[go: up one dir, main page]

WO2005108432A2 - Peptides de liaison de cd80 (b7-1) et utilisations - Google Patents

Peptides de liaison de cd80 (b7-1) et utilisations Download PDF

Info

Publication number
WO2005108432A2
WO2005108432A2 PCT/US2005/011209 US2005011209W WO2005108432A2 WO 2005108432 A2 WO2005108432 A2 WO 2005108432A2 US 2005011209 W US2005011209 W US 2005011209W WO 2005108432 A2 WO2005108432 A2 WO 2005108432A2
Authority
WO
WIPO (PCT)
Prior art keywords
molecule
amino acids
immune system
patient
amino acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2005/011209
Other languages
English (en)
Other versions
WO2005108432A3 (fr
Inventor
Mythily Srinivasan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Indiana University Research and Technology Corp
Original Assignee
Indiana University Research and Technology Corp
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 Indiana University Research and Technology Corp filed Critical Indiana University Research and Technology Corp
Publication of WO2005108432A2 publication Critical patent/WO2005108432A2/fr
Publication of WO2005108432A3 publication Critical patent/WO2005108432A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes

Definitions

  • CD80 (B7-1) BINDING PEPTIDES AND USES THEREOF
  • Persistent activation of auto reactive T cells plays a central role in the pathogenesis of many autoimmune diseases. Martin, R., H. F. McFarland, D. E. McFarlin, (1992), "Immunological aspects of demyelinating diseases," Annu. Rev. Inimunol. 10:153. Bar-Or, A., E. M. Oliveira, D. E. Anderson, D. A. Hafler,
  • CD80 (B7-1) is a membrane-bound protein expressed primarily on antigen presenting cells (APCs) that binds the costimulatory receptors CD28 and CD152 on T cells. Binding of CD80 to CD28 or CD 152 affects T-cell behavior and helps to regulate the immune response. Boise, L. H., A.
  • CTLA-4 a negative regulator of autoimmune disease. J. Exp. Med. 184:783.
  • Boussiotis V. A., G. J. Freeman, J. G. Gribben, L. M. Nadler, (1996), "The role of B7-l/B7-2:CD28/CLTA-4 pathways in the prevention of anergy, induction of productive immunity and down-regulation of the immune response," Immunol. Rev. 153:5. Chang, T. T., C. Jabs, R. A. Sobel, V. K. Kuchroo, A. H.
  • T- cell surface costimulatory molecules Two structurally and functionally well characterized T- cell surface costimulatory molecules are CD 28 and the cytotoxic T lymphocyte associated antigen (CTLA4)/CD152, both of which bind the same ligands, CD80 (B7-1) and CD 86 (B7-2), on antigen presenting cells (ATC). Signaling via the CD 28 pathway mediates T cell activation, ligation of CD 152 down-regulates T-cell proliferation and function. Lenschow, D. et al. (1996) Annu. Rev. Immunol. 14, 233-258. Given, their importance in immune regulation CD80/CD86- CD28/CD152 costimulatory molecules are potential therapeutic targets for modulating T cell responses.
  • Blockade of the B7-1:CD28/CD152 costimulatory pathway by CD152- fusion protein or anti-B7-l monoclonal antibody suppresses symptoms of some diseases in some models of pathologies.
  • Hohlfeld, R (1997), "Biotechnological agents for the immunotherapy of multiple sclerosis: principles, problems and perspectives," Brain 120:865.
  • Perrin, P. J., D. Scott, C. H. June, M. K. Racke, (1995) "B7-mediated costimulation can either provoke or prevent clinical manifestations of experimental allergic encephalomyelitis," Immunol. Res. 14:189.
  • a molecule that interacts with the antigen presenting cell (APC) ligand CD80 (B7-1), in which a molecule is, for example, a polypeptide that includes the L-amino acid sequence MQPPGX (SEQ ID 1), where X is at least one amino acid selected from the group of amino acids consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • the polypeptide MQPPGC (SEQ LD 2) at least substantially adopts a polyproline type 11 helical conformation under physiological conditions and interacts with the receptor binding regions of molecules such as CD80 and other member of the B-1 family.
  • the molecules can contain between about 20 to about 6 amino acid residues.
  • the molecule is end capped.
  • the molecule is water soluble.
  • the molecule includes the sequence MQPPGC.
  • Another embodiment is a molecule that interacts with the antigen presenting cell (APC) ligand CD80 (B7-1), in which a molecule includes for example, a retro-inverso peptide mimic that includes the D-amino acid sequence XGPPQM (SEQ LD 3), where X is at least one amino acid selected from the group consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • the polypeptide XGPPQM (SEQ ID 3) at least substantially adopts a polyproline type 11 helical conformation under physiological conditions and interacts with the receptor binding regions of molecules such as CD80 and other member of the B-1 family.
  • the molecules can contain between about 20 to about 6 amino acid residues. In one embodiment the molecule is end capped. In one embodiment the molecule is water soluble. In one embodiment of the molecule includes the sequence CGPPQM. Still another embodiment is a method of modulating the immune response in animals, including down regulating and in some instances completely blocking or almost completely blocking T-cell costimulation by antigen presenting cell (APC) bearing, for example, the ligand CD80 (B7-1). This method comprises the steps of providing a molecule that interacts with CD80 and in some embodiments with other or additional molecules in the B-1 family to varying degrees.
  • APC antigen presenting cell
  • these molecule include the sequence MQPPGX (SEQ LD 1), where X is at least one amino acid selected from the group of amino acids consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • SEQ LD 1 sequence MQPPGX
  • X is at least one amino acid selected from the group of amino acids consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • These molecules may adopt a polyproline LI helical structure that interacts with molecules such as CD80.
  • Other steps in the method include contacting at least a portion of the immune system with these modulating molecules.
  • These molecules depending upon there composition may be end blocked, and/or water soluble and/or include between about 20 to about 6 amino acids.
