Bispecific antibodies that neutralize both tnf-alpha and il-6: novel therapeutic agent for autoimmune disease

Abstract

The present invention concerns compositions and methods of use of bispecific antibodies comprising at least one anti-TNF-α antibody or antigen-binding fragment thereof and at least one anti-IL-6 antibody or antigen-binding fragment thereof. Preferably, the bispecific antibody is in the form of a DNL® complex. The anti-TNF-α or anti-IL-6 antibodies may comprise specific CDR sequences disclosed herein. The compositions and methods are of use to treat autoimmune disease, immune system dysfunction or inflammatory disease, as disclosed herein.

What is claimed is: 
     
         1 . A method of treating a disease selected from the group consisting of autoimmune disease, immune system dysfunction and inflammatory disease, comprising administering to a subject in need thereof a bispecific antibody comprising at least one anti-TNF-α (tumor necrosis factor alpha) antibody or antigen-binding fragment thereof and at least one anti-IL-6 (interleukin 6) antibody or antigen-binding fragment thereof. 
     
     
         2 . The method of  claim 1 , wherein the bispecific antibody comprises a chimeric or humanized anti-TNF-α IgG antibody and four chimeric or humanized anti-IL-6 antibody fragments 
     
     
         3 . The method of  claim 1 , wherein the bispecific antibody comprises a chimeric or humanized anti-TNF-α IgG antibody and one or more chimeric or humanized anti-IL-6 antibody fragments. 
     
     
         4 . The method of  claim 1 , wherein the antibody fragments are selected from the group consisting of F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, sFv, scFv and single domain antibody fragments. 
     
     
         5 . The method of  claim 1 , wherein the anti-IL-6 antibody fragments are Fab antibody fragments. 
     
     
         6 . The method of  claim 1 , wherein the anti-TNF-α antibody or antigen-binding fragment thereof and the anti-IL-6 antibody or antigen-binding fragment thereof are fusion proteins. 
     
     
         7 . The method of  claim 1 , wherein the anti-IL-6 antibody or fragment thereof comprises the heavy chain CDR sequences CDR1 (GFTFSRFGMH, SEQ ID NO:107), CDR2 (YIGRGSSTIYYADTVKG, SEQ ID NO:108) and CDR3 (SNWDGAMDY, SEQ ID NO:109) and the light chain CDR sequences CDR1 (RASGNIHNFLA, SEQ ID NO:110), CDR2 (NAETLAD, SEQ ID NO:111) and CDR3 (QHFWSTPWT, SEQ ID NO:112). 
     
     
         8 . The method of  claim 1 , wherein the anti-TNF-α antibody or fragment thereof comprises the heavy chain CDR sequences CDR1 (GFWN, SEQ ID NO:113), CDR2 (YISYSGRTYYNPSLKS, SEQ ID NO:114) and CDR3 (DANYVLDY, SEQ ID NO:115) and the light chain CDR sequences CDR1 (KSSQSLLNSSTQKNYLA, SEQ ID NO:116), CDR2 (FASARES, SEQ ID NO:117) and CDR3 (QQHYRTPFT, SEQ ID NO:118). 
     
     
         9 . The method of  claim 1 , wherein the bispecific antibody is conjugated to at least one diagnostic or therapeutic agent. 
     
     
         10 . The method of  claim 8 , wherein the therapeutic agent is selected from the group consisting of a drug, an anti-angiogenic agent, a pro-apoptotic agent, an antibiotic, a hormone, a hormone antagonist, an immunomodulator, a cytokine, a chemokine, a prodrug, and an enzyme. 
     
     
         11 . The method of  claim 1 , wherein the antibody allotype is selected from the group consisting of nG1m1, G1m3, nG1m1,2 and Km3. 
     
     
         12 . The method of  claim 1 , wherein the disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, inflammatory bowel disease, type II diabetes, obesity, atherosclerosis, juvenile idiopathic arthritis, Castleman's disease, systemic sclerosis, polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, cryoglobulinemia, glomerulonephritis, rheumatoid vasculitis, arthritis, sepsis, septic shock, inflammation, non-septic hyperinflammatory disorder, nephritis, inflammatory liver injury, acute pancreatitis, acute respiratory distress syndrome, ischemia-reperfusion injury, ischemic stroke, graft-vs.-host disease and cachexia related to cancer. 
     
     
         13 . The method of  claim 1 , wherein the autoimmune disease is selected from the group consisting of acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sjögren's syndrome, multiple sclerosis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndrome, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis obliterans, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, rheumatoid arthritis, polymyositis/dermatomyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, fibrosing alveolitis, juvenile diabetes, graft-versus-host disease and organ transplant rejection.