Immunotherapy of autoimmune disorders using antibodies which target B-cells

Abstract

Antibodies that bind with a B-cell antigen provide an effective means to treat autoimmune disorders. Antibodies and fragments, which may be conjugated or naked, are used alone or in multimodal therapies. The antibodies may be bispecific antibodies which may be produced recombinantly as fusion proteins, or as hybrid, polyspecific antibodies.

What is claimed is:  
     
         1 . A method for treating an autoimmune disorder, comprising administering to a subject having an autoimmune disorder a therapeutic composition comprising a pharmaceutically acceptable carrier and at least one antibody to a B-cell antigen.  
     
     
         2 . The method of  claim 1 , wherein said therapeutic composition is administered parenterally in a dosage of from 20 to 2000 mg per dose.  
     
     
         3 . The method of  claim 2 , wherein said subject receives said antibody in repeated parenteral dosages.  
     
     
         4 . The method of  claim 1 , wherein said antibody is selected from the group consisting of subhuman primate antibody, murine monoclonal antibody, chimeric antibody, humanized antibody, and human antibody.  
     
     
         5 . The method of  claim 4 , wherein said antibody is the murine, chimeric, or humanized LL2 antibody.  
     
     
         6 . The method of  claim 1 , wherein said therapeutic composition comprises at least two monoclonal antibodies that bind with distinct CD22 epitopes, wherein said CD22 epitopes are selected from the group consisting of epitope A, epitope B, epitope C, epitope D and epitope E.  
     
     
         7 . The method of  claim 1 , wherein said autoimmune disease is selected from the group consisting acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, poly glandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis ubiterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pamphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis and fibrosing alveolitis.  
     
     
         8 . The method of  claim 1 , further comprising separately administering a secondary therapeutic directed against T-cells, plasma cells, or macrophages or inflammatory cytokines.  
     
     
         9 . The method of  claim 8 , wherein said secondary therapeutic is administered prior to the administration of said therapeutic composition.  
     
     
         10 . The method of  claim 9 , wherein said secondary therapeutic is administered concurrently with the administration of said therapeutic composition.  
     
     
         11 . The method of  claim 10 , wherein said secondary therapeutic is administered after the administration of said therapeutic composition.  
     
     
         12 . The method of  claim 1 , wherein said B-cell antigen is selected from the group consisting of CD19, CD20, CD22, HLA-DR and CD74.  
     
     
         13 . The method of  claim 1 , wherein said B-cell antigen is CD22.  
     
     
         14 . The method of  claim 1 , wherein said antibody is a naked antibody.  
     
     
         15 . The method of  claim 14 , wherein said antibody is a naked anti-CD22 antibody.  
     
     
         16 . The method of  claim 1 , further comprising administering a secondary therapeutic directed against T-cells, plasma cells, macrophages, or inflammatory cytokines wherein said secondary therapeutic is conjugated to an anti-B-cell antibody or is separately administered.  
     
     
         17 . The method of  claim 1 , further comprising administering a secondary therapeutic which is a conjugate of an anti-B-cell antibody with IL-2 or GM-CSF.  
     
     
         18 . The method of  claim 16 , wherein said conjugate is used in combination with a naked B-cell antibody.  
     
     
         19 . The method of  claim 1 , further comprising administering a secondary therapeutic directed against an inflammatory cytokine.  
     
     
         20 . The method of  claim 19 , wherein said secondary therapeutic is an anti-TNFα or anti-IL-1 agent.  
     
     
         21 . The method of  claim 1 , comprising administering a naked anti-CD22, anti-CD19, anti-CD20, or anti-CD74 antibody in combination with a conjugate of an anti-CD22, anti-CD19, anti-CD20, or anti-CD74 antibody with a drug, toxin, enzyme, cytokine, hormone, boron compound or therapeutic radionuclide.  
     
     
         22 . The method of  claim 21 , wherein said naked antibody and said conjugated antibody are directed against the same antigen or epitope.  
     
     
         23 . The method of  claim 21 , wherein said naked antibody and said conjugated antibody are directed against different antigens or epitopes.  
     
     
         24 . The method of  claim 21 , wherein said conjugate is a drug conjugate in which the drug is one that acts against B-cells, plasma cells, or T-cells.  
     
     
         25 . The method of  claim 21 , wherein said conjugate is a drug conjugate in which the drug is one that acts against an inflammatory cytokine.  
     
     
         26 . The method of  claim 21 , wherein said conjugate comprises an enzyme.  
     
     
         27 . The method of  claim 26 , wherein said enzyme is an RNAse.  
     
     
         28 . The method of  claim 1 , wherein said therapeutic composition comprises a hybrid antibody which binds more than one B-cell antigen.  
     
     
         29 . The method of  claim 1 , wherein said therapeutic composition comprises a hybrid antibody which binds more than one epitope of the same B-cell antigen.  
     
     
         30 . The method of  claim 1 , wherein said therapeutic composition comprises a bispecific fusion protein, in which at least one arm targets a B-cell and a second arm targets a T-cell, plasma cell or macrophage antigen.  
     
     
         31 . The method of  claim 1 , comprising administering a conjugate of an anti-CD19, anti-CD20, anti-CD22 or anti-CD74 antibody with a drug, toxin, enzyme, cytokine, hormone, boron compound or therapeutic radionuclide.  
     
     
         32 . The method of  claim 16 , wherein said drug is selected from the group consisting of methotrexate, phenyl butyrate, bryostatin, cyclophosphamide, etoposide, bleomycin, doxorubicin, carmustine, vincristine, procarbazine, dexamethasone, leucovorin, prednisone, maytansinoids such as DM1, calicheamicin, rapamycin, leflunomide, FK506, immuran, fludarabine, azathiopine, mycophenolate, and cyclosporin.  
     
     
         33 . The method of  claim 16 , wherein said drug is selected from the group consisting of immuran, methotrexate, and fludarabine.  
     
     
         34 . The method of  claim 1 , wherein said antibody comprises an arm that is specific for a low-molecular weight hapten and wherein a low-molecular weight hapten with an attached therapeutic agent is administered after the antibody has bound to the B-cell antigen.  
     
     
         35 . The method of  claim 34 , wherein said hapten is a chelator.  
     
     
         36 . The method of  claim 17 , wherein said conjugate is used in combination with a naked B-cell antibody.