  • the molecule used to modulate the immune system includes the retro-inverso peptide mimic that includes the D-amino acid sequence XGPPQM (SEQ ID 3), where X is at least one amino acid selected from the group consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • the polypeptide XGPPQM (SEQ ID 3) at least substantially adopts a polyproline type 11 helical conformation under physiological conditions and interacts with the receptor binding regions of molecules such as CD80 and other member of the B-1 family.
  • Still another embodiment is a method treating a patient comprising the steps of providing at least one molecule that interacts with CD80 or similar molecules and administering at least one therapeutically effective dose of the molecule to a patient.
  • These molecules may include sequences such as the L- amino acid sequence MQPPGX (SEQ ED 1), where X is at least one amino acid selected from the group of amino acids consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • SEQ ED 1 L- amino acid sequence
  • X is at least one amino acid selected from the group of amino acids consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • These molecules have a tendency to at least substantially adopts a polyproline type 11 helical conformation under physiological conditions and interacts with the receptor binding regions of molecules such as CD80
  • a method treating a patient comprising the steps of providing at least one molecule that interacts with CD80 or similar molecules and administering at least one therapeutically effective dose of the molecule to a patient.
  • These molecules include the D-amino acid sequence XGPPQM (SEQ LD 3), where X is at least one amino acid selected from the group consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • the polypeptide XGPPQM (SEQ LD 3) has a tendency to adopt a polyproline type 11 helical conformation under physiological conditions and interacts with the receptor binding regions of molecules such as CD80 and other member of the B-1 family.
  • Diseases that can be treated using these methods include, for example, but are not necessarily limited to autoimmune diseases and inflammatory diseases that at least implicate portions of the immune system.
  • Specific diseases include, but are not limited to, multiple sclerosis, colitis (inflammatory bowel disease LBD), Crohn's Disease, rheumatoid arthritis, diabetes mellitus, Sjorgren's syndrome and solid tissue transplant rejection.
  • Yet another embodiment provides methods for either the in vitro or in vivo study of the immune system. These methods include methods for modeling at least some components of the immune system. The steps comprise providing a molecule that interacts with CD80 or similar components of the immune system and contacting the molecules with at least a portion of the immune system.
  • Molecules that may be used to interact with the immune system include molecules that substantially adopt a polyproline type LI helical conformation under physiological local conditions.
  • the molecules used in modeling or otherwise studying features of the immune system include the D-amino acid sequence XGPPQM (SEQ LD 3), where X is at least one amino acid selected from the group consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • the polypeptide XGPPQM (SEQ LD 3). Still another embodiment is a method of screening for drug candidates that interact with components of the immune system such as CD80 and similar molecules. These methods may include the steps of providing molecules that interact with the immune system and the contacting prospective drug candidates and assaying for change in the behavior of the assay system.
  • the molecules that may be screen for drug candidates include the L-amino acid sequence MQPPGX (SEQ LD 1), where X is at least one amino acid selected from the group of amino acids consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • the molecules are used in screening for additional molecules that interact with the immune system include the contacting prospective drug candidates with molecules that include the D-amino acid sequence XGPPQM (SEQ LD 3), where X is at least one amino acid selected from the group consisting of A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V.
  • XGPPQM SEQ LD 3
  • FIG. 1 Panels A, B, C and D superimposition of the CD80-CAP1 (SEQ LD).
  • FIG 2 A Computer generated image of the docked complex of CD80-CAP1
  • FIG 2 B Computer generated image (18) of all atoms within 5 A of CD80-
  • FIG. 3 The circular dichroism (CD) spectrum (20) of CD80-CAP1 (SEQ ID NO.
  • LD 2 (22) and CD80-CAP3 (SEQ ED 17) (24) peptide (lOO ⁇ M in water) at 5°C in a q mM sodium citrate, 1 mM sodium borate, 1 mM sodium phosphate buffer and 15 mM NaCl with the pH adjusted at 7.0 and CD spectrum of CD80-CAP1 the presence of 6 M CaCl 2 (26).
  • FIG. 4 Graphical summary of binding data collected using an Enzyme
  • Panel A shows the percent CD80 binding CD28 in the presence of either control peptide or CD80-CAP1; data were collected using 3 concentrations 125, 250, or 500 ⁇ M of either CD80-CAP1 or control.
  • Panel B shows the percent CD80 binding CD162 in the presence of either control peptide or CD80-CAP1; data were collected using 3 concentrations 125, 250, or 500 ⁇ M of either CD80-CAP1 or control.
  • Panel C shows the percent CD86 binding CD28 in the presence of either control peptide or CD80-CAP1; data were collected using 3 concentrations 125, 250, or 500 ⁇ M of either CD80-CAP1 or control.
  • Panel D shows the percent CD86 binding CD28 in the presence of either control peptide or CD80-CAP1; data were collected using 3 concentrations 125, 250, or 500 ⁇ M of either CD80-CAP1 or control.
  • FIG. 5 Shows change in absorbance over time for CD28-CD80 (panel A) and CD152-CD80 (panel B) reactions were measured over the time period of 1 to 300 seconds (s) with a mix time of 0.30 s. Readings were made at various times with a 5 s interval between data points. Concentrations of CD80-CAP1 used in the assays were as follows: 0, 25, 50 and 500 ⁇ M. The maximal velocity (mean optical density min "1 ) of CD28-CD80 (panel C) and CD152-CD80 (panel D) was measured at the following concentrations of CD80-CAP1 0, 25, 50, 100, and 200 ⁇ M.
  • FIG. 6 The CD80-CAP1 inhibits T cell proliferation.
