WO1996020722A1 - Composes inhibant la proliferation des lymphocytes t et methodes les utilisant - Google Patents

Composes inhibant la proliferation des lymphocytes t et methodes les utilisant Download PDF

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Publication number
WO1996020722A1
WO1996020722A1 PCT/US1996/000230 US9600230W WO9620722A1 WO 1996020722 A1 WO1996020722 A1 WO 1996020722A1 US 9600230 W US9600230 W US 9600230W WO 9620722 A1 WO9620722 A1 WO 9620722A1
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seq
peptide
group
amino acid
compound
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PCT/US1996/000230
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English (en)
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Bradford A. Jameson
Robert Korngold
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Thomas Jefferson University
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Publication of WO1996020722A1 publication Critical patent/WO1996020722A1/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

Definitions

  • This invention relates to the field of immunology and in particular to the inhibition of undesired immune responses such as undesired activation of helper T cells.
  • autoimmune diseases are characterized as an immune reaction against "self" antigens.
  • Autoimmune diseases include systemic lupus erythematosus (SLE) , rheumatoid arthritis (RA) and multiple sclerosis (MS) .
  • SLE and RA have previously been treated with anti-inflammatory/immuno- suppressive drugs such as steroids or anti-inflammatory drugs in combination with im unosuppressive drugs. No effective treatment has previously been found for MS although ACTH and other immunosuppressive drugs have elicited some degree of response when administered during relapse.
  • T cells are an integral part of the immune response. Thus, treatment directed to inhibition of T cell proliferation would be greatly desired to treat such undesired immune responses.
  • T cells have also been implicated in graft rejection and graft versus host disease (GVHD) .
  • Administration of immunosuppression drugs such as cyclosporin A is one method - 2 - which is presently used in an attempt to combat graf rejection.
  • GVHD has previously been treated by depleting cells from the donor bone marrow.
  • the undesired immune response may be targeted at th T cell level to reduce rejection of transplanted organs an prevent the recognition by T cells of a host organism o transplanted cells as "foreign".
  • abnormal T cell growth associated wit T cell leukemias may be treated by inhibiting the proliferatio of T cells.
  • Patients suffering from leukemias have lo survival rates and are generally treated with chemotherapy
  • Methods directed toward the undesired proliferation of T cell may be useful for treatment of such leukemias.
  • Human T cells are one of the primary targets o infection by the human immunodeficiency virus (HIV) , th etiologic agent linked to acquired immune deficiency syndrom
  • HIV particles attach to CD4 molecule on human T cells.
  • the present invention relates to compounds having th formula:
  • R ⁇ - R 2 - R 3 - R 4 - R 5 - R 6 wherein: R- L is cysteine or a linking moiety capabl of binding to R 2 and R 6 to cyclicize the molecule; R 2 is selected from the group consisting of E, E-V, E-I, E-L or E-R 21 wherein R 21 is a moiety which links E of R 2 and R 3 in the same spatial relationship as V, I and L do;
  • R 3 is selected from the group consisting of E-D-Q, A-D-Q, E-D-A, E-N-Q, A-N-Q, E-N-A, E-D * -Q, A-D * -Q, E-D * - A, E-N * -Q, A-N * -Q and E-N * -A; and
  • R 4 is selected from the group consisting of K-E-E, K * -E-E, K-E * -E, K-E-E * and K * -E-E * ;
  • R 5 is P-G-P or a moiety which links R 4 and R 6 in the same spatial relationship as P-G-P;
  • R 6 is cysteine or a linking moiety capable of binding to R 5 and R 1 to cyclicize the molecule; wherein * denotes a D amino acid.
  • the present invention relates to pharmaceutical compositions which comprise such compounds in combination with a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to methods of treating an individual who is suspected of suffering from or being susceptible to a condition characterized by undesired immune response or who is infected by a human immunodeficiency virus comprising the step of administering to the individual such pharmaceutical compositions.
  • the present invention relates to compounds which are useful for modulating immune responses in mammals and which are useful for inhibiting human immunodeficiency virus (HIV) infection.
  • the present invention relates to pharmaceutical compositions which include such compounds.
  • the present invention relates to methods of modulating immune responses in mammals and top methods of treating individuals who have bee infected with HIV.
