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.

1 .- 19 . (canceled) 
     
     
         20 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier or diluent;   an anti-IL-6R antibody or antigen-binding fragment thereof; and   a second therapeutic agent 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; 
 (f) an anti-ErbB4 antibody; and 
   a combination of any of (a)-(f).   
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the anti-IL-6R antibody or antigen-binding fragment thereof comprises:
 a heavy chain variable region (HCVR) comprising CDRs having the amino acid sequences of SEQ ID NOs:4, 5 and 6; and   a light chain variable region (LCVR) comprising CDRs having the amino acid sequences of SEQ ID NOs:7, 8 and 9.   
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the anti-IL-6R antibody or antigen-binding fragment thereof comprises:
 a heavy chain variable region (HCVR) comprising an amino acid sequence of SEQ ID NO:2; and   a light chain variable region (LCVR) comprising an amino acid sequence of SEQ ID NO:3.   
     
     
         23 . The pharmaceutical composition of claim  1 ,
 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.   
     
     
         24 . The pharmaceutical composition of  claim 20 , wherein the second therapeutic agent is an anti-EGFR antibody or antigen binding fragment thereof. 
     
     
         25 . The pharmaceutical composition of  claim 20 , wherein the second therapeutic agent is an anti-EGFRvIII antibody or antigen binding fragment thereof. 
     
     
         26 . The pharmaceutical composition of  claim 20 , wherein the second therapeutic agent is an anti-ErbB3 antibody or antigen binding fragment thereof. 
     
     
         27 . The pharmaceutical composition of  claim 20 , wherein the second therapeutic agent is an anti-ErbB4 antibody or antigen binding fragment thereof. 
     
     
         28 . The pharmaceutical composition of  claim 20 , wherein the IL-6R antibody and the second therapeutic agent are in a single combined dosage formulation. 
     
     
         29 . The pharmaceutical composition of  claim 28 , which is formulated for intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, or oral delivery. 
     
     
         30 . A kit, comprising:
 a first pharmaceutical composition comprising an anti-IL-6R antibody or antigen-binding fragment thereof; and   a second pharmaceutical composition comprising a second therapeutic agent 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; 
 (f) an anti-ErbB4 antibody; and 
   combination of any of (a)-(f).   
     
     
         31 . The kit of  claim 30 , wherein the IL-6R antibody and the second therapeutic agent are each separately formulated for intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, or oral delivery. 
     
     
         32 . The kit of  claim 31 , wherein the IL-6R antibody and the second therapeutic agent are each separately formulated for the same route of delivery. 
     
     
         33 . The kit of  claim 31 , wherein the IL-6R antibody and the second therapeutic agent are each separately formulated for different routes of delivery. 
     
     
         34 . The pharmaceutical composition of  claim 31 , wherein the IL-6R antibody and the second therapeutic agent are present in equal amounts. 
     
     
         35 . The pharmaceutical composition of  claim 31 , wherein the IL-6R antibody and the second therapeutic agent are present in different amounts. 
     
     
         36 . The kit of  claim 30 , 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) having the amino acid sequence of SEQ ID NO:2 and wherein the LCVR comprises the CDRs having the amino acid sequence of SEQ ID NO:3. 
     
     
         37 . The kit of  claim 36 ,
 wherein the HCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:4, 5 and 6; and   wherein the LCVR comprises CDRs having the amino acid sequences of SEQ ID NOs:7, 8 and 9.   
     
     
         38 . The kit of  claim 30 ,
 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.