  • Panel A shows the counts per minute of [ 3 H]-thymadine produced by mouse lymph node cells (LNC) sensitized to collagen LT in the presence of one of the following CD80-CAP1, CD80-CAP3 or control peptide; these molecules were added at the following concentrations 0, 125, 250, or 500 ⁇ M.
  • Panel B shows the counts per minute of [ 3 H]-thymadine mouse lymph node cells (LNC) sensitized to collagen V in the presence of one of the following CD80-CAP1, CD80-CAP3 or control peptide; these molecules were added at the following concentrations 0, 125, 250, or 500 ⁇ M.
  • FIG. 8 Treatment of lymph node cells (LNC) with CD80-CAP1 SEQ LD 2 inhibits T cells.
  • FIG. 9 Results of enzyme-linked immunosorbent assay (ELISA) showing evidence that CIA mice responded to treatment with CD80-CAP1.
  • ELISA enzyme-linked immunosorbent assay
  • Tissue culture supernatants from either the stimulated CD4 T cells or the sera from the CIA mice were assayed by ELISA for murine LL-12 (Panel A), LNF- ⁇ (Panel B) and LL-6 (Panel C). Assays were performed using commercially available paired antibodies in accordance with the manufacturer's instructions (eBioscience, San Diego, CA).
  • CD80-CAP1 can be used to treat an animal model of colitis
  • Colitis was induced in population of mice by injecting T cells purified from normal mouse spleens into SCLD mice. One group of mice was treated with 500 ⁇ g of CD80-CAP1 on the same day that the spleen cells were injected into the mice. Panel A shows percent gain in weight in individual mouse followed for the 10 to 27 day post transfer period. Panel B shows average percent gain in weight was followed for the 14 to 27 day post transfer period.
  • Dextrorotary (D) or Levorotary (L) amino acids these abbreviations are as follows: Alanine: Ala, A; Arginine: Arg, R; Asparagine: Asn, N; Aspartic Acid: Asp, D; Asparagine or aspartic acid: Asx, B; Cysteine: Cys, C; Glutamine: Gin, Q; Glutamic acid: Glu, E; Glutamine or glutamic acid: Glx, Z; Glycine: Gly, G; Histidine: His, H; Isoleucine: Lie, I; Leucine: Leu, L; Lysine: Lys, K; Methionine: Met, M; Phenylalanine: Phe, F; Proline: Pro, P; Serine: Ser, S; Threonine: Thr, T; Tryptophan: Trp, W; Tyrosine: Tyr, Y; and Valine: Val,
  • Amino acids may be joined together by peptide bonds or by other bonds so long as the structure of the polypeptide, peptide or peptide mimic formed is such that it interacts with the APC CD80 (B7-1) ligand and effects the behavior of T- cells that interact with the CD80 ligand.
  • Creating a retro-inverso peptide mimic may involve using D in place of L amino acids and reversing of amide bonds within the peptide backbone.
  • One effect of this is to create an analog such that the reversed amide bonds (NHCO) in the modified peptide retains both the planarity and conformational restriction of peptide bonds (CONH).
  • All sequences submitted on Compact disk or on a diskette are incorporated herein by reference. Some sequences are identified and or referred to by use of their Protein Data Bank (PDB) numbers these sequences are incorporated herein by reference from their source for example PDB or Genebank. Some sequences are included in incorporated by reference references accordingly these sequences are themselves incorporated by reference.
  • the B-7 family of molecules includes for example B7-1, B7-2 and the like.
  • CD80 is a member of the B-7 family and is identical to B7-1.
  • CD80, B7-1, CD80 (B7-1) used in the context of same animal or synthetic source all of these labels refer to the same molecule.
  • the names or labels B-7-1-CAP, CD80-CAP, and CD80 (B7-1)-CAP, used in the same context refer to the same molecule.
  • a competitive antagonist of a receptor ligand may function as a pseudo receptor by effectively competing with the receptor for binding of the ligand, thereby interfering with the receptor ligand binding.
  • CAP molecules such as CD80-CAP1 are also referred to as pseudoreceptors.
  • Classical methodologies for the identification and development of useful therapeutic agents include, but are not limited to rational structure based drug design, high throughput screening and virtual screening.
  • the protein-protein interaction between the receptor-ligand is mediated by a subset of critical residues found in the native receptor-ligand pair then it may be possible to develop or identify a relatively small molecule that can effect the receptor-ligand interaction. If enough information is known about the physical characteristics of a receptor-ligand interface, one structure based approach for developing or identifying molecules that interfere with the interaction involves constructing pseudo-receptors or mini-receptors. These molecules may be modeled on what is learned by solving the structure of the interface or by at least modeling the interface. Mini-receptors mimic the physiological receptors in their binding of ligand.
  • One promising target for this approach to candidate design and identification is the interaction between certain types of T-cells and certain types of Antigen Presenting Cells (APC).
  • APC Antigen Presenting Cells
  • T-cells The stimulation and proliferation of T-cells is thought to involve two binding events.
  • One event includes an interaction between the receptor CD3 on the T-cell surface and an antigenic peptide presented to the receptor by either a class I or class LI MCH protein localized to the surface of an Antigen Presenting Cell (APC).
  • APC Antigen Presenting Cell
  • Antigenic stimulation alone produces anegy and T-cell death by apoptosis.
  • a second T cell APC interaction must occur.
  • the second interaction is oftentimes referred to as a costimulatory signal and involves an interaction between receptor-ligand pairs expressed on the surface of APCs and T cells.
  • T cell receptors involved in the costimulatory response include the receptors CD28 and CD 152.
  • the T cell costimulatory receptors CD28 and CD 152 are members of the immunoglobulin superfamily (IgSF). These receptors include an IgV like extracellular domain. Huang, Z., S. Li, R. Korngold, (1997), "linmunoglobulin superfamily proteins: structure, mechanisms, and drug discovery," Biopolymers 43:367. Significantly, these receptors share a highly conserved "MYPPPY” (SEQ ED 12) motif in the CDR-3 like loop region that forms the ligand-binding core (Bajorath, J., W. J. Metzler, P. S. Linsley, (1997), "Molecular modeling of CD28 and three-dimensional analysis of residue conservation in the CD28/CD152 family," /. Mci. Graph. Model. 15:135); WO 02/042915 Kaumaya; Pravin, T., P.