  • the term “compound” refers t molecules which include peptides and non-peptides including but not limited to molecules which comprise amino acid residue joined by at least some non-peptidyl bonds.
  • the term “peptide as used herein refers to polypeptides formed from naturall occurring amino acid subunits joined by native peptide bonds Thus, this term effectively refers to naturally occurrin subunits or their close homologs.
  • amino acid may als refer to moieties which have portions similar to naturall occurring peptides but which have non-naturally occurrin portions. Thus, peptides may have altered amino acids o linkages. Peptides may also comprise other modification consistent with the spirit of this invention. Such peptide are best described as being functionally interchangeable ye structurally distinct from natural peptides.
  • the terms “compounds” and “peptides” are used interchangeably
  • the compounds of the invention are able to mimic som intermolecular interactions of CD4. By doing so, the compound of the invention are capable of inhibiting a T cel proliferation and thereby are useful in the treatment an prevention of disorders and conditions characterized b undesirable T cell proliferation.
  • the compounds of th invention inhibit HIV infection of cells.
  • R 1 is cysteine or a linking moiety capabl of binding to R 2 and R 6 to cyclicize the molecule;
  • R 2 is selected from the group consisting o E, E-V, E-I, E-L or E-R 21 wherein R 21 is a moiety which links of R 2 and R 3 in the same spatial relationship as V, I and L do; R 3 is selected from the group consisting o
  • R 4 is selected from the group consisting of K-E-E, K * -E-E, K-E * -E, K-E-E * and K * -E-E * ;
  • R 5 is P-G-P or a moiety which links R 4 and R 6 in the same spatial relationship as P-G-P;
  • R 6 is cysteine or a linking moiety capable of binding to R 5 and R x to cyclicize the molecule; wherein: R x and R 6 are linked by an intermolecular bond, and * denotes a D amino acid.
  • the peptides of the invention have a restricted conformation.
  • R ⁇ and R 6 The purpose of R ⁇ and R 6 is to cyclicize the molecule and thereby maintain R 2 - R 3 - R 4 - R 5 in a constrained conformation which produces a specific biologically active surface.
  • R ⁇ and R 6 may be any moieties capable of forming bonds with each other and R 2 and R 5 , respectively.
  • R x and R 6 may each be cysteine.
  • the molecule is cyclicized by the formation of disulfide bonds between the two cysteines and the formation of peptides bonds between R x and R 6 with R 2 and R 5 respectively.
  • R x and R 6 may each be any other moiety that will allow for the cyclization of the molecule. That is, R x may be any moiety capable of forming bonds with R 2 to R 6 and R 6 may be any moiety capable of forming bonds with R x to R 5 . When R l is cysteine, it is preferred that R 6 is also cysteine. Those having ordinary skill in the art can readily prepare peptides according to the present invention in which R 1 and R 6 are moieties capable of forming bonds to each other. In preferred embodiments, R x and R 6 are both cysteine and are linked to each other by an intermolecular disulfide bond.
  • R 2 is E-V.
  • the V may be conservatively substituted with smilar amino acids, particularly L or I .
  • the V in R 2 is not believed to contribute to the surface of the compounds which confers activity. Accordingly, the V is optional and may be substituted such as when R 2 is E-L or E-I, or omitted such as when R 2 is E or when R 2 is E-R 21 and R 21 is a moiety which serves the same function a V, L or I in that is connects the E of R 2 to R 3 and maintain the E and R 3 at the proper spatial relationship to each other
  • R 5 The purpose of R 5 is to circularize peptides int functional conformations.
  • the amino aci sequence proline-glycine-proline (PGP) may be used to impose constrained turn in the peptides.
  • Critical to the PGP tur motif is the rigid constraints that the amino acid proline ca impose on the backbone of a peptide chain.
  • the side chain o proline, a cyclic five member ring (prolidyl ring) is bonde covalently to the nitrogen atom of the peptide group, therefor dramatically limiting rotation about the N-C ⁇ (phi) bond of th backbone, with the adjacent peptide bond more likely to adop a cis configuration.
  • R 5 does not contribute to portion the surface from which biological activity is derive but rather R s contributes to the formation of the correc conformation to produce the surface which produces th biological active of the compounds. Therefore, in addition t P-G-P, R 5 may be any moiety that links R 4 and R 6 in the sam relative spatial positions as those which the occupy whe linked by P-G-P.
