Anti-ox40 antibodies, anti-gitr antibodies, and methods of use thereof

Abstract

The present disclosure provides antibodies that specifically bind to human OX40 receptor (OX40) and/or human GITR receptor (GITR), including multispecific antibodies that bind, e.g., to OX40 and GITR, and compositions comprising such antibodies. The antibodies disclosed herein modulate OX40 and/or GITR activity e.g., enhance, activate, induce, reduce, deactivate, or inhibit OX40 and/or GITR activity. The present disclosure also provides methods for treating disorders, such as cancer, autoimmune diseases or disorders, or inflammatory diseases or disorders, by administering an antibody that specifically binds to human OX40 and/or human GITR and modulates OX40 and/or GITR activity.

1 - 129 . (canceled) 
     
     
         130 . An isolated antibody that specifically binds to human OX40, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3 and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein:
 (a) CDRH1 comprises the amino acid sequence of X 1 X 2 X 3 MH (SEQ ID NO: 41), wherein
 X 1  is G, Q, H, or E, 
 X 2  is S, E, or Y, and 
 X 3  is A, S, or G; 
   (b) CDRH2 comprises the amino acid sequence of RIRSKX 1 X 2 X 3 X 4 X 5 TAYAASVKG (SEQ ID NO: 42), wherein
 X 1  is A, S, or Y, 
 X 2  is N, E, or Y, 
 X 3  is S, Q, or G, 
 X 4  is Y, E, or Q, and 
 X 5  is A, E, or L; 
   (c) CDRH3 comprises the amino acid sequence of GIX 1 X 2 X 3 X 4 X 5 X 6 X 7 Y (SEQ ID NO: 43), wherein
 X 1  is Y or A, 
 X 2  is D or A, 
 X 3  is S, T, or W, 
 X 4  is S, E, or L, 
 X 5  is G or A, 
 X 6  is Y or A, and 
 X 7  is D or A; 
   (d) CDRL1 comprises the amino acid sequence of SEQ ID NO: 32;   (e) CDRL2 comprises the amino acid sequence of SEQ ID NO: 33; and   (f) CDRL3 comprises the amino acid sequence of MQX 1 X 2 X 3 X 4 PLT (SEQ ID NO: 46), wherein
 X 1  is A or G, 
 X 2  is L or S, 
 X 3  is Q or K, and 
 X 4  is T or W, 
   and wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences of the antibody are not respectively either SEQ ID NOs: 16, 21, 25, 32, 33, and 34 or SEQ ID NOs: 16, 21, 25, 32, 33, and 38.   
     
     
         131 . The isolated antibody of  claim 130 , wherein CDRH1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 16-20. 
     
     
         132 . The isolated antibody of  claim 130 , wherein CDRH2 comprises the amino acid sequence of RIRSKAXSYATAYAASVKG (SEQ ID NO: 44), wherein: X is N or Y, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 21-24. 
     
     
         133 . The isolated antibody of  claim 130 , wherein CDRH3 comprises the amino acid sequence of GIX 1 X 2 SSGX 3 X 4 Y (SEQ ID NO: 45), wherein: X 1  is Y or A; X 2  is D or A; X 3  is Y or A; and X 4  is D or A, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 25-31. 
     
     
         134 . The isolated antibody of  claim 130 , wherein CDRL3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-38. 
     
     
         135 . The isolated antibody of  claim 130 , wherein CDRH1, CDRH2, and CDRH3 comprise the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs: 16, 21, and 25; 16, 22, and 25; 16, 21, and 26; 16, 21, and 27; 16, 21, and 28; 16, 21, and 29; 17, 21, and 30; 18, 23, and 25; 19, 24, and 25; or 20, 21, and 31, respectively. 
     
     
         136 . The isolated antibody of  claim 130 , wherein CDRL1, CDRL2, and CDRL3 comprise the CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 32, 33, and 34; 32, 33, and 35; 32, 33, and 36; 32, 33, and 37; or 32, 33, and 38, respectively. 
     
     
         137 . The isolated antibody of  claim 130 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 16, 22, 25, 32, 33, and 34; 16, 21, 26, 32, 33, and 34; 16, 21, 27, 32, 33, and 34; 16, 21, 28, 32, 33, and 34; 16, 21, 29, 32, 33, and 34; 17, 21, 30, 32, 33, and 38; 18, 23, 25, 32, 33, and 38; 19, 24, 25, 32, 33, and 38; 20, 21, 31, 32, 33, and 38; 16, 21, 25, 32, 33, and 35; 16, 21, 25, 32, 33, and 36; or 16, 21, 25, 32, 33, and 37, respectively. 
     
     
         138 . The isolated antibody of  claim 130 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 47 or 48. 
     
     
         139 . The isolated antibody of  claim 130 , wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence which is at least 75% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10. 
     
     
         140 . The isolated antibody of  claim 130 , wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10. 
     
     
         141 . The isolated antibody of  claim 130 , wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 49. 
     
     
         142 . The isolated antibody of  claim 130 , wherein the antibody comprises a light chain variable region comprising an amino acid sequence which is at least 75% to an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-15. 
     
     
         143 . The isolated antibody of  claim 130 , wherein the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-15. 
     
     
         144 . The isolated antibody of  claim 130 , wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 2 and 11; 3 and 11; 4 and 11; 5 and 11; 6 and 11; 7 and 15; 8 and 15; 9 and 15; 10 and 15; 1 and 12; 1 and 13; or 1 and 14, respectively. 
     
     
         145 . A pharmaceutical composition comprising the antibody of  claim 130  and a pharmaceutically acceptable carrier or excipient. 
     
     
         146 . A pharmaceutical composition comprising the antibody of  claim 135  and a pharmaceutically acceptable carrier or excipient. 
     
     
         147 . A pharmaceutical composition comprising the antibody of  claim 136  and a pharmaceutically acceptable carrier or excipient. 
     
     
         148 . A pharmaceutical composition comprising the antibody of  claim 137  and a pharmaceutically acceptable carrier or excipient. 
     
     
         149 . A pharmaceutical composition comprising the antibody of  claim 144  and a pharmaceutically acceptable carrier or excipient.