  • IgSF immunoglobulin superfamily
  • proline rich regions are often found in situations requiring the rapid recruitment or interchange of several proteins, such as during the initiation of transcription, signaling cascades and cytoskeletal rearrangements (Kay, B. K., M. P. Williamson, M. Sudol, (2000), "The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains," FASEB J. 14:23 1, Creamer, T. P., and Campbell, M. N. (2002) Adv Protein Chem 62, 263-282. These types of proline rich regions often play a critical role in positioning proteins so as to increase the probability that the two proteins will interact with one another.
  • proline rich regions are seen in exposed portions of globular proteins which have fast on and off rates for binding to other proteins.
  • these proline rich regions can be found in some portions of IgSF superfamily members that are involved in receptor-ligand interactions (Terasawa, H, Kohda, D., Hatanaka, H., Tsuchiya, S., Ogura, K., Nagata, K., Ishii, S., Mandiyan, V., Ullrich, A., Schlessinger, J., and et al. (1994) Nat Struct Biol 1, 891-897).
  • polyproline stretches within the loop like structures are known to have a tendency to adopt a polyproline type II (PP ⁇ ) helical conformation (Creamer, T. P., and Campbell, M. N. (2002) Adv Protein Chem 62, 263-282).
  • PP ⁇ polyproline type II
  • PPII helices are super-secondary structural elements that serve as flexible links between other secondary structures such as alpha helices and beta sheets.
  • MYPPPY (SEQ ED 12) motif of CD152 adopts a polyproline type LI (PPII) helical conformation upon binding the ligand 17.
  • Weak binding interactions can be advantageous to receptor-ligand interactions as they increase the rate of structural modulation allowing the binding pair to readily sample a number of possible binding motifs. Weak binding interactions may also permit relatively small changes in the sequence of the proline-rich sequence or its binding domain to dramatically effect the receptor and ligand dissociation constant (K d ) (Kay, B. K., M. P. Williamson, M. Sudol, (2000), "The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains," FASEB J. 14:23 1).
  • One aspect of the invention is a peptide, polypeptide, or peptide mimic designed with reference to amino acid residues present at the interface of CD80(B7-1)/CD152:CD28 complex. Residues in the binding region may have a propensity to adopt a PP LT helical conformation. Accordingly, if a peptide or peptide mimic has the same or similar propensity to adopt a PP LI helical conformation it may be able to interfere with the binding or the receptor and ligand. For example, a pseudo-receptor with PP II helical or PP LT helical like structure may be able to disrupt the binding of T-cells to APCs.
  • Such molecules have the potential to help regulate aspects of the immune response related to T-cell interaction with antigen presenting cells (APCs) (Hohlfeld, R, (1997), “Biotechnological agents for the immunotherapy of multiple sclerosis: principles, problems and perspectives," Brain 120:865).
  • APCs antigen presenting cells
  • One embodiment provides a peptide, of about 20 amino acid residues, including an amino acid sequence corresponding to MQPPGC (SEQ LD 2), or a retro-inverso peptide mimic thereof (a corresponding D form of the L amino acid including the D-amino acid sequence CGPPQM (SEQ LD 4).
  • Another embodiment provides a peptide of about 10 amino acid residues, including the amino acid sequence corresponding to MQPPGC (SEQ ID 2), or a retro-inverso peptide mimic thereof. Still another embodiment includes a peptide that includes about ten amino acid residues, such that the peptide may adopt a PP LI helical conformation and interact with CD80 (B7-1).
  • One such peptide which interacts with the CD80 receptor includes a polypeptide with the amino acid sequence MQPPGC (SEQ LD 2), or a retro-inverso peptide mimic thereof.
  • Yet another embodiment includes a CD80 (B7-1) binding molecule, which includes the amino acid sequence of MQPPGC (SEQ LD 2), or a retro-inverso peptide mimic thereof.
  • the ligand is a protein or short polypeptide having, for example, about 20 amino acids.
  • the molecule is in a water-soluble form.
  • an effective amount of the compounds can be defined as the amount of the compound necessary to affect T-cell costimulation. Means for measuring this include, but are not limited to, measuring the effect of the compounds on T cell proliferation and T cell apoptosis.
  • compositions that include at least one of the proteins, polypeptides, or peptide mimics or retro-inverso peptides or other CD80 (B7-1) pseudo-receptors mentioned in the disclosure. These molecules may be combined with a pharmaceutically acceptable carrier.
  • the peptide or peptide-containing molecule of the invention can be incorporated into compositions suitable for administration to human or animal patients.
  • the peptide in such compositions is in a biologically compatible form suitable for pharmaceutical administration in vivo.
  • the definition of a therapeutically active amount of the therapeutic compositions according to the present invention includes, but is not limited to, an amount effective to partially or completely relieve the symptoms associated with a specific disease or disorder.
  • the actual amount of a compound of the invention necessary to elicit a desired therapeutic response in a particular patient may vary according to factors such as the disease state, age, sex, and weight of the individual patient. Dosage regimes may be adjusted to optimize therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the amount of the therapeutic required to treat a given condition will depend upon the nature and severity of the condition being treated, the type of defect or disease being treated and what if any additional conditions or treatments a given patient is, or has been, subject to. Ultimately, the size of the therapeutically effective dosages will likely be determined during clinical trials. Initially, human patients will be administered doses in accord with those derived from animal studies.
  • the therapeutic composition may be administered when patients exhibit clinical symptoms of the disease.