  • the compounds of th present invention may be represented by the formula:
  • R X1 is selected from the group consisting o
  • R 12 is selected from the group consisting o E-D-Q, A-D-Q, E-D-A, E-N-Q, A-N-Q, E-N-A, E-D * -Q, A-D * -Q, E-D * A, E-N * -Q, A-N * -Q and E-N * -A; and R 13 is selected from the group consisting of
  • K-E-E-P-G-P-C SEQ ID NO:l, K * -E-E-P-G-P-C, K-E * -E-P-G-P-C, K-E-E-
  • Some embodiments of compounds of the invention are circular peptides having the following formulas, wherein the peptides is circularized by the formation of intermolecular disulfide bonds between the terminal cysteines and * denotes a
  • Peptide 10 C-E-V-A-D-Q-K * -E-E * -P-G-P-C
  • Peptide 11 C-E-V-E-D-A-K-E-E-P-G-P-C (SEQ ID NO:4)
  • Peptide 20 C-E-V-E-N-Q-K * -E-E * -P-G-P-C
  • Peptide 21 C-E-V-A-N-Q-K-E-E-P-G-P-C (SEQ ID NO:6)
  • Peptide 65 C-E-L-E-D-Q-K * -E-E * -P-G-P-C
  • Peptide 66 C-E-L-A-D-Q-K-E-E-P-G-P-C (SEQ ID NO: 9)
  • Peptide 67 C-E-L-A-D-Q-K * -E-E-P-G-P-C
  • Peptide 69 C-E-L-A-D-Q-K-E-E * -P-G-P-C
  • Peptide 70 C-E-L-A-D-Q-K * -E-E * -P-G-P-C
  • Peptide 102 C-E-L-E-D * -A-K * -E-E-P-G-P-C
  • Peptide 103 C-E-L-E-D * -A-K-E * -E-P-G-P-C
  • Peptide 111 C-E-L-A-N * -Q-K-E-E-P-G-P-C
  • Peptide 112 C-E-L-A-N * -Q-K * -E-E-P-G-P-C
  • Peptide 121 C-E-I-E-D-Q-K-E-E-P-G-P-C (SEQ ID N0.14)
  • Peptide 122 C-E-I-E-D-Q-K * -E-E-P-G-P-C
  • Peptide 126 C-E-I-A-D-Q-K-E-E-P-G-P-C (SEQ ID N0:15)
  • Peptide 127 C-E-I-A-D-Q-K * -E-E-P-G-P-C
  • Peptide 131 C-E-I-E-D-A-K-E-E-P-G-P-C (SEQ ID N0:16)
  • Peptide 132 C-E-I-E-D-A-K * -E-E-P-G-P-C
  • Peptide 136 C-E-I-E-N-Q-K-E-E-P-G-P-C (SEQ ID N0:17)
  • Peptide 137 C-E-I-E-N-Q-K * -E-E-P-G-P-C
  • Peptide 139 C-E-I-E-N-Q-K-E-E * -P-G-P-C
  • Peptide 140 C-E-I-E-N-Q-K * -E-E * -P-G-P-C
  • Peptide 150 C-E-I-E-N-A-K * -E-E * -P-G-P-C
  • Peptide 158 C-E-I-A-D * -Q-K-E * -E-P-G-P-C
  • Peptide 159 C-E-I-A-D * -Q-K-E-E * -P-G-P-C
  • autoimmun diseases such as rheumatoid arthritis, multiple sclerosis, an SLE may be treated by administration of compounds of th present invention to a patient suffering from such a autoimmune disease in order to inhibit this undesired immun response.
  • Inhibition of T cell proliferation is one route b which an undesired immune response may be inhibited.
  • Compounds of the present invention are also useful fo treatment of patients suffering from graft rejection and graft versus host disease.
  • rejection of the foreign material may be avoided by inhibiting an undesired immune response whic may cause rejection.
  • compounds of the present invention may be administered to patients suffering from graft versus host disease to inhibit the "self" recognizing immune response.
  • Administration of compounds may inhibit T cell proliferation in some embodiments of the present invention.
  • compounds of the present invention may be administered to a patient in order to reduce the likelihood of an undesired immune response which may result in rejection of the transplant.
