Combination of dr5 agonist and anti-pd-1 antagonist and methods of use

Abstract

Provided are methods and compositions for treating cancer using an effective amount of a PD-1 antagonist (e.g., an antibody) in combination with a DR4 or DR5 agonist (e.g., an antibody).

1 - 30 . (canceled) 
     
     
         31 . A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a PD-1 antagonist and a DR4 or DR5 agonist. 
     
     
         32 . The method of  claim 31 , wherein the PD-1 antagonist and the DR4 or DR5 agonist are selected from the group consisting of a ligand, antibody, and multivalent agent. 
     
     
         33 . The method of  claim 32 , wherein the DR5 agonist is an antibody selected from the group consisting of Lexatumumab, Tigatuzumab, Conatumumab, Drozitumab, HGSTR2J/KMTRS, and LBY-135. 
     
     
         34 . The method of  claim 32 , wherein the DR5 agonist is a multivalent agent comprising TAS266. 
     
     
         35 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-1 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 15. 
     
     
         36 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-1 antibody comprising:
 (a) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO: 17;   (b) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO: 18;   (c) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO: 19;   (d) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO: 20;   (e) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO: 21; and   (f) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO: 22.   
     
     
         37 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-1 antibody comprising heavy and light chain variable regions having the sequences set forth in SEQ ID NOs: 13 and 15, respectively. 
     
     
         38 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-1 antibody comprising heavy and light chains having the sequences as set forth in SEQ ID NOs: 11 and 12, respectively. 
     
     
         39 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-L1 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 1, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 3. 
     
     
         40 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-L1 antibody comprising:
 (a) a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO: 5   (b) a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO: 6;   (c) a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO: 7;   (d) a light chain variable region CDR1 having the sequence set forth in SEQ ID NO: 8;   (e) a light chain variable region CDR2 having the sequence set forth in SEQ ID NO: 9; and   (f) a light chain variable region CDR3 having the sequence set forth in SEQ ID NO: 10.   
     
     
         41 . The method of  claim 31 , wherein the PD-1 antagonist is an anti-PD-L1 antibody comprising heavy and light chain variable regions having the sequences set forth in SEQ ID NOs: 1 and 3, respectively. 
     
     
         42 . The method of  claim 31 , wherein administration of the PD-1 antagonist and DR5 agonist reduces tumor size by at least 50%. 
     
     
         43 . A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a PD-1 antagonist and a DR5 agonist, wherein
 (a) the PD-1 antagonist is an antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 15 or an antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 1, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 3; and   (b) the DR5 agonist is an antibody.   
     
     
         44 . The method of  claim 31 , wherein the PD-1 antagonist and the DR5 agonist are administered separately. 
     
     
         45 . The method of  claim 31 , wherein the DR5 agonist and the PD-1 antagonist are administered simultaneously. 
     
     
         46 . The method of  claim 31 , wherein the cancer is a cancer selected from the group consisting of leukemia, lymphoma, blastoma, carcinoma and sarcoma. 
     
     
         47 . The method of  claim 31 , which comprises administration of an additional therapeutic agent. 
     
     
         48 . A composition comprising a PD-1 antagonist and a DR5 agonist. 
     
     
         49 . A method of treating cancer in a subject, comprising administering the subject the composition of  claim 48 . 
     
     
         50 . A kit for treating a cancer in a subject, the kit comprising:
 (a) a dose of a PD-1 antagonist;   (b) a dose of a DR5 agonist; and   
       (c) instructions for using the PD-1 antagonist and DR5 agonist in the method of  claim 31 .