  • the therapeutic composition may be administered when patients have clinical symptoms, or when a genetic mutation in a patient is indicative of diabetes mellitus.
  • autoimmune diseases such as multiple sclerosis, experimental autoimmune encephalomyelitis, rheumatoid arthritis, and insulin-dependent diabetes mellitus, inflammatory bowel disease and allograft transplant rejection.
  • the therapeutic compound may be administered in a convenient manner such as by injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, or rectal administration.
  • the therapeutic compound may be coated with a material which, for example, protects the compound from or at least slows the degradation or inactivation of the compound.
  • Degraditive processes include, for example, the action of proteolytic enzymes or other naturally occurring agents or conditions which may tend to degrade the therapeutic compound.
  • a therapeutic peptide compound made in accordance with at least one embodiment may be administered to an individual in an appropriate carrier, diluent or adjuvant, co-administered with enzyme inhibitors or in an appropriate carrier such as liposomes.
  • Pharmaceutically acceptable diluents for the practice of at least some aspects and embodiments include saline and aqueous buffer solutions.
  • the term 'adjuvant' is used in its broadest sense and includes any immune stimulating compound, such as interferon.
  • Adjuvants contemplated herein include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether, and n- hexadecyl polyethylene ether.
  • Some embodiments include enzyme inhibitors, for example, pancreatic trypsin inhibitor, diisopropylfluorophosphate (DEP), trasylol, and other inhibitors of enzyme activities that may reduce the half -life and/or effectiveness of the therapeutic compounds.
  • enzyme inhibitors for example, pancreatic trypsin inhibitor, diisopropylfluorophosphate (DEP), trasylol, and other inhibitors of enzyme activities that may reduce the half -life and/or effectiveness of the therapeutic compounds.
  • the term 'liposomes' used herein includes water-in-oil-in-water emulsions, aqueous solutions-in-hydrohopic compounds-in aqueous solutions as well as a vesicles comprised at least in part of a phospholipids bilayer.
  • Therapeutic compositions in accordance with various embodiments may be administered parenterally, or intraperitoneally or both parenterally and intraperitoneally.
  • compositions suitable for injectable use include sterile aqueous solutions (where the active ingredient is sufficiently water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the composition should be aseptic and fluid enough to promote syringability exists.
  • the composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • Suitable carriers for the active ingredient include, but are not limited to, to solvents or dispersion media containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity of the composition can be maintained, by for example, the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants.
  • Aseptic condition can be achieved and/or promoted by the addition of antibacterial and antifungal agents including, but limited to, parabens, chiorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the peptide in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by, for example, filter sterilization.
  • dispersions are prepared by incorporating the active ingredients into a sterile vehicle that includes a basic dispersion medium and additional or required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (e.g., peptide) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the peptide may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Polypeptide, peptides, and peptide mimics of the invention can be prepared in any suitable manner including, for example, by synthetic methods such as solid- phase chemical methods, by recombinant production in a host cell that expresses a nucleic acid encoding the amino acid sequence of the peptide, or a combination thereof.
  • a suitable nucleic acid e.g.
  • DNA DNA
  • DNA DNA
  • molecule can be obtained or prepared having a nucleotide sequence encoding the amino acid sequence of the desired peptide.
  • nucleotide sequences can be readily identified with reference to the known, degenerative genetic code for humans and other animals, and/or by reference to known coding regions possibly in combination.
  • the nucleotide sequence can be incorporated into a suitable vector, such as a viral vector, along with a promoter (e.g. a constitutive promoter) operably linked to the sequence and effective to drive the expression of the encoded peptide in a host cell, such as a bacterial (e.g. E. coli) or animal (e.g. human or non-human animal) host cell.
  • a promoter e.g. a constitutive promoter
  • the vector can then be used to transfect the host cell, and the host cell cultured under conditions effective to express the peptide.
  • the synthetically or recombinantly produced peptides can be purified for use if desired, e.g. purified to substantial homogeneity or otherwise suitable for pharmaceutical and/or research purposes, using chromatographic and/or other standard techniques thereof.
  • Peptides, peptide mimics, and retro-inverso mimics of the invention may also have free ends, or may be end-blocked as well known in the art.
  • peptides of the invention may be incorporated as a part of larger polypeptides or proteins, or other molecules, having utility in binding B7-1 (CD80) or otherwise.
  • Peptides of the invention and compositions containing them may be used, for example, to modulate T cell activation in vivo by blocking T cell costimulation, and to suppress chronic inflammatory processes in autoimmune disease, graft versus host disease, and/or transplant rejection.
  • Peptides of the invention may also be used, for example, in vitro in experimental studies relating to T cell activation.
  • Peptides of the invention owing to their binding properties, may also be used for purposes identified in numerous patent publications and patents in fields relating to the inhibition of T cell stimulation, including for example WO 02/42415 A2 dated May 30, 2002, and U.S. Patent Nos. 6,641,809 and 6,444,792.
  • the unbound mouse CD152 (SEQ LD 6) (PDB 1DQT, chain A) and human CD152 (PDB 1AH1) and ligand bound human CD152 (SEQ LD 7) (PDB 118 L chain C) were selected for use as templates.
