Therapeutic antibodies binding il 12rbeta1

Abstract

The present invention relates to antibodies that specifically bind to IL12Rβ1, the non-signal transducing chain of the heterodimeric IL12 receptor (together with IL12Rβ2 chain) as well as IL23 receptor (together with IL23Rα chain). The invention more specifically relates to specific antibodies that are IL12 and IL23 receptor antagonists capable of inhibiting IL12/IL18 induced IFNy production of T cells and compositions and methods of use for said antibodies to treat pathological disorders that can be treated by inhibiting IFNy production, such as rheumatoid arthritis, psoriasis or inflammatory bowel diseases or other autoimmune and inflammatory disorders.

1 . A method of treating a pathological disorder that is mediated by IL12Rβ1, or that can be treated by inhibiting IFNγ production, comprising administering to a subject an isolated antibody or an antigen-binding portion of an antibody that binds IL12Rβ1 (SEQ ID NO:41), with a K D  of 100 nM or less and inhibits IL12 and/or IL23 binding to IL12Rβ1 polypeptide as measured in an in vitro competitive binding assay, said antibody further inhibits IL12 dependent INF-γ production in human blood cells with an IC 50  of 1 nM or less. 
     
     
         2 . The method according to  claim 1 , wherein the disorder is an autoimmune or inflammatory disorder. 
     
     
         3 . The method according to  claim 2 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases. 
     
     
         4 . The method according to  claim 1 , wherein said antibody or an antigen-binding portion is a fully human or humanized antibody or antigen binding portion. 
     
     
         5 . The method according to  claim 1 , wherein said antibody or an antigen-binding portion comprises a mutated or chemically modified amino acid Fc region, wherein said mutated or chemically modified Fc region provides no or decreased ADCC activity when compared with wild type Fc region. 
     
     
         6 . The method according to  claim 5 , wherein the mutated or chemically modified amino acid Fc region is a silent IgG1 Fc region. 
     
     
         7 . The method of  claim 1 , wherein antigen-binding portion comprises a pegylated antigen-binding portion of an antibody that binds IL12Rβ1 (SEQ ID NO:41). 
     
     
         8 . The method according to  claim 7 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases. 
     
     
         9 . The method according to  claim 8 , wherein said antibody or an antigen-binding portion is a fully human or humanized antibody or antigen binding portion. 
     
     
         10 . The method according to  claim 1 , wherein said antibody or an antigen-binding portion comprises:
 a) a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence of SEQ ID NO: 1, 5, and 9, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence of SEQ ID NO: 13, 17, and 21, respectively;   b) a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence of SEQ ID NO: 2, 6, and 10, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence of SEQ ID NO: 14, 18, and 22, respectively;   c) a heavy chain variable region CDR1, CDR2, and CDR3 comprising a sequence of SEQ ID NO: 3, 7, and 11, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising a sequence of SEQ ID NO: 15, 19, and 23, respectively; or   d) a heavy chain variable region CDR1, CDR2, and CDR3 comprising a sequence of SEQ ID NO: 4, 8, and 12, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising a sequence of SEQ ID NO: 16, 20, and 24, respectively.   
     
     
         11 . The method according to  claim 10 , wherein the disorder is an autoimmune or inflammatory disorder. 
     
     
         12 . The method according to  claim 11 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases. 
     
     
         13 . The method according to  claim 1 , wherein said antibody or an antigen-binding portion comprises:
 (a) a heavy chain variable sequence of SEQ ID NO:29 and a light chain variable sequence of SEQ ID NO:25;   (b) a heavy chain variable sequence of SEQ ID NO:30 and a light chain variable sequence of SEQ ID NO:26;   (c) a heavy chain variable sequence of SEQ ID NO:31 and a light chain variable sequence of SEQ ID NO:27; or,   (d) a heavy chain variable sequence of SEQ ID NO:32 and a light chain variable sequence of SEQ ID NO:28.   
     
     
         14 . The method according to  claim 13 , wherein the disorder is an autoimmune or inflammatory disorder. 
     
     
         15 . The method according to  claim 14 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases. 
     
     
         16 . The method according to  claim 15 , wherein said antibody or an antigen-binding portion comprises V H  and V L  sequences having at least 90 percent sequence identity to:
 (a) a heavy chain variable sequence of SEQ ID NO:29 and a light chain variable sequence of SEQ ID NO:25;   (b) a heavy chain variable sequence of SEQ ID NO:30 and a light chain variable sequence of SEQ ID NO:26;   (c) a heavy chain variable sequence of SEQ ID NO:31 and a light chain variable sequence of SEQ ID NO:27; or,   (d) a heavy chain variable sequence of SEQ ID NO:32 and a light chain variable sequence of SEQ ID NO:28.   
     
     
         17 . The method according to  claim 16 , wherein the disorder is an autoimmune or inflammatory disorder. 
     
     
         18 . The method according to  claim 17 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases. 
     
     
         19 . The method according to  claim 1 , wherein said antibody or antigen-binding portion is cross-blocked from binding to IL12Rβ1 (SEQ ID NO:41) by an antibody, or antigen binding fragment thereof, having a heavy chain variable sequence and a light chain variable sequence selected from the group consisting of:
 (a) a heavy chain variable sequence of SEQ ID NO:29 and a light chain variable sequence of SEQ ID NO:25; 
 (b) a heavy chain variable sequence of SEQ ID NO:30 and a light chain variable sequence of SEQ ID NO:26; 
 (c) a heavy chain variable sequence of SEQ ID NO:31 and a light chain variable sequence of SEQ ID NO:27; or, 
 (d) a heavy chain variable sequence of SEQ ID NO:32 and a light chain variable sequence of SEQ ID NO:28. 
 
     
     
         20 . The method according to  claim 19 , wherein the disorder is an autoimmune or inflammatory disorder. 
     
     
         21 . The method according to  claim 20 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases. 
     
     
         22 . A method of treating a pathological disorder that is mediated by IL12Rβ1, or that can be treated by inhibiting IFNγ production, comprising administering to a subject a composition comprising an isolated antibody or an antigen-binding portion of an antibody that binds IL12Rβ1 (SEQ ID NO:41), with a K D  of 100 nM or less and inhibits IL12 and/or IL23 binding to IL12Rβ1 polypeptide as measured in an in vitro competitive binding assay, said antibody further inhibits IL12 dependent INF-γ production in human blood cells with an IC 50  of 1 nM or less. 
     
     
         23 . The method according to  claim 22 , wherein the disorder is an autoimmune or inflammatory disorder. 
     
     
         24 . The method according to  claim 23 , wherein the autoimmune or inflammatory disorder is rheumatoid arthritis, psoriasis or inflammatory bowel diseases.