Antagonists of tweak and of tweak receptor and their use to treat immunological disorders

Abstract

The present invention relates to reagents which modify the activity of TWEAK and their use as therapeutic agents for the treatment of immunological disorders.

1 . A method for blocking the development or treating or reducing the severity or effects of an immunological disorder in an animal comprising the step of administering a pharmaceutical composition which comprises a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier. 
     
     
         2 . A method for inhibiting an immune response in an animal comprising the step of administering a pharmaceutical composition which comprises an effective amount of a TWEAK blocking agent and a pharmaceutically effective carrier. 
     
     
         3 . The method according to  claim 1 , wherein the TWEAK blocking agent is selected from the group consisting of: (a) an antibody directed against the TWEAK ligand; (b) an antibody directed against the TWEAK receptor; (c) an agent that modifies the binding of the TWEAK ligand to the receptor; (d) an agent that modifies the cell surface receptor clustering; and an agent that can interrupt the intra cellular signaling of the TWEAK receptor. 
     
     
         4 . The method according to  claim 1 , wherein the animal is mammalian. 
     
     
         5 . The method according to  claim 4 , wherein the mammal is human. 
     
     
         6 . The method according to  claim 1 , wherein the TWEAK blocking agent comprises a soluble TWEAK receptor having a ligand binding domain that can selectively bind to a surface TWEAK ligand. 
     
     
         7 . The method of  claim 6 , wherein the soluble TWEAK receptor comprises a human immunoglobulin IgG domain. 
     
     
         8 . The method of  claim 7 , wherein the human immunoglobulin IgG domain comprises regions responsible for specific antigen binding. 
     
     
         9 . The method according to  claim 1 , wherein the antibody directed against the TWEAK receptor comprises a monoclonal antibody. 
     
     
         10 . The method according to  claim 1 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK surface ligand. 
     
     
         11 . The method according to  claim 10 , wherein the antibody is directed against a subunit of the TWEAK ligand. 
     
     
         12 . The method according to  claim 2 , wherein the immune response is a Th1 cell-mediated immune response. 
     
     
         13 . The method according to  claim 2 , wherein the immune response is a Th2 cell-mediated immune response. 
     
     
         14 . The method according to  claim 2 , wherein the immune response includes both a Th1 and a Th2 cell-mediated response. 
     
     
         15 . The method according to  claim 2 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK receptor. 
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier. 
     
     
         17 . The composition according to  claim 16 , wherein the TWEAK blocking agent is selected from the group consisting of: (a) an antibody directed against the TWEAK ligand; (b) an antibody directed against the TWEAK receptor; (c) an agent that modifies the binding of the TWEAK ligand to the receptor; (d) an agent that modifies the cell surface receptor clustering; and (e) an agent that can interrupt the intracellular signaling of the TWEAK receptor 
     
     
         18 . The composition according to  claim 16 , wherein the TWEAK blocking agent comprises a soluble TWEAK receptor having a ligand binding domain that can selectively bind to a surface TWEAK ligand. 
     
     
         19 . The composition according to  claim 18 , wherein the soluble TWEAK receptor comprises a human immunoglobulin IgG domain into which regions responsible for specific antigen binding have been inserted. 
     
     
         20 . The composition of  claim 16 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK receptor. 
     
     
         21 . The composition according to  claim 16 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK surface ligand. 
     
     
         22 . The composition according to  claim 21 , wherein the antibody is directed against a subunit of the TWEAK ligand. 
     
     
         23 . A method of treating a Th1 mediated disorder in a mammal comprising administering to said mammal an effective amount of an antagonist molecule, wherein said antagonist is selected from the group consisting of
 a) an anti-TWEAK antibody;   b) an anti-TWEAK receptor antibody;   c) a fusion protein comprising the extracellular domain of TWEAK receptor and all or part of an immunoglobulin;   d) an agent or molecule which blocks or interrupts intracellular signaling of TWEAK receptor.   
     
     
         24 . A method of treating a Th2 mediated disorder in a mammal comprising administering to said mammal an effective amount of an antagonist molecule, wherein said antagonist is selected from the group consisting of
 a) an anti-TWEAK antibody;   b) an anti-TWEAK receptor antibody;   c) a fusion protein comprising the extracellular domain of TWEAK receptor and all or part of an immunoglobulin;   d) an agent or molecule which blocks or interrupts intracellular signaling of TWEAK receptor.   
     
     
         25 . The method of  claim 24 , wherein the disorder is mediated by both Th1 and Th2. 
     
     
         26 . The method of  claim 23  or  24 , wherein the anti-TWEAK antibody or the anti-TWEAK receptor antibody is chimeric or humanized. 
     
     
         27 . The method  claim 23  or  24 , wherein the wherein the disorder is an auto-immune disease. 
     
     
         28 . The method of any one of  claims 1 ,  23 , and  24 , wherein the disorder is selected from graft-versus-host disease (GVHD), myasthenia gravis, autoimmune hemolytic anemia, Chagas' disease, Graves' disease, idiopathic thrombocytopenia purpura (ITP), systemic lupus erythematosus (SLE), Wegener's granulomatosis, poly-arteritis nodosa; rapidly progressive crescentic glomerulonephritis; retinal uveitis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, allergic inflammation, asthma, and eosinophilia. 
     
     
         29 . A method for blocking the development or treating or reducing the severity or effects of an immunological disorder in an animal comprising the step of administering a therapeutically effective amount of an antibody that binds to a TWEAK polypeptide consisting of SEQ ID NO:1 or SEQ ID NO:2, wherein the immunological disorder is rheumatoid arthritis or inflammatory bowel disease. 
     
