Anti-Interferon Gamma Antibodies and Methods of Use Thereof

Abstract

The invention relates to fully human antibodies, and fragments thereof, that bind to human interferon gamma (hIFNγ), thereby modulating the interaction between IFNγ and its receptor, IFNγ-R, and/or modulating the biological activities of IFNγ. The invention also relates to the use of such anti-IFNγ antibodies in the prevention or treatment of immune-related disorders and in the amelioration of a symptom associated with an immune-related disorder.

1 . An isolated fully human monoclonal anti-IFNγ antibody or fragment thereof, wherein said antibody comprises:
 (a) a V H  CDR1 region comprising the amino acid sequence SYAMS (SEQ ID NO:3) or SNAMS (SEQ ID NO:43);   (b) a V H  CDR2 region comprising the amino acid sequence AISGSGGSTYYADSVKG (SEQ ID NO:4) or TLTGSGGTAYYADSVEG (SEQ ID NO:44), and   (c) a V H  CDR3 region comprising an amino acid sequence selected from the group consisting of DGSSGWYVPHWFDP (SEQ ID NO:5); DHSSGWYVISGMDV (SEQ ID NO:13); DLTVGGPWYYFDY (SEQ ID NO:21); DGWNALGWLES (SEQ ID NO:29); GTELVGGGLDN (SEQ ID NO:45); RSFDSGGSFEY (SEQ ID NO:64); VGSWYLEDFDI (SEQ ID NO:69); GGNYGDYFDYFDY (SEQ ID NO:76); and DFWVITSGNDY (SEQ ID NO:89),   wherein said antibody binds IFNγ.   
     
     
         2 . The antibody of  claim 1 , wherein said antibody further comprises:
 (d) a V L  CDR1 region comprising an amino acid sequence selected from the group consisting of TRSSGSIASNYVQ (SEQ ID NO:8); TRSSGSIASNYVQ (SEQ ID NO:16); TRSGGSIGSYYVQ (SEQ ID NO:32); TRSSGTIASNYVQ (SEQ ID NO:39); TGSGGSIATNYVQ (SEQ ID NO:48); TGSSGSIASNYVQ (SEQ ID NO:55); TRSSGSIASNYVH (SEQ ID NO:72); TGRNGNIASNYVQ (SEQ ID NO:84); AGSSGSIASNYVQ (SEQ ID NO:97) and TRSSGSIVSNYVQ (SEQ ID NO:106);   (e) a V L  CDR2 region comprising an amino acid sequence selected from the group consisting of EDNQRPS (SEQ ID NO:9); EDNQRPS (SEQ ID NO:17); DDDQRPS (SEQ ID NO:25); DDKKRPS (SEQ ID NO:33); EDTQRPS (SEQ ID NO:85) and EDNRRPS (SEQ ID NO:107); and   (f) a V L  CDR3 region comprising an amino acid sequence selected from the group consisting of QSYDGSNRWM (SEQ ID NO:10); QSNDSDNVV (SEQ ID NO:18); QSYDSSNVV (SEQ ID NO:26); QSYDSNNLVV (SEQ ID NO:34); QSYDNSNHWV (SEQ ID NO:40); QSYDSDNHHVV (SEQ ID NO:49); QSYDSSNQEVV (SEQ ID NO:56); QSYDSNNFWV (SEQ ID NO:61); QSSDTTYHGGVV (SEQ ID NO:73); QSYEGF (SEQ ID NO:79); QSSDSNRVL (SEQ ID NO:86); QSFDSTNLVV (SEQ ID NO:92); and QSYSYNNQVV (SEQ ID NO:98).   
     
     
         3 . The antibody of  claim 1 , wherein said antibody is an IgG isotype. 
     
     
         4 . The antibody of  claim 2 , wherein said antibody comprises a V H  CDR1 region comprising the amino acid sequence SYAMS (SEQ ID NO:3); a V H  CDR2 region comprising the amino acid sequence AISGSGGSTYYADSVKG (SEQ ID NO:4), a V H  CDR3 region comprising the amino acid sequence DGSSGWYVPHWFDP (SEQ ID NO:5); a V L  CDR1 region comprising the amino acid sequence TRSSGSIASNYVQ (SEQ ID NO:8); a V L  CDR2 region comprising the amino acid sequence EDNQRPS (SEQ ID NO:9); and a V L  CDR3 region comprising an amino acid sequence QSYDGSNRWM (SEQ ID NO:10). 
     
     
         5 . The antibody of  claim 1 , wherein said antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:7. 
     
     
         6 . An isolated fully human monoclonal antibody, wherein said antibody comprises a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 12, 20, 28, 36, 42, 51, 58, 63, 68, 75, 81, 88, 94 or 103, wherein said antibody binds IFNγ. 
     
     
         7 . The antibody of  claim 6 , wherein said antibody further comprises a light chain variable amino acid sequence selected from the group consisting of SEQ ID NOS: 7, 15, 23, 31, 38, 47, 54, 60, 66, 71, 78, 83, 91, 96 or 105, wherein said antibody binds IFNγ. 
     
