Human ctla-4 antibodies and their uses

Abstract

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

What is claimed is: 
     
         1 . A monoclonal antibody or antigen-binding portion thereof, comprising a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region and light chain variable region CDR3 domains are selected from the group consisting of:
 (a) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35; and   (b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:38; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:36; and   wherein the antibody or antigen-binding portion thereof binds to human CTLA-4 with a binding affinity of about 10 8  M −1  or greater.   
     
     
         2 . The antibody or antigen-binding portion thereof of  claim 1 , wherein the heavy chain variable region and light chain variable region CDR2 domains are selected from the group consisting of:
 (a) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID No:32; and a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:29;   (b) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:33; and a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:30; and   (c) a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:34; and a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:31.   
     
     
         3 . The antibody or antigen-binding portion thereof of  claim 2 , wherein the heavy chain variable region and light chain variable region CDR1 domains are selected from the group consisting of:
 (a) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27; and a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:24;   (b) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27; and a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:25; and   (c) a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:28; and a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:26.   
     
     
         4 . A monoclonal antibody or an antigen-binding portion thereof that specifically binds to human CTLA-4 and comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:17, 19 and 23. 
     
     
         5 . The monoclonal antibody or antigen-binding portion thereof of  claim 4 , wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:17. 
     
     
         6 . The monoclonal antibody or antigen-binding portion thereof of  claim 4 , wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:19. 
     
     
         7 . The monoclonal antibody or antigen-binding portion thereof of  claim 4 , wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:23. 
     
     
         8 . A monoclonal antibody or an antigen-binding portion thereof that specifically binds to human CTLA-4 and comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:7, 9 and 13. 
     
     
         9 . The monoclonal antibody or antigen-binding portion thereof of  claim 8 , wherein the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:7. 
     
     
         10 . The monoclonal antibody or antigen-binding portion thereof of  claim 8 , wherein the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:9. 
     
     
         11 . The monoclonal antibody or antigen-binding portion thereof of  claim 8 , wherein the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO:13. 
     
     
         12 . A monoclonal antibody or antigen-binding portion thereof that specifically binds to human CTLA-4 and comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3; and a light chain variable region comprising CDR1, CDR2, and CDR3, wherein the heavy chain CDR1, CDR2, and CDR3 are selected from the group consisting of:
 (a) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:32, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37;   (b) a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:33, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37; and   a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:28, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:34, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:38.   
     
     
         13 . The antibody or antigen-binding portion thereof of  claim 12 , comprising a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:32, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37. 
     
     
         14 . The antibody or antigen-binding portion thereof of  claim 12 , comprising a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:27, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:33, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37. 
     
     
         15 . The antibody or antigen-binding portion thereof of  claim 12 , comprising a heavy chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:28, a heavy chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:34, and a heavy chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:38. 
     
     
         16 . A monoclonal antibody or antigen-binding portion thereof that specifically binds to PD-1 and comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3, and a light chain variable region that comprises CDR1, CDR2, and CDR3, wherein the light chain CDR1, CDR2, and CDR3 are selected from the group consisting of:
 (a) a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:24, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:29, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35;   (b) a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:25, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:30, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35; and   (c) a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:26, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:31, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:36.   
     
     
         17 . The monoclonal antibody or antigen-binding portion thereof of  claim 16 , comprising a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:24, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:29, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35. 
     
     
         18 . The monoclonal antibody or antigen-binding portion thereof of  claim 16 , comprising a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:25, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:30, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35. 
     
     
         19 . The monoclonal antibody or antigen-binding portion thereof of  claim 16 , comprising a light chain CDR1 comprising amino acids having the sequence set forth in SEQ ID NO:26, a light chain CDR2 comprising amino acids having the sequence set forth in SEQ ID NO:31, and a light chain CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:36. 
     
     
         20 . An isolated nucleic acid encoding the heavy chain variable region of  claim 4 . 
     
     
         21 . An isolated nucleic acid encoding the light chain variable region of  claim 8 . 
     
     
         22 . A method for increasing an immune response to an antigen in a subject, which method comprising administering to the subject the antibody or antigen-binding portion thereof of  claim 1 . 
     
     
         23 . A method for treating cancer in a subject, which method comprising administering to the subject the antibody or antigen-binding portion thereof of  claim 1 .