     
         30 . The method of  claim 29 , wherein the immunological disorder is rheumatoid arthritis. 
     
     
         31 . The method of  claim 29 , wherein the immunological disorder is inflammatory bowel disease. 
     
     
         32 . The method of  claim 31 , wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. 
     
     
         33 . The method of  claim 29 , wherein the animal is a mammal. 
     
     
         34 . The method of  claim 33 , wherein the mammal is human. 
     
     
         35 . The method of  claim 29 , wherein the antibody binds to the human TWEAK polypeptide consisting of SEQ ID NO:2. 
     
     
         36 . The method of  claim 35 , wherein the antibody is a monoclonal antibody. 
     
     
         37 . The method of  claim 36 , wherein the monoclonal antibody is a monoclonal antibody produced by a hybridoma. 
     
     
         38 . The method of  claim 37 , wherein the monoclonal antibody is an AB.D3 monoclonal antibody produced by a hybridoma having ATCC Accession No. HB-12622. 
     
     
         39 . The method of  claim 35 , wherein the antibody is a recombinant antibody. 
     
     
         40 . The method of  claim 35 , wherein the antibody is a humanized antibody. 
     
     
         41 . The method of  claim 35 , wherein the antibody is a chimeric antibody. 
     
     
         42 . The method of  claim 35 , wherein the antibody comprises a human constant domain. 
     
     
         43 . The method of  claim 35 , wherein the antibody is an IgG. 
     
     
         44 . The method of  claim 35 , wherein the antibody is a chimera of antibody AB.D3 produced by a hybridoma having ATCC Accession No. HB-12622. 
     
     
         45 . The method of  claim 35 , wherein the antibody comprises variable domains of antibody AB.D3 produced by the hybridoma deposited with ATCC under Accession No. HB-12622. 
     
     
         46 . The method of  claim 35 , wherein the antibody comprises variable domain sequences responsible for specific antigen binding from antibody AB.D3 produced by the hybridoma deposited with ATCC under Accession No. HB-12622. 
     
     
         47 . The method of  claim 35 , wherein the antibody is administered by a parenteral, subcutaneous, or intravenous route. 
     
     
         48 . The method of  claim 35 , wherein the antibody is administered as a liquid composition. 
     
     
         49 . The method of  claim 35 , wherein the liquid composition is a sterile, isotonic composition. 
     
     
         50 . The method of  claim 35 , wherein the antibody blocks the binding of human TWEAK-Flag polypeptide to HT29 cells. 
     
     
         51 . The method of  claim 35 , wherein the antibody also binds to a polypeptide consisting of SEQ ID NO:1. 
     
     
         52 . A monoclonal antibody that specifically recognizes the epitope to which monoclonal antibody AB.D3, produced by the hybridoma having ATCC Accession No. HB-12622, specifically binds. 
     
     
         53 . The monoclonal antibody of  claim 52 , wherein the antibody has a characteristic selected from the group consisting of:
 (a) binding to human TWEAK polypeptide of SEQ ID NO:2;   (b) binding to murine TWEAK polypeptide of SEQ ID NO:1;   (c) blocking the binding of human TWEAK-Flag polypeptide to a cell surface receptor; and   (d) blocking the binding of murine TWEAK-Flag polypeptide to a cell surface receptor.   
     
     
         54 . The monoclonal antibody of  claim 52 , wherein the antibody is a murine monoclonal antibody. 
     
     
         55 . The monoclonal antibody of  claim 52 , wherein the antibody is a human monoclonal antibody. 
     
     
         56 . The monoclonal antibody of  claim 52 , wherein the antibody is produced by a hybridoma. 
     
     
         57 . The monoclonal antibody of  claim 52 , wherein the antibody is recombinant. 
     
     
         58 . The monoclonal antibody of  claim 52 , wherein the antibody is humanized. 
     
     
         59 . The monoclonal antibody of  claim 52 , wherein the antibody is chimeric. 
     
     
         60 . The monoclonal antibody of  claim 52 , wherein the antibody comprises a human constant domain. 
     
     
         61 . The monoclonal antibody of  claim 52 , wherein the antibody is an IgG. 
     
     
         62 . The monoclonal antibody of  claim 52 , wherein the antibody is a chimera of antibody AB.D3 produced by the hybridoma having ATCC Accession No. HB-12622. 
     
     
         63 . The monoclonal antibody of  claim 52 , wherein the antibody comprises variable domains of antibody AB.D3 produced by the hybridoma having ATCC Accession No. HB-12622. 
     
     
         64 . The monoclonal antibody of  claim 52 , wherein the antibody comprises variable domain sequences responsible for specific antigen binding from antibody AB.D3 produced by the hybridoma deposited with ATCC under Accession No. HB-12622. 
     
     
         65 . The monoclonal antibody of  claim 52 , wherein the antibody is monoclonal antibody AB.D3 produced by the hybridoma having ATCC Accession No. HB-12622. 
     
     
         66 . A hybridoma producing the monoclonal antibody of  claim 52 . 
     
     
         67 . The hybridoma of  claim 64 , wherein the hybridoma produces monoclonal antibody AB.D3 and has ATCC Accession No. HB-12622. 
     
     
         68 . A pharmaceutical composition comprising the monoclonal antibody of  claim 52 , and a pharmaceutically acceptable carrier.