     
         8 . The antibody of  claim 7 , wherein said antibody comprises a V H  CDR1 region comprising the amino acid sequence SYAMS (SEQ ID NO:3); a V H  CDR2 region comprising the amino acid sequence AISGSGGSTYYADSVKG (SEQ ID NO:4), a V H  CDR3 region comprising the amino acid sequence DGSSGWYVPHWFDP (SEQ ID NO:5); a V L  CDR1 region comprising the amino acid sequence TRSSGSIASNYVQ (SEQ ID NO:8); a V L  CDR2 region comprising the amino acid sequence EDNQRPS (SEQ ID NO:9); and a V L  CDR3 region comprising an amino acid sequence QSYDGSNRWM (SEQ ID NO:10). 
     
     
         9 . The antibody of  claim 4 , wherein said antibody is an IgG isotype. 
     
     
         10 . A pharmaceutical composition comprising an antibody of  claim 1  and a carrier. 
     
     
         11 . A pharmaceutical composition comprising an antibody of  claim 4  and a carrier. 
     
     
         12 . A method of alleviating a symptom of an autoimmune disease or inflammatory disorder, the method comprising administering an antibody of  claim 1  to a subject in need thereof in an amount sufficient to alleviate the symptom of the autoimmune disease or inflammatory disorder in the subject. 
     
     
         13 . The method of  claim 12 , wherein said subject is a human. 
     
     
         14 . The method of  claim 12 , wherein said antibody comprises a V H  CDR1 region comprising the amino acid sequence SYAMS (SEQ ID NO:3); a V H  CDR2 region comprising the amino acid sequence AISGSGGSTYYADSVKG (SEQ ID NO:4), a V H  CDR3 region comprising the amino acid sequence DGSSGWYVPHWFDP (SEQ ID NO:5); a V L  CDR1 region comprising the amino acid sequence TRSSGSIASNYVQ (SEQ ID NO:8); a V L  CDR2 region comprising the amino acid sequence EDNQRPS (SEQ ID NO:9); and a V L  CDR3 region comprising an amino acid sequence QSYDGSNRWM (SEQ ID NO:10). 
     
     
         15 . The method of  claim 14 , wherein said antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:7. 
     
     
         16 . The method of  claim 12 , wherein said autoimmune disease or inflammatory disorder is selected from the group consisting of Crohn's Disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, vasculitis, atopic dermatitis and secondary progressive multiple sclerosis. 
     
     
         17 . The method of  claim 12 , wherein said antibody is administered intravenously. 
     
     
         18 . The method of  claim 12 , wherein said antibody is co-administered with an second agent selected from the group consisting of:
 (a) an anti-cytokine that recognizes one or more cytokines selected from interleukin 1 (IL-1), IL-2, IL-4, IL-6, IL-12, IL-13, IL-15, IL-17, IL-18, IL-20, IL-21, IL-22, IL-23, IL-27 and IL-31;   (b) an anti-chemokine reagent that recognizes one or more cytokines selected from IL-1, IL-2, IL-4, IL-6, IL-12, IL-13, IL-15, IL-17, IL-18, IL-20, IL-21, IL-22, IL-23, IL-27 and IL-31;   (c) a chemokines selected from MIP1 alpha, MIP1 beta, RANTES, MCP1, IP-10, ITAC, MIG, SDF and fractalkine.   
     
     
         19 . A method of reducing MHC class II expression on a cell, the method comprising contacting a cell with an antibody of  claim 1  in an amount sufficient to reduce MHC class II expression on said cell. 
     
     
         20 . The method of  claim 19 , wherein said cell is a human melanoma cell. 
     
     
         21 . The method of  claim 19 , wherein said antibody comprises a V H  CDR1 region comprising the amino acid sequence SYAMS (SEQ ID NO:3); a V H  CDR2 region comprising the amino acid sequence AISGSGGSTYYADSVKG (SEQ ID NO:4), a V H  CDR3 region comprising the amino acid sequence DGSSGWYVPHWFDP (SEQ ID NO:5); a V L  CDR1 region comprising the amino acid sequence TRSSGSIASNYVQ (SEQ ID NO:8); a V L  CDR2 region comprising the amino acid sequence EDNQRPS (SEQ ID NO:9); and a V L  CDR3 region comprising an amino acid sequence QSYDGSNRWM (SEQ ID NO:10). 
     
     
         22 . The method of  claim 21 , wherein said antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:7. 
     
     
         23 . The method of  claim 19 , wherein said cell is contacted with a second agent selected from the group consisting of:
 (a) an anti-cytokine that recognizes one or more cytokines selected from interleukin 1 (IL-1), IL-2, IL-4, IL-6, IL-12, IL-13, IL-15, IL-17, IL-18, IL-20, IL-21, IL-22, IL-23, IL-27 and IL-31;   (b) an anti-chemokine reagent that recognizes one or more cytokines selected from IL-1, IL-2, IL-4, IL-6, IL-12, IL-13, IL-15, IL-17, IL-18, IL-20, IL-21, IL-22, IL-23, IL-27 and IL-31;   (c) a chemokines selected from MIP1 alpha, MIP1 beta, RANTES, MCP1, IP-10, ITAC, MIG, SDF and fractalkine.