Methods of treating cancer using pd-l1 axis binding antagonists and vegf antagonists

Abstract

The present invention describes combination treatment comprising a PD-1 axis binding antagonist, chemotherapy and optionally a VEGF antagonist and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer.

1 . A method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of an antagonist anti-PD-1 antibody, a VEGF antagonist, oxaliplatin, leucovorin and 5-FU. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the anti-PD-1 antibody is a PD-1 binding antagonist. 
     
     
         4 . The method of  claim 3 , wherein the anti-PD-1 antibody inhibits the binding of PD-1 to its ligand binding partners. 
     
     
         5 . The method of  claim 4 , wherein the anti-PD-1 antibody inhibits the binding of PD-1 to PD-L1. 
     
     
         6 . The method of  claim 4 , wherein the anti-PD-1 antibody inhibits the binding of PD-1 to PD-L2. 
     
     
         7 . The method of  claim 4 , wherein the anti-PD-1 antibody inhibits the binding of PD-1 to both PD-L1 and PD-L2. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 4 , wherein the anti-PD-1 antibody is MDX-1106. 
     
     
         10 . The method of  claim 4 , wherein the anti-PD-1 antibody is Merck 3475. 
     
     
         11 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the anti-PD-1 antibody is a monoclonal antibody. 
     
     
         18 . The method of  claim 1 , wherein the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′) 2  fragments. 
     
     
         19 . The method of  claim 1 , wherein the anti-PD-1 antibody is a humanized antibody. 
     
     
         20 . The method of  claim 1 , wherein the anti-PD-1 antibody is a human antibody. 
     
     
         21 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the VEGF antagonist is an anti-VEGF antibody. 
     
     
         30 . The method of  claim 29 , wherein said anti-VEGF antibody binds the same epitope as the monoclonal anti-VEGF antibody A4.6.1 produced by hybridoma ATCC HB 10709. 
     
     
         31 . The method of  claim 29 , wherein the anti-VEGF antibody is a humanized antibody. 
     
     
         32 . The method of  claim 29 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         33 . The method of  claim 29 , wherein the anti-VEGF antibody has a heavy chain variable region comprising the following amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 22) 
                 
                   EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA  
                 
                     
                 
                   PGKGLEWVGW INTYTGEPTY AADFKRRFTF SLDTSKSTAY  
                 
                     
                 
                   LQMNSLRAED TAVYYCAKYP HYYGSSHWYF DVWGQGTLVT VSS. 
                 
             
                
                
                
                
                
                
               
            
           
         
         and a light chain variable region comprising the following amino acid sequence: 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 23) 
                 
                     
                   DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP  
                 
                     
                     
                 
                     
                   GKAPKVLIYF TSSLHSGVPS RFSGSGSGTD FTLTISSLQP  
                 
                     
                     
                 
                     
                   EDFATYYCQQ YSTVPWTFGQ GTKVEIKR. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         34 . The method of  claim 1 , wherein the treatment results in a sustained response in the individual after cessation of the treatment. 
     
     
         35 . The method of  claim 1 , wherein the cancer is colorectal cancer. 
     
     
         36 . A kit comprising an antagonist anti-PD-1 antibody and a package insert comprising instructions for using the anti-PD-1 antibody in combination with a VEGF antagonist oxaliplatin, leucovorin and 5-FU to treat or delay progression of cancer in an individual. 
     
     
         37 . The kit of  claim 36  further comprising a VEGF antagonist, oxaliplatin, leucovorin and 5-FU. 
     
     
         38 - 40 . (canceled) 
     
     
         41 . The method of  claim 29 , wherein the anti-VEGF antibody comprises a heavy chain variable region and a light chain variable region, wherein:
 (a) the heavy chain variable region comprises a CDRH1, CDRH2 and CDRH3, and wherein:
 (i) the CDRH1 comprises the amino acid sequence of SEQ ID NO: 24; 
 (ii) the CDRH2 comprises the amino acid sequence of SEQ ID NO:25; 
 (iii) the CDRH3 comprises the amino acid sequence of SEQ ID NO:26; and 
   (b) the light chain variable region comprises a CDRL1, CDRL2 and CDRL3, and wherein:
 (iv) the CDRL1 comprises the amino acid sequence of SEQ ID NO:27; 
 (v) the CDRL2 comprises the amino acid sequence of SEQ ID NO:28; and 
 (vi) the CDRL3 comprises the amino acid sequence of SEQ ID NO:29. 
   
     
     
         42 . The method of  claim 1 , wherein the cancer is selected from the group consisting of lung cancer, bladder cancer, breast cancer, colon cancer and colorectal cancer.