  • the structural overlap for the secondary structure comparison for the CD28 and CD 152 queries and the three templates were between about 51 and 67 percent.
  • the Geno3D program produces comparative protein structure by satisfying spatial restraints (distances and dihedrals).
  • the Geno3D prediction system uses 'topology mapping' to predict a 3D structure from a supplied amino acid sequence.
  • Geno 3D program does blast the sequence in a database of protein sequences composed of proteins whose 3D structures are known. It maps a sequence onto close relatives and then does an energy minimization of the tentative structure using the amino acid side chains in the searched sequence.
  • This approach first extracts homology derived spatial constraints on many atom-atom distances and dihedral angles from the template structures. An alignment is used to derive equivalent residues between the target and the template. The homology derived and the stereochemical constraints are then used to generate protein models that best satisfy the criteria. CD28 residues (1-119 from the start of translation) were modeled using the human CD 152 (PDB) as the templates. While Geno 3D does not providing exact 3D structures of proteins, it can provide useful insight into what the structure might be.
  • CD80-CAP CD80-competitive antagonist peptides
  • B7-1 CAP molecules these molecules are sometimes referred to herein as pseudo-receptors.
  • the interface between both CD152/CD80 and CD152/CD86 is large, burying a total of 1255 and 1290 A of the solvent-accessible surfaces of CD80 and CD86, respectively.
  • proline-rich region of the CD152 CDR-3-like loop packs against the hydrophobic patch of residues that form a shallow cavity on the front face of CD80 and CD86. Similar proline-rich regions commonly occur in globular domains involved in transient protein-protein interactions. Typically, proline-rich regions preferentially adopt a PPn helical conformation.
  • proline-rich regions preferentially adopt a PPn helical conformation.
  • the Pro 101 of CD 152 is in PPn helical conformation with the dihedral angles of ⁇ and ⁇ measuring -75 and 164, respectively (Table 1).
  • a competitive antagonist for this receptor ligand interaction should not only be small as to occupy the shallow binding site of CD80 (surface area of 655 A), but it should also mimic the PPn helical conformation of the physiological receptor.
  • Amino acids exhibit varied frequencies of occurrence at the protein interface and distinct pairing preferences at sites of protein-protein interactions.
  • residues vary in the propensity to form PPn helix.
  • a polypeptide backbone possesses both ⁇ helix and PPn helix propensity. The extent to which the PPn helix is adopted is determined by the degree of backbone solvation and modulated by side chain interactions.
  • CD80-CAP was superimposed with the ligand binding motif of free murine CD152 (Protein Data Bank code 1DQT) (SEQ LD 6), free human CD152 (Protein Data Bank code 1 AH1) (SEQ LD 13), and CD80 (Protein Data Bank code 118L) (12)/CD86 (Protein Data Bank code 1185) (SEQ LD 9), bound CD 152 (SEQ LD 7).
  • CD80-CAP1 MQPPGC
  • CD80-CAP1 is a close mimic of the ligand binding regions of the mouse CD152 and the CD80-bound human CD152 structures. Similar superimposition of CD80-CAP3 (MAVPAT) over free mouse CD 152 and free human CD152 yielded an r.m.s. deviation value of 1.47 and 1.19 A, respectively. All CD80-CAPs that were within 5-A r.m.s. deviation when superimposed over free murine or human CD152 and ⁇ 1-A r.m.s. deviation when superimposed over CD80-bound CD152 were selected for in silico docking. Some estimated physical properties of CD80-CAP1 (SEQ LD 2) and the consensus sequence MYPPPY (SEQ ID 12) are presented in Table 2.
  • Example 3 Docking of mouse CD80 CD28
  • the extracellular domain of mouse CD80 (SEQ LDIO) was modeled by Geno3D using the solution structure of human CD80 (B7-1) (SEQ EDI 1), human B7-2 (SEQ LD 14) (PDB INCN) and the docked human CD80 (B7-1) (SEQ LD 8) as the templates.
  • Superimposition of the residues in the CDR1 and CDR3 like regions thought to be involved in receptor binding yielded an RMSD of 1.87 A.
  • a RMSD value of this magnitude suggests high similarity between the searched sequence and the proteins structures that were used to model it.
  • mouse CD28 SEQ LD 5
  • SEQ LD 6 and SEQ LD 13 the extracellular domain of mouse CD28 (SEQ LD 5) was modeled by Geno3D using the solution structure of mouse and human CTLA-4 (SEQ LD 6 and SEQ LD 13) (PDB: 1 DQT and PDB 1AH1) as the templates.
  • the MYPPPY (SEQ LD 6 and 12) motif was localized to the FG loop in both, the proline in the YPP sequence had the phi and psi angles of a PPLT type LT helix in CD28 and not in CD152.
  • the PPP sequence in CD28 is in a cis-trans-trans orientation favoring PP LI helical conformation, while in CD 152 it is in a cis-trans-cis orientation.
  • Docking of the mouse CD80 and a six-residue peptide having the amino acid sequence MQPPGC (SEQ ED 2) CD80-CAP1 was performed using the known BIGGER software, which utilizes the soft docking algorithm.
  • each CD80-CAP was systematically rotated (in discrete steps of 15) and translated against the surface of CD80.
  • the top 100 docked structures of each complex generated were screened by superimposition with the human CD80-CD152 complex (Protein Data Bank code 118L).
  • Potential CD80-CAP- CD80-docked structures with r.m.s. deviation of ⁇ 5 A were then subjected to energy minimization to optimize the binding conformation of the amino acids by Grammos.
  • Figure 2 shows the energy-minimized CD80-CAP1 occupying the binding cleft of CD80.
  • the conserved CD80 residues critical for binding (Tyr , Val 89 , and Leu 93 ) are within 5 A of the CD80-CAP1, suggesting near native docking (12).
  • Example 4 Structure of the CD80-CAP1 A molecular model of the mouse CD28 was generated by homology modeling by a web based server (Geno3D) that uses distant geometry, simulated annealing and energy minimization algorithms to build the protein 3D model.
  • the mouse CD152 (PDB 1DQT) and the ligand bound human CD152 (PDB: 118L Chain A and B) were specified as the templates.
  • Superimposition of the model with the chain A of 1DQT yielded an RMSD of 1.10 A and with chain B of 1DQT yielded an RMSD of 1.04A validating the accuracy of the model.
