Anti-cd137 antibodies and methods of use thereof

Abstract

The instant disclosure provides antibodies that specifically bind to CD137 (e.g., human CD137) and increases CD137 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

1 - 110 . (canceled) 
     
     
         111 . An isolated antibody that specifically binds to human CD137, the antibody comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) CDRH1, CDRH2, and CDRH3, and a light chain variable region (VL) comprising CDRs CDRL1, CDRL2, and CDRL3, wherein:
 (a) CDRH1 comprises the amino acid sequence of GYYMH (SEQ ID NO: 1);   (b) CDRH2 comprises the amino acid sequence of WINPNSGGTNYAQKFQG (SEQ ID NO: 2);   (c) CDRH3 comprises the amino acid sequence of EPGYX 1 GX 2 GLDX 3  (SEQ ID NO: 86), wherein
 X 1  is Y or F; 
 X 2  is S or T; and 
 X 3  is Y; 
   (d) CDRL1 comprises the amino acid sequence of GGDDIGDKRVH (SEQ ID NO: 4);   (e) CDRL2 comprises the amino acid sequence of EDRYRPS (SEQ ID NO: 5); and/or   (f) CDRL3 comprises the amino acid sequence of QVWX 1 X 2 X 3 X 4 X 5 X 6 PGV (SEQ ID NO: 87), wherein
 X 1  is D, N, or Y; 
 X 2  is S; 
 X 3  is S; 
 X 4  is S or P; 
 X 5  is D; and 
 X 6  is H or Y; 
   
       wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 do not comprise the amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. 
     
     
         112 . The isolated antibody of  claim 111 , wherein:
 (a) CDRH3 comprises the amino acid sequence of EPGYYGTGLDY (SEQ ID NO: 59); and/or   (b) CDRL3 comprises the amino acid sequence of QVWNSSSDHPGV (SEQ ID NO: 60), QVWDSSSDYPGV (SEQ ID NO: 61), or QVWYSSPDHPGV (SEQ ID NO: 62).   
     
     
         113 . The isolated antibody of  claim 111 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 1, 2, 59, 4, 5, and 6; 1, 2, 3, 4, 5, and 60; 1, 2, 3, 4, 5, and 61; or 1, 2, 3, 4, 5, and 62, respectively. 
     
     
         114 . The isolated antibody of  claim 111 , wherein the antibody comprises a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 99% identical to the amino acid sequence of SEQ ID NO: 7; and/or a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, or 99% identical to the amino acid sequence of SEQ ID NO: 8, wherein the VH and VL do not comprise the amino acid sequences of SEQ ID NO: 7 and 8, respectively. 
     
     
         115 . The isolated antibody of  claim 114 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 63, 64, or 65. 
     
     
         116 . The isolated antibody of  claim 115 , wherein X is glutamine (Q). 
     
     
         117 . The isolated antibody of  claim 115 , wherein X is pyroglutamate (pE). 
     
     
         118 . The isolated antibody of  claim 114 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 66, 67, or 68. 
     
     
         119 . The isolated antibody of  claim 114 , wherein the antibody comprises a VH and a VL comprising the amino acid sequences of SEQ ID NOs: 64 and 66; or 65 and 68, respectively. 
     
     
         120 . The isolated antibody of  claim 119 , wherein X is glutamine (Q). 
     
     
         121 . The isolated antibody of  claim 119 , wherein X is pyroglutamate (pE). 
     
     
         122 . The isolated antibody of  claim 111 , wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. 
     
     
         123 . The isolated antibody of  claim 122 , wherein:
 (a) the heavy chain constant region is human IgG1 comprising an N297A mutation;   (b) the heavy chain constant region is human IgG1 comprising S267E and L328F mutations;   (c) the heavy chain constant region is human IgG2 comprising an N297A mutation; or   (d) the heavy chain constant region is human IgG4 comprising an S228P mutation.   
     
     
         124 . The isolated antibody of  claim 122 , wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 15-20. 
     
     
         125 . The isolated antibody of  claim 111 , the antibody comprising:
 (a) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73-78; and/or   (b) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 79-81.   
     
     
         126 . The isolated antibody of  claim 125 , wherein the heavy chain and light chain comprise the amino acid sequences of SEQ ID NOs: 75 and 79; 76 and 79; 77 and 81; or 78 and 81, respectively. 
     
     
         127 . A pharmaceutical composition comprising the antibody of  claim 111 ; and a pharmaceutically acceptable carrier or excipient.