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 polynucleotide encoding a heavy chain variable region and/or a light chain variable region of an antibody that specifically binds to human OX40, wherein the antibody comprises 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 polynucleotide of  claim 130 , wherein
 (a) CDRH1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 16-20;   (b) 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;   (c) 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;   (d) CDRL3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-38;   (e) CDRH1, CDRH2, and CDRH3 comprise the 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;   (f) CDRL1, CDRL2, and CDRL3 comprise the 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; or   (g) 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.   
     
     
         132 . A vector comprising the polynucleotide of  claim 130 . 
     
     
         133 . A recombinant host cell comprising the polynucleotide of  claim 130 . 
     
     
         134 . A method of producing an antibody that specifically binds to human OX40, a multispecific antibody comprising a first antigen-binding domain that specifically binds to human OX40 and a second antigen-binding domain, or a multispecific antibody comprising a first antigen-binding domain that specifically binds to human OX40 and a second antigen-binding domain that specifically binds to human GITR, the method comprising culturing the host cell of  claim 133  so that the polynucleotide is expressed and the antibody or the multispecific antibody is produced. 
     
     
         135 . An isolated polynucleotide encoding a heavy chain variable region and/or a light chain variable region of an antibody that specifically binds to human GITR, wherein the antibody comprises 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 the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 regions comprise the amino acid sequences set forth in SEQ ID NOs: 60, 64, 68, 69, 71, and 72, respectively. 
     
     
         136 . A vector comprising the polynucleotide of  claim 135 . 
     
     
         137 . A recombinant host cell comprising the polynucleotide of  claim 135 . 
     
     
         138 . A method of producing an antibody that specifically binds to human GITR, a multispecific antibody comprising a first antigen-binding domain and a second antigen-binding domain that specifically binds to human GITR, or a multispecific antibody comprising a first antigen-binding domain that specifically binds to human OX40 and a second antigen-binding domain that specifically binds to human GITR, the method comprising culturing the host cell of  claim 137  so that the polynucleotide is expressed and the antibody or the multispecific antibody is produced.