  • the phi and psi angles of the CD28 (SEQ LD 5) model and the bound and unbound CD 152 molecules are given in Table 1.
  • CD80-CAP1 with the hydrophobic motif of free murine CD 152 (SEQ ID 6) (PDB 1DQT), free human CD152 (PDB 1AH1) (SEQ LD 12) and ligand bound CD152 (SEQ LD 7) (PDB 118L) yields a root mean square deviation of 0.11 A, 0.84A and 0.34A respectively.
  • SEQ ID 6 free murine CD 152
  • PDB 1AH1 free human CD152
  • SEQ LD 12 ligand bound CD152
  • SEQ LD 7 ligand bound CD152
  • Example 6 The CD80-CAP1 competes with the physiological receptors for binding CD80
  • the ability of the CD80-CAP1 (SEQ LD 2) to compete with physiological receptors_(CD28/CD152) for binding the ligands (CD80/CD86) was evaluated by enzyme-linked immunosorbent assay. Referring now to figure 4 panels A, B, C and D, the ability of the CD80-CAP1 to compete with physiological receptors (CD28/CD152) for binding the ligand (CD80/CD86) was assayed by ELISA. The synthetic CD80-CAP1 significantly inhibited the binding of both CD28-Fc and CD152-Fc to CD80. There was no inhibition of the receptor binding to CD86 ligand.
  • CD80-CAP3 50 ⁇ M also competed effectively, decreasing with the maximum velocity of CD80 binding to CD28 and CD152 to 435.5 and 406 MOD/min, respectively (data not shown).
  • the optical density experiments showed significant reduction in the association rate of select CD80-CAP and to CD28 or CD 152 consistently in multiple experiments. Taken together, these data suggest that both CD80-CAP1 and CD80- CAP3 can selectively block CD80-CD28/CD152 interactions.
  • small molecule inhibitors thought to bind at the "MYPPPY" binding site on CD80 exhibited relatively weak inhibition of CD152-CD80 interactions as compared with CD28-CD152 interaction.
  • Example 7 The CD80-CAP1 inhibits T cell response
  • CD80-CAP1 The ability of the CD80-CAP1 to block the CD80-CD28/CD152 interactions on lymph node cells were assessed by T cell proliferation assays.
  • panel A a significant decrease in the lymph node cell proliferative responses to collagen LT was observed in cells treated with CD80-CAP1.
  • CD80-CAP3 (SEQ ID 15) was not inhibitory at all concentrations tested, as was the control peptide.
  • CD80-CAP3 adopted PPn helical conformation none of the top 100 predicted docked structures exhibited significant proximity to the critical residues (Tyr 28 , Val 79 ) at the binding pocket of CD80. This may explain the lack of inhibitory potential of CD80-CAP3 (SEQ LD 15) despite its ability to compete with CD80-Fc for binding CD28 and CD 152.
  • mice The biological potential of CD80-CAP1 to block the development of inflammatory CIA during antigen priming in vivo was tested.
  • Groups of DBA/1 Lac J mice were immunized with lOO ⁇ g of bCLT in CFA.
  • Groups of mice were administered intravenously 500 ⁇ g of CD80-CAP1 or control peptide or vehicle on the day of immunization.
  • Severity of arthritis was evaluated by assigning a score of 0 to 4 based on the degree of inflammation for each limb, with 4 indicating severe arthritis and 0 indicating no arthritis and a maximum score of 16 per mouse.
  • Example 9 The CD80-CAP inhibits T cells recovered lymph node cells of mice with CIA.
  • Synovial cells from CIA induced and treated with 500 ⁇ g of CD80-CAP or control peptide or vehicle peptide treated mice were isolated 30 days post-CTL immunization were cultured with 20 ⁇ g/ml bCII for a total of 72 h of culture including a 16 h pulse with 3 H thymidine.
  • base line proliferation of LNC cultures in the absence of bCLT was 2846 cpm.
  • Example 10 CD80-CAP1 down regulates the production of molecules linked to the inflammatory response
  • a wide array of cytokines and chemokines has been reported to be involved in inflammation associated with arthritis (Tellander, A. C, Pettersson, U.,
  • lymph node cells from CD80-binding pseudo-receptor treated mice secreted significantly lower amounts of pro-inflammatory cytokine LL-12 as compare to vehicle treated mice following restimulation in vitro with type II collagen figure 9, panel B.
  • Example 11 Treatment with CD80-CAP1 reduces symptoms of colitis in animal models of the disease Inflammatory Bowel Disease (LBD) is a chronic relapsing and remitting inflammatory condition widespread in the Untied States and Europe.
  • LBD Inflammatory Bowel Disease
  • T-cell activation involves a multitude of signaling molecules, including the CD28 and cytotoxic T-lymphocyte antigen (CTLA) receptors on the T-cell surface, and their ligands, the B7 molecules.
  • CTLA cytotoxic T-lymphocyte antigen
  • Weight loss is a common system of LBS and accordingly body weight measurements were used to asses the progress of the disease.
  • change in body weight is expressed as percentage of the original weight (A) for individual mice and (B) as average for individual groups, data represented as mean +/_ standard deviation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne des molécules liant le ligand CD80 (B7-1) présenté par des cellules présentatrices d'antigène et inhibant ainsi sélectivement la costimulation de lymphocytes T. Diverses formes et préparations de ces molécules peuvent se lier au ligand CD80 dans des conditions i>in vivo ou <i>in vitro . Ces molécules pouvant être désignées en tant que pseudo-récepteurs contiennent des polypeptides contenant la séquence d'acides aminés MQPPGC, et un analogue de peptide rétro-inverse contenant la séquence d'acides D-aminés CGPPQM. Ces molécules ont une propension à adopter une conformation hélicoïdale de polyproline de type II dans des conditions physiologiques. Ces molécules peuvent être employées pour l'étude du système immunitaire, le criblage d'autres composés affectant le système immunitaire ou au moins des composants du système immunitaire, et le traitement de maladies auto-immunitaires telles que la sclérose en plaques, la colite (maladie intestinale inflammatoire), l'arthrite rhumatoïde, la maladie de Crohn, le syndrome de Sjorgen, le diabète sucré et le rejet de transplantation de tissus solides.
PCT/US2005/011209 2004-03-30 2005-03-30 Peptides de liaison de cd80 (b7-1) et utilisations Ceased WO2005108432A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US55774604P 2004-03-30 2004-03-30
US60/557,746 2004-03-30