  • Compounds of the present invention may also be administered to treat abnormal T cell growth such as T cell growth associated with T cell leukemia.
  • compounds are administered to a patient suffering from such abnormal T cell growth to inhibit the abnormal proliferation of T cells.
  • peptides of the present invention may be prepared by any of the following known techniques. Conveniently, the peptides may be prepared using the solid-phase synthetic technique initially described by Merrifield, in J. Am . Chem. Soc , 15:2149-2154 (1963) . Other peptide synthesis techniques may be found, for example, in M. Bodanszky et al . , (1976) Peptide Synthesis, John Wiley & Sons, 2d Ed. ; Kent and Clark- Lewis in Synthetic Peptides in Biology and Medicine, p. 295- 358, eds .
  • these synthetic methods involve the sequential addition of one or more amino acid residues or suitable protected amino acid residues to a growing peptide chain.
  • amino acid residues or suitable protected amino acid residues Normally, either the amino or carboxyl group of the first amino acid residue is protected by a suitable, selectively-removable protecting group.
  • a different, selectively removable protecting group is utilized for amino acids containing a reactive side group, such as lysine.
  • the protected or derivatized amino acid is attached to an inert solid support through its unprotected carboxyl or amino group.
  • the protecting group of the amino or carboxyl group is then selectively removed and the next amino acid in the sequence having the complementary (amino or carboxyl) group suitably protected is admixed and reacted with the residue already attached to the solid support.
  • the protecting group of the amino or carboxyl group is then removed from this newly added - 1.4 - amino acid residue, and the next amino acid (suitabl protected) is then added, and so forth.
  • an remaining terminal and side group protecting groups are removed sequentially or concurrently, to provid the final peptide.
  • the peptide of the invention are preferabl devoid of benzylated or methylbenzylated amino acids.
  • Suc protecting group moieties may be used in the course o synthesis, but they are removed before the peptides are used Additional reactions may be necessary, as described elsewhere to form intramolecular linkages to restrain conformation.
  • Some of the peptides of the invention may also b prepared by recombinant DNA techniques.
  • peptides which comprise L amino acids may comprise on or more D amino acids . Because most enzymes involved i degradation recognize a tetrahedral alpha-carbon, the D-amin acids were utilized in order to avoid enzyme recognition an subsequent cleavage. Peptides which comprise one or more amino acids are less susceptible to degradation.
  • amino acid sequenc amino acid sequenc
  • Those having ordinary skill in the art ca readily design compounds with conservative substitutions fo amino acids. For example, following what are referred to a Dayhof's rules for amino acid substitution (Dayhof, M.D. (1978 Na t . Biomed. Res . Found. , Washington, D.C. Vol. 5, supp. 3) amino acid residues in a peptide sequence may be substitute with comparable amino acid residues. Such substitutions ar well known and are based the upon charge and structura characteristics of each amino acid.
  • Circularization may be facilitated by disulfid bridges between cysteine residues.
  • Cysteine residues may b included in positions on the peptide which flank the portion of the peptide which form the surfaces that interact wit cellular molecules to render the compounds biologically active Cysteine residues of the compounds may be deleted and/o conservatively substituted to eliminate the formation o disulfide bridges involving such residues.
  • the peptides may be circularized by means of covalent bonds, such as amide bonds, between amino acid residues of the peptide such as those at or near the amino and carboxy termini .
  • routine assays may be performed using such peptides to determine whether the peptides possess the requisite activity; i.e. whether the peptide can inhibit T cell proliferation.
  • the peptides ability to inhibit T cell proliferation may be determined by observing its activity in T cell proliferation assays.
  • T cell proliferation assays are well known to those having ordinary skill in the art and may be constructed from readily available starting materials. Examples set out below provide description of assays that can be used to determine whether or not a compound has the requisite activity.
  • Peptides having the structural characteristics described above may be synthesized routinely. Such peptides may be tested using standard assays to determine if they can be used in pharmaceutical compositions and methods according to the present invention.
  • the present invention provides pharmaceutical compositions that comprise the compounds of the invention and pharmaceutically acceptable carriers or diluents.
  • T h e pharmaceutical composition of the present invention may be formulated by one having ordinary skill in the art with compositions selected depending upon the chosen mode of administration. Suitable pharmaceutical carriers are described in Remington ' s Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
  • peptides of the present invention can be used alone or in combination with other diagnostic, therapeutic or additional agents.
