Methods of inhibiting tumor growth by antagonizing il-6 receptor

Abstract

The present invention provides methods for inhibiting or attenuating tumor growth in a subject by administering an IL-6 antagonist to the subject. In certain embodiments, the methods of the invention are used to inhibit the growth of an anti-VEGF-resistant tumor in a subject. The IL-6 antagonist may be, e.g., an antibody that specifically binds IL-6R. The IL-6 antagonist may be administered in combination with a VEGF antagonist, and/or an EGFR antagonist.

What is claimed is: 
     
         1 . A method for inhibiting or attenuating the growth of an anti-VEGF-resistant tumor in a subject, the method comprising administering to the subject an anti-IL-6R antibody or antigen-binding fragment thereof. 
     
     
         2 . The method of  claim 1  further comprising administering to the subject VEGF antagonist. 
     
     
         3 . The method of  claim 1 , wherein the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises the complementarity determining regions (CDRs) of SEQ ID NO:2, and wherein the LCVR comprises the CDRs of SEQ ID NO:3. 
     
     
         4 . The method of  claim 3 , wherein the HCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:4, 5, and 6; and wherein LCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:7, 8 and 9. 
     
     
         5 . The method of  claim 2 , wherein the VEGF antagonist is a fusion protein comprising Ig domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and a multimerizing domain. 
     
     
         6 . The method of  claim 5 , wherein the Ig domain 2 of VEGFR1 comprises amino acids 27 to 129 of SEQ ID NO:11, the Ig domain 3 of VEGFR2 comprises amino acids 130 to 231 of SEQ ID NO:11, and the multimerizing domain comprises amino acids 232 to 457 of SEQ ID NO:11. 
     
     
         7 . A method of cancer therapy comprising: (i) measuring the level of IL-61STAT3 signaling in a sample from a subject; and (ii) administering an anti-IL-6R antibody or antigen-binding fragment thereof to the subject if the sample exhibits increased IL-6/STAT3 signaling. 
     
     
         8 . A method for determining if a tumor-bearing patient has an anti-VEGF-resistant tumor, the method comprising measuring the level of IL-6/STAT3 signaling in a sample from the patient, wherein increased IL-6/STAT3 signaling in the sample identifies the patient as having an anti-VEGF-resistant tumor. 
     
     
         9 . The method of  claim 8 , wherein the sample is tumor biopsy. 
     
     
         10 . The method of  claim 8 , further comprising administering to the patient an anti-IL-6R antibody or antigen-binding fragment thereof if the tumor biopsy is found to exhibit increased IL-6/STAT3 signaling. 
     
     
         11 . The method of  claim 8 , further comprising administering to the patient an anti-IL-6R antibody or antigen-binding fragment thereof and a VEGF antagonist if the tumor biopsy is found to exhibit increased IL-6/STAT3 signaling. 
     
     
         12 . A method for inhibiting or attenuating the growth of a tumor in a subject, the method comprising administering to the subject an anti-IL-6R antibody or antigen-binding fragment thereof and an EGFR antagonist. 
     
     
         13 . The method of  claim 12 , wherein the EGFR antagonist is selected from the group consisting of an anti-EGFR antibody, an anti-EGFRvIII antibody, an anti-ErbB2 antibody, an anti-ErbB3 antibody, and an anti-ErbB4 antibody. 
     
     
         14 . The method of  claim 13 , wherein the anti-IL-6R antibody or antigen-specific binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises the complementarity determining regions (CDRs) of SEQ ID NO:2, and wherein the LCVR comprises the CDRs of SEQ ID NO:3. 
     
     
         15 . The method of  claim 14 , wherein the HCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:4, 5, and 6; and wherein LCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:7, 8 and 9. 
     
     
         16 . A pharmaceutical composition comprising an anti-IL-6R antibody or antigen-binding fragment thereof, a second therapeutic agent, and a pharmaceutically acceptable carrier or diluent;
 wherein the second therapeutic agent is selected from the group consisting of: (a) a fusion protein comprising Ig domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and a multimerizing domain; (b) an anti-EGFR antibody; (c) an anti-EGFRvIII antibody; (d) an anti-ErbB2 antibody; (e) an anti-ErbB3 antibody; and (f) an anti-ErbB4 antibody.   
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the anti-IL-6R antibody or antigen-specific binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises the complementarity determining regions (CDRs) of SEQ ID NO:2, and wherein the LCVR comprises the CDRs of SEQ ID NO:3. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the HCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:4, 5, and 6; and wherein LCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:7, 8 and 9. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the second therapeutic agent is a fusion protein comprising Ig domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and a multimerizing domain, wherein the Ig domain 2 of VEGFR1 comprises amino acids 27 to 129 of SEQ ID NO:11, the Ig domain 3 of VEGFR2 comprises amino acids 130 to 231 of SEQ ID NO:11, and the multimerizing domain comprises amino acids 232 to 457 of SEQ ID NO:11.