Antibodies against ox-40 and uses thereof

Abstract

Provided herein are antibodies, or antigen binding portions thereof, that bind to OX40. Also provided are uses of these proteins in therapeutic applications, such as in the treatment of cancer. Further provided are cells that produce the antibodies, polynucleotides encoding the heavy and/or light chain variable region of the antibodies, and vectors comprising the polynucleotides encoding the heavy and/or light chain variable region of the antibodies.

1 - 25 . (canceled) 
     
     
         26 . A method of producing an antibody which binds to human OX40 (anti-OX40 antibody), comprising (a) culturing a cell which comprises a nucleic acid encoding a heavy chain variable region (VH) and/or a light chain variable region (VL) of the anti-OX40 antibody, and (b) recovering the anti-OX40 antibody that is produced. 
     
     
         27 . The method of  claim 26 , wherein the VH and the VL of the anti-OX40 antibody comprise the amino acid sequence set forth in
 (a) SEQ ID NOs: 318 and 94, respectively;   (b) SEQ ID NOs: 17 and 18, respectively;   (c) SEQ ID NOs: 28 and 29, respectively;   (d) SEQ ID NOs: 28 and 30, respectively;   (e) SEQ ID NOs: 37 and 38, respectively;   (f) SEQ ID NOs: 48 and 49, respectively;   (g) SEQ ID NOs: 48 and 50, respectively;   (h) SEQ ID NOs: 57 and 58, respectively;   (i) SEQ ID NOs: 65 and 66, respectively;   (j) SEQ ID NOs: 73 and 74, respectively;   (k) SEQ ID NOs: 84 and 85, respectively;   (l) SEQ ID NOs: 84 and 86, respectively; or   (m) SEQ ID NOs: 93 and 94.   
     
     
         28 . The method of  claim 27 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 318 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 94. 
     
     
         29 . An immunoconjugate comprising an antibody which binds to human OX40 (anti-OX40 antibody) linked to an agent, wherein the anti-OX40 antibody comprises a heavy chain CDR1, CDR2, and CDR3, and a light chain CDR1, CDR2, and CDR3, wherein the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 87, the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 317, the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 89, the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 90, the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 91, and the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 92. 
     
     
         30 . The immunoconjugate of  claim 29 , wherein the anti-OX40 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 318 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 94. 
     
     
         31 . The immunoconjugate of  claim 29 , wherein the anti-OX40 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 124 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 116. 
     
     
         32 . A method of enhancing an anti-tumor immunotherapy in a subject in need thereof, comprising administering to the subject the anti-tumor immunotherapy in combination with an isolated antibody which binds to human OX40 (“anti-OX40 antibody”), wherein the anti-OX40 antibody comprises a heavy chain CDR1, CDR2, and CDR3, and a light chain CDR1, CDR2, and CDR3, wherein:
 (a) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 87, 317, and 89, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 90-92, respectively; 
 (b) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 11-13, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 14-16, respectively; 
 (c) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 19-21, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 22-24, respectively; 
 (d) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 19-21, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 25-27, respectively; 
 (e) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 31-33, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 34-36, respectively; 
 (f) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 39-41, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 42-44, respectively; 
 (g) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 39-41, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 45-47, respectively; 
 (h) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 51-53, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 54-56, respectively; 
 (i) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 59-61, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 62-64, respectively; 
 (j) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 67-69, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 70-72, respectively; 
 (k) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 75-77, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 78-80, respectively, wherein, optionally, the Asp-Gly sequence in SEQ ID NO: 76 is replaced an amino acid sequence that does not undergo isomerization; 
 (l) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 75-77, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 81-83, respectively; or 
 (m) the heavy chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 87-89, respectively, and the light chain CDR1, CDR2, and CDR3 comprises the amino acid sequences set forth in SEQ ID NOs: 90-92, respectively. 
 
     
     
         33 . The method of  claim 32 , wherein the anti-OX40 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise the amino acid sequence set forth in:
 (a) SEQ ID NOs: 318 and 94, respectively;   (b) SEQ ID NOs: 17 and 18, respectively;   (c) SEQ ID NOs: 28 and 29, respectively;   (d) SEQ ID NOs: 28 and 30, respectively;   (e) SEQ ID NOs: 37 and 38, respectively;   (f) SEQ ID NOs: 48 and 49, respectively;   (g) SEQ ID NOs: 48 and 50, respectively;   (h) SEQ ID NOs: 57 and 58, respectively;   (i) SEQ ID NOs: 65 and 66, respectively;   (j) SEQ ID NOs: 73 and 74, respectively;   (k) SEQ ID NOs: 84 and 85, respectively;   (l) SEQ ID NOs: 84 and 86, respectively; or   (m) SEQ ID NOs: 93 and 94.   
     
     
         34 . The method of  claim 32 , wherein the anti-OX40 antibody comprises a heavy chain and a light chain, wherein the heavy chain and the light chain comprise the amino acid sequence set forth in:
 (a) SEQ ID NOs: 124 and 116, respectively;   (b) SEQ ID NOs: 95 and 96, respectively;   (c) SEQ ID NOs: 97 and 98, respectively;   (d) SEQ ID NOs: 99 and 100, respectively;   (e) SEQ ID NOs: 101 and 102, respectively;   (f) SEQ ID NOs: 103 and 104, respectively;   (g) SEQ ID NOs: 105 and 106, respectively;   (h) SEQ ID NOs: 107 and 108, respectively;   (i) SEQ ID NOs: 109 and 110, respectively;   (j) SEQ ID NOs: 111 and 112, respectively;   (k) SEQ ID NOs: 113 and 114, respectively;   (l) SEQ ID NOs: 115 and 116, respectively;   (m) SEQ ID NOs: 117 and 118, respectively;   (n) SEQ ID NOs: 119 and 120, respectively;   (o) SEQ ID NOs: 121 and 122, respectively;   (p) SEQ ID NOs: 123 and 116, respectively; and   (q) SEQ ID NOs: 125 and 116, respectively.   
     
     
         35 . The method of  claim 32 , wherein the anti-tumor immunotherapy comprises an immune checkpoint inhibitor. 
     
     
         36 . The method of  claim 35 , wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody. 
     
     
         37 . The method of  claim 32 , wherein the subject has a cancer. 
     
     
         38 . The method of  claim 37 , wherein the cancer comprises a cervical cancer, colorectal cancer, bladder cancer, ovarian cancer, or combinations thereof. 
     
     
         39 . The method of  claim 32 , comprising administering one or more additional therapeutic agents to the subject. 
     
     
         40 . The method of  claim 39 , wherein the one or more additional therapeutic agents comprise an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, anti-TGFβ antibody, or combinations thereof. 
     
     
         41 . The method of  claim 26 , wherein the anti-OX40 antibody is a human antibody. 
     
     
         42 . The immunoconjugate of  claim 29 , wherein the anti-OX40 antibody is a human antibody. 
     
     
         43 . The method of  claim 32 , wherein the anti-OX40 antibody is a human antibody. 
     
     
         44 . A composition comprising the immunoconjugate of  claim 29  and a carrier. 
     
     
         45 . The composition of  claim 44 , which comprises one or more additional therapeutic agents.