  • additional agents include excipients such as flavoring, coloring, stabilizing agents, thickening materials, osmotic agents and antibacterial agents. Such agents may enhance the peptide' s use in vi tro, the stability of the composition during storage, or othe properties important to achieving optimal effectiveness.
  • the peptides of th invention can be, for example, formulated as a solution, suspension, emulsion or lyophilized powder in association wit a pharmaceutically acceptable parenteral vehicle.
  • parenteral vehicle examples o such vehicles are water, saline, Ringer's solution, dextros solution, and 5% human serum albumin. Liposomes and nonaqueou vehicles such as fixed oils may also be used.
  • the vehicle o lyophilized powder may contain additives that maintai isotonicity (e.g., sodium chloride, mannitol) and chemica stability (e.g., buffers and preservatives) .
  • the formulatio is sterilized by commonly used techniques.
  • parenteral composition suitable for administration by injectio is prepared by dissolving 1.5% by weight of active ingredien in 0.9% sodium chloride solution.
  • the pharmaceutical compositions according to th present invention may be administered as a single dose or i multiple doses.
  • the pharmaceutical compositions of the present invention may be administered either as individual therapeutic agents or in combination with other therapeutic agents.
  • the treatments of the present invention may be combined wit conventional therapies, which may be administered sequentiall or simultaneously.
  • the pharmaceutical compositions of the present invention may be administered by any means that enables the active agent to reach the targeted cells. Because peptides are subject to being digested when administered orally, parenteral administration, i.e., intravenous, subcutaneous, intramuscular, would ordinarily be used to optimize absorption. Intravenous administration may be accomplished with the aid of an infusion pump.
  • the pharmaceutical compositions of the present invention may be formulated as an emulsion.
  • the dosage administered varies depending upon factors such as: pharmacodynamic characteristics; its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment; and frequency of treatment.
  • the dosage of peptide can be about 1 to 3000 milligrams per 50 kilograms of body weight; preferably 10 to 1000 milligrams per 50 kilograms of body weight; more preferably 25 to 800 milligrams per 50 kilograms of body weight.
  • Ordinarily 8 to 800 milligrams are administered to an individual per day in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.
  • compositions of the present invention may be formulated and administered to most effectively. Modes of administration will be apparent to one skilled in the art in view of the present disclosure.
  • Peptides were synthesized on an Applied Biosyste (Foster City, CA) 430A fully automated peptide synthesizer according to methods of Jameson et al . , Science 1988, 240, 1335.
  • the peptides containing internal cysteine residues were refolded and oxidized by dissolving them at 100 ⁇ g/ml in 0.1 M NH 4 HC0 3 and stirring overnight exposed to air at 23°C.
  • the peptides show greater than 95% intramolecular disulfide bonding at the end of this procedure as monitored by Ellmans reagents, HPLC analysis and gel filtration.
  • Peptides were lyophilized, resuspended in complete medium and filtered through a 0.22 ⁇ filter prior to use in biological assays.
  • 22D11 is a CD4+, PCC specific T cell hybridoma, maintained in DMEM supplemented with 1 M sodium pyruvate, 1 mM
  • D10.G4.1 is a CD4+ conalbumin-specific T cell clone and was obtained from ATCC, Rockville, MD (ATCC #TIB224) .
  • Clones were stimulated every 10 to 14 days with 100 ⁇ g/ml Ag and feede cells (C3H irradiated spleen cells) in RPMI 1640 supplemente with 1 mM glutamine, 5 X 10 5 M 2-ME, and penicillin- streptomycin.
  • CT20 is an IL-2 dependent T cell clone, and was maintained in RPMI 1640, 10% FCS, and supplemented with Ly phocult (Biotest, Denville, NJ) , a source of IL-2.
  • the hybridomas GK1.5 ( ⁇ L3T4) , 145-2C11 ( ⁇ CD3e) , H57-597 ( ⁇ TCR-S"C) and MKD6 ( ⁇ I-A d ) were maintained as described for example, by Wilde et al . , J. Immunol . 1983, 131, 2178; Leo et al . , Proc . Natl . Acad. Sci . U. S. A . 1987, 84, 1374; Kubo et al . , J. Immunol . 1989, 142, 2736; and Kappler et al . , J. Exp . Med. 1981, 53, 1198.
