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 Sjogren's syndrome, 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. 
     
     
         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 a monoclonal antibody selected from the group consisting of 1D11. 
     
     
         5 . The method of  claim 1 , wherein said inhibitor interferes with the binding of an NKG2D ligand to the NKG2D receptor. 
     
     
         6 - 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 when compared to the level of said cells in a control 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 Sjogren's syndrome, 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 . The method of  claim 16 , wherein said antibody is made suitable for human administration by humanizing or chimerizing it. 
     
     
         18 . The method of  claim 16 , further comprising a step in which a cytotoxic agent is linked to said antibody. 
     
     
         19 . The method of  claim 18 , wherein said cytotoxic agent is a radioactive isotope, a toxic polypeptide, or a toxic small molecule. 
     
     
         20 . The method of  claim 16 , wherein said antibody reduces the binding of said ligand to said receptor by at least a percentage selected from the group consisting of 50%, 60%, 70%, 80%, 90%, 95%, and 99%. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The method of  claim 16 , further comprising a step in which the activity of said NKG2D receptor on said T cells is assessed in the presence of said ligand and said antibody. 
     
     
         24 . The method of  claim 23 , wherein said activity is assessed using an assay selected from the group consisting of cytotoxicity assays, cytokine release assays, and proliferation assays. 
     
     
         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 . (canceled)