Methods and compositions for treating autoimmune diseases or conditions

Abstract

The present invention relates to methods of treating immune disorders, particularly autoimmune and inflammatory disorders such as rheumatoid arthritis, and methods of producing antibodies for use in therapeutic strategies for treating such disorders. Generally, the present methods involve the use of antibodies that specifically bind to NKG2D receptors present on the surface of cells underlying the disorders.

1 . A method of treating a patient with an inflammatory or autoimmune disorder, said method comprising administering to said patient a pharmaceutical composition comprising an inhibitor of an NKG2D receptor, and a pharmaceutically acceptable carrier. 
     
     
         2 . The method of  claim 1 , wherein said inhibitor is a monoclonal antibody, or a fragment or derivative thereof. 
     
     
         3 . The method of  claim 2 , wherein said antibody is humanized, chimeric, or human. 
     
     
         4 . The method of  claim 2 , wherein said antibody is derived from the monoclonal antibody clone 1D11. 
     
     
         5 . The method of  claim 1 , wherein said inhibitor interferes with the binding of an NKG2D ligand to the NKG2D receptor. 
     
     
         6 . The method of  claim 1 , wherein said inflammatory or autoimmune disorder is selected from systemic lupus erythematosus, multiple sclerosis, Wegener's granulomatosus, temporal arteritis, Bechet's disease, or gastrointestinal inflammation. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein said method further comprises the administration of a pharmaceutical composition comprising a therapeutic compound selected from the group consisting of an inhibitor of TNF-alpha and an inhibitor of IL-15. 
     
     
         9 . The method of  claim 1 , wherein said patient has an elevated level of NKG2D-expressing T cells. 
     
     
         10 . The method of  claim 9 , wherein said T cells are CD4 + . 
     
     
         11 . The method of  claim 10 , wherein said T cells are CD28 − . 
     
     
         12 . The method of  claim 1 , wherein said method further comprises a diagnostic step in which, prior to the administration of said inhibitor, the prevalence of NKG2D-expressing CD4 + CD28 −  T cells in said patient is assessed, wherein a detection of elevated levels of said cells in said patient indicates that the patient is suitable for the administration of said inhibitor. 
     
     
         13 . The method of  claim 12 , wherein said diagnostic step comprises an immunoassay to detect the presence of CD4, CD28, or NKG2D on T cells obtained from said patient. 
     
     
         14 . The method of  claim 2 , wherein said antibody is a cytotoxic antibody. 
     
     
         15 . The method of  claim 14 , wherein said cytotoxic antibody comprises an element selected from the group consisting of a toxic peptide and a toxic small molecule. 
     
     
         16 . A method of producing an antibody suitable for use in the treatment of an autoimmune or inflammatory disorder, said method comprising:
 i) providing a NKG2D receptor-expressing CD4 + CD28 −  T cell and a plurality of monoclonal antibodies;   ii) testing the ability of each of said antibodies to interfere with the binding of a ligand to said NKG2D receptor on said cells;   iii) selecting an antibody from said plurality that reduces the binding of said ligand to said receptor; and   iv) rendering said antibody suitable for human administration.   
     
     
         17 - 24 . (canceled) 
     
     
         25 . An antibody produced using the method of  claim 16 . 
     
     
         26 . A pharmaceutical composition comprising an antibody produced using the method of  claim 16 , and a pharmaceutically acceptable carrier. 
     
     
         27 . A kit comprising an antibody produced by the method of  claim 16 , and instructions for using said antibody in the treatment of rheumatoid arthritis. 
     
     
         28 . A method for reducing CD4 +  NKG2D +  autoreactive T cell stimulation in a patient in need thereof, said method comprising administering to said patient a pharmaceutical composition comprising an inhibitor of an NKG2D receptor, and a pharmaceutically acceptable carrier. 
     
     
         29 . The method of  claim 28 , wherein the patient has an autoimmune disorder selected from rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Wegener's granulomatosus, temporal arteritis, Bechet's disease or gastrointestinal inflammation.