  • the mixed lymphocyte reaction is the response of one individual's T lymphocytes to those of a major histocompatibility complex (MHC) mismatched donor.
  • MHC major histocompatibility complex
  • CD4+ T cells recognize the foreign MHC proteins and proliferate in response to this, in a manner highly dependent on the CD4 molecule. Mice were sacrificed and spleens aseptically removed.
  • 1 X 10 5 responder cells BALB/c spleen cells
  • 1 X 10 5 stimulator cells C3H spleen cells, 2000 rad irradiated
  • final volume 200 ⁇ l final volume 200 ⁇ l
  • peptide .01, .1, 1, 10, 100 and 1000 ⁇ M peptide
  • 1 ⁇ Ci/WELL OF [ 3 H] TdR was added 12 hours before thymidine incorporation was measured.
  • Lymphocyte yield varied between 5-8xl0 7 .
  • Beta Counter of Beta plate reader (1205 BS Betaplate Liquid Scintillation Counter, Wallac) with scintillation fluid.
  • Both cell lines were cultured in 96-well flat-bottomed microtitre plates at 2 x 10 cells per well (200 ⁇ l media) .
  • A3D8 peptide was added at th beginning of the culture and 1 ⁇ Ci [ 3 H] TdR/well (25 ⁇ l) wa added for the final 6 hours of a 24 hour incubation at 37°C, 7 C0 2 .
  • Cells were harvested using a fiberfilter cell harveste
  • Beta Counter o (e.g., Harvester 96, Tomtec) and counted in a Beta Counter o
  • Beta plate reader (1205 BS Betaplate Liquid Scintillatio

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Abstract

On décrit des composés qui sont utiles pour inhiber la prolifération des lymphocytes T. Ces composés peuvent être formulés avec des vecteurs excipients acceptables sur le plan pharmaceutique pour former des compositions pharmaceutiques. On décrit des méthodes de traitement d'un individu atteint ou susceptible d'être atteint d'une maladie caractérisée par une réponse immunitaire indésirable. On décrit également des méthodes de traitement d'individus souffrant d'une infection à VIH. Les méthodes consistent à administrer à un tel individu une composition pharmaceutique comprenant les composés en question.
PCT/US1996/000230 1995-01-03 1996-01-03 Composes inhibant la proliferation des lymphocytes t et methodes les utilisant WO1996020722A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002028385A1 (fr) * 2000-10-03 2002-04-11 Philadelphia, Health And Education Corporation Compositions et procedes pour l'elaboration et l'utilisation de compositions inhibant les lymphocytes t auxiliaires actives
US6989435B2 (en) 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7067117B1 (en) 1997-09-11 2006-06-27 Cambridge University Technical Services, Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7238711B1 (en) 1999-03-17 2007-07-03 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011014A1 (fr) * 1992-11-13 1994-05-26 Thomas Jefferson University Composes inhibant la proliferation des lymphocytes t et leurs procedes d'utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011014A1 (fr) * 1992-11-13 1994-05-26 Thomas Jefferson University Composes inhibant la proliferation des lymphocytes t et leurs procedes d'utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
IMMUNOMETHODS, Vol. 1, issued 1992, McDONNELL et al., "Rational Design of a Peptide Analog of the L3T4 CDR3-Like Region", pages 33-39. *
NATURE, Vol. 368, issued 21 April 1994, JAMESON et al., "A Rationally Designed CD4 Analogue Inhibits Experimental Allergic Encephalomyelitis", pages 744-746. *
STN INTERNATIONAL, CHEMICAL ABSTRACTS SERVICE, "Fastnotes", pages 1-2. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6989435B2 (en) 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7067117B1 (en) 1997-09-11 2006-06-27 Cambridge University Technical Services, Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7700087B2 (en) 1997-09-11 2010-04-20 Cambridge Enterprise Limited Compounds and methods to inhibit or augment an inflammatory response
US7238711B1 (en) 1999-03-17 2007-07-03 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
WO2002028385A1 (fr) * 2000-10-03 2002-04-11 Philadelphia, Health And Education Corporation Compositions et procedes pour l'elaboration et l'utilisation de compositions inhibant les lymphocytes t auxiliaires actives

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