferation and methods for using the same

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US5589458A (en) * 1992-11-13 1996-12-31 Thomas Jefferson University Compounds that inhibit T cell proliferation and methods for using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BLOOD, 15 October 1996, Vol. 88, No. 8, TOWNSEND et al., "Inhibitory Effect of CD4-CDR3 Peptide Analog on Graft-Versus-Host Disease Across a Major Histocompatibility Complex-Haploidentical Barrier", pages 3038-3047. *
THE JOURNAL OF BIOLOGICAL CHEMISTRY, 15 August 1993, Vol. 268, No. 23, LANGEDIJK et al., "Location of CD4 Dimerization Site Explains Critical Role CDR3-like Region in HIV-1 Infection and T Cell Activation and Implies a Model for Complex of Coreceptor-MHC", pages 16875-16878. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010891A3 (fr) * 1999-08-05 2001-08-16 Res Corp Technologies Inc Antagonistes d'il-16
US6723697B2 (en) 1999-08-05 2004-04-20 Research Corporation Technologies, Inc. IL-16 antagonists
US7019118B2 (en) 1999-08-05 2006-03-28 Trustees Of Boston University IL-16 antagonists
US7232801B2 (en) 1999-08-05 2007-06-19 Trustees Of Boston University IL-16 antagonists
US6638962B2 (en) 2001-01-18 2003-10-28 Les Laboratoires Servier Cycloheptene compounds

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