Publications (2)

Publication Number Publication Date
WO2005108432A2 true WO2005108432A2 (fr) 2005-11-17
WO2005108432A3 WO2005108432A3 (fr) 2006-05-18

Family

ID=35320790

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/011209 Ceased WO2005108432A2 (fr) 2004-03-30 2005-03-30 Peptides de liaison de cd80 (b7-1) et utilisations

Country Status (1)

Country Link
WO (1) WO2005108432A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113019A3 (fr) * 2010-03-12 2012-02-02 Abbott Biotherapeutics Corp. Protéines ctla4 et leurs utilisations
EP2720719A4 (fr) * 2011-06-15 2015-12-09 Glaxosmithkline Ip No 2 Ltd Procédé de sélection d'indications thérapeutiques
US20210340214A1 (en) * 2018-08-29 2021-11-04 Five Prime Therapeutics, Inc. Cd80 extracellular domain fc fusion protein dosing regimens
TWI882746B (zh) * 2024-03-27 2025-05-01 臺北醫學大學 一種新穎胜肽

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6528060B1 (en) * 2000-03-16 2003-03-04 Genzyme Corporation Therapeutic compounds
EP1425040A2 (fr) * 2001-09-14 2004-06-09 Cytos Biotechnology AG Activation in vivo de cellules presentant un antigene en vue d'augmenter les reponses immunes induites par des particules de type virus

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113019A3 (fr) * 2010-03-12 2012-02-02 Abbott Biotherapeutics Corp. Protéines ctla4 et leurs utilisations
US8642557B2 (en) 2010-03-12 2014-02-04 Abbvie Biotherapeutics Inc. CTLA4 proteins and their uses
US9587007B2 (en) 2010-03-12 2017-03-07 Abbvie Biotherapeutics Inc. CTLA4 proteins and their uses
EP2720719A4 (fr) * 2011-06-15 2015-12-09 Glaxosmithkline Ip No 2 Ltd Procédé de sélection d'indications thérapeutiques
US20210340214A1 (en) * 2018-08-29 2021-11-04 Five Prime Therapeutics, Inc. Cd80 extracellular domain fc fusion protein dosing regimens
TWI882746B (zh) * 2024-03-27 2025-05-01 臺北醫學大學 一種新穎胜肽

Also Published As

Publication number Publication date
WO2005108432A3 (fr) 2006-05-18

Similar Documents

Publication Publication Date Title
Mezo et al. Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn
ES2679994T3 (es) Péptidos relacionados con TCR-V-BETA para el tratamiento y diagnóstico de enfermedad autoinmune
US20170020956A1 (en) Peptides Having Anti-Inflammatory Properties
US20160304580A1 (en) Cd86 variants with improved affinity for ctla-4
US20150079085A1 (en) Methods of modulating immune responses by modulating tim-1, tim-2 and tim-4 function
JP6364352B2 (ja) 部分的ｍｈｃコンストラクト及びその使用方法
WO2000012130A1 (fr) Agonistes et antagonistes de rp105
RS20070027A (sr) Antitela anti-cd154
Srinivasan et al. Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28
JP2009029833A (ja) Ｃｄ２８／ｃｔｌａ−４阻害性ペプチド模倣物、それらの医薬組成物、およびそれらを使用する方法
JPH08503222A (ja) Ｔ細胞増殖を阻害する化合物及び同化合物の使用方法
NZ549731A (en) Methods and compositions for treatment of autoimmune diseases
Allen et al. Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade
US6299875B1 (en) Methods to block IGE binding to cell surface receptors of mast cells
US8999937B2 (en) Glucocorticoid induced leucine zipper mimetics as therapeutic agents in multiple sclerosis
EP2692733B1 (fr) Acides nucléiques codant pour des formes solubles du CD83
US20010049122A1 (en) Phosphatidyl serine receptors and uses thereof
US6180600B1 (en) CD8 antagonists
US6218363B1 (en) MHC peptides and methods of use
US7531168B2 (en) Method for downmodulating immune response in type I diabetes
WO2005108432A2 (fr) Peptides de liaison de cd80 (b7-1) et utilisations
Srinivasan et al. CD80 binding polyproline helical peptide inhibits T cell activation
WO2020221927A1 (fr) Molécules de liaison anti-lag-3
Akhter A comparative review on TLQP-21 receptors: rodent versus human
WO2025140345A1 (fr) Polypeptide tigit et protéine de fusion tigit/ctla4

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase