Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof

Abstract

Provided herein are antibodies, or antigen binding portions thereof, that bind to glucocorticoid-inducible TNF receptor (GITR). 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 - 68 . (canceled) 
     
     
         69 . A method for inhibiting the growth of tumor cells in a subject, the method comprising administering to the subject an antibody that binds to human glucocorticoid-inducible TNF receptor (GITR) and comprises a heavy chain constant region comprising (1) an amino acid sequence selected from the group consisting of SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543 or (2) a heavy chain constant region that differs therefrom in at most 5 amino acids or is at least 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence of SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543, wherein the amino acid modification(s) are not at the specific amino acid(s) in SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543 that are not present in the naturally-occurring human heavy chain constant regions. 
     
     
         70 . The method of  claim 69 , wherein the antibody comprises:
 (a) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively;   (b) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 33, 34, and 35, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 36, 37, and 38, respectively;   (c) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 46, 47, and 48, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 49, 50, and 51, respectively;   (d) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 62, 63, and 64, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 65, 66, and 67, respectively;   (e) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 62, 63, and 64, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 68, 69, and 70, respectively;   (f) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 78, 79, and 80, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 81, 82, and 83, respectively;   (g) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 91, 92, and 93, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 94, 95, and 96, respectively;   (h) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 106, 107, and 108, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 109, 110, and 111, respectively;   (i) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 106, 107, and 108, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 112, 113, and 114, respectively;   (j) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 122, 123, and 124, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 125, 126, and 127, respectively;   (k) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 138, 139, and 140, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 141, 142, and 143, respectively;   (l) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 138, 139, and 140, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 144, 145, and 146, respectively; or   (m) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 342-344, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 345-347, respectively.   
     
     
         71 . The method of  claim 69 , wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively. 
     
     
         72 . The method of  claim 69 , wherein the antibody comprises heavy and light chain variable region sequences at least 85% identical to the amino acid sequences selected from the group consisting of:
 (a) SEQ ID NOs: 13 and 14, respectively;   (b) SEQ ID NOs: 26 and 27, respectively;   (c) SEQ ID NOs: 39 and 40, respectively;   (d) SEQ ID NOs: 52 and 53, respectively;   (e) SEQ ID NOs: 52 and 54, respectively;   (f) SEQ ID NOs: 71 and 72, respectively;   (g) SEQ ID NOs: 84 and 85, respectively;   (h) SEQ ID NOs: 97 and 98, respectively;   (i) SEQ ID NOs: 97 and 99, respectively;   (j) SEQ ID NOs: 115 and 116, respectively;   (k) SEQ ID NOs: 128 and 129, respectively;   (l) SEQ ID NOs: 128 and 130, respectively; and   (m) SEQ ID NOs: 335 and 336, respectively.   
     
     
         73 . The method of  claim 69 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14. 
     
     
         74 . The method of  claim 69 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 394. 
     
     
         75 . The method of  claim 69 , wherein the antibody comprises a heavy chain constant region comprising an amino acid sequence identical to SEQ ID NO: 394, except wherein the Ser at position 267 is Glu. 
     
     
         76 . A method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that binds to human glucocorticoid-inducible TNF receptor (GITR) and comprises a heavy chain constant region comprising (1) an amino acid sequence selected from the group consisting of SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543 or (2) a heavy chain constant region that differs therefrom in at most 5 amino acids or is at least 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence of SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543, wherein the amino acid modification(s) are not at the specific amino acid(s) in SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543 that are not present in the naturally-occurring human heavy chain constant regions. 
     
     
         77 . The method of  claim 76 , wherein the antibody comprises:
 (a) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively;   (b) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 33, 34, and 35, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 36, 37, and 38, respectively;   (c) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 46, 47, and 48, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 49, 50, and 51, respectively;   (d) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 62, 63, and 64, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 65, 66, and 67, respectively;   (e) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 62, 63, and 64, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 68, 69, and 70, respectively;   (f) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 78, 79, and 80, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 81, 82, and 83, respectively;   (g) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 91, 92, and 93, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 94, 95, and 96, respectively;   (h) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 106, 107, and 108, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 109, 110, and 111, respectively;   (i) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 106, 107, and 108, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 112, 113, and 114, respectively;   (j) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 122, 123, and 124, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 125, 126, and 127, respectively;   (k) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 138, 139, and 140, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 141, 142, and 143, respectively;   (l) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 138, 139, and 140, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 144, 145, and 146, respectively; or   (m) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 342-344, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 345-347, respectively.   
     
     
         78 . The method of  claim 76 , wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively. 
     
     
         79 . The method of  claim 76 , wherein the antibody comprises heavy and light chain variable region sequences at least 85% identical to the amino acid sequences selected from the group consisting of:
 (a) SEQ ID NOs: 13 and 14, respectively;   (b) SEQ ID NOs: 26 and 27, respectively;   (c) SEQ ID NOs: 39 and 40, respectively;   (d) SEQ ID NOs: 52 and 53, respectively;   (e) SEQ ID NOs: 52 and 54, respectively;   (f) SEQ ID NOs: 71 and 72, respectively;   (g) SEQ ID NOs: 84 and 85, respectively;   (h) SEQ ID NOs: 97 and 98, respectively;   (i) SEQ ID NOs: 97 and 99, respectively;   (j) SEQ ID NOs: 115 and 116, respectively;   (k) SEQ ID NOs: 128 and 129, respectively;   (l) SEQ ID NOs: 128 and 130, respectively; and   (m) SEQ ID NOs: 335 and 336, respectively.   
     
     
         80 . The method of  claim 76 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14. 
     
     
         81 . The method of  claim 76 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 394. 
     
     
         82 . The method of  claim 76 , wherein the antibody comprises a heavy chain constant region comprising an amino acid sequence identical to SEQ ID NO: 394, except wherein the Ser at position 267 is Glu. 
     
     
         83 . The method of  claim 76 , wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, uterine/cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer. 
     
     
         84 . The method of  claim 76 , wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer. 
     
     
         85 . The method of  claim 76 , further comprising administering one or more additional therapeutics. 
     
     
         86 . The method of  claim 85 , wherein the one or more additional therapeutics is selected from an anti-PD1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, or an anti-PD-L1 antibody. 
     
     
         87 . A method of detecting the presence of glucocorticoid-inducible TNF receptor (GITR) in a sample comprising contacting the sample with an antibody that binds to human glucocorticoid-inducible TNF receptor (GITR) and comprises a heavy chain constant region comprising (1) an amino acid sequence selected from the group consisting of SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543 or (2) a heavy chain constant region that differs therefrom in at most 5 amino acids or is at least 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence of SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543, wherein the amino acid modification(s) are not at the specific amino acid(s) in SEQ ID NOs: 223-226, 283-290, 383-446 and 480-543 that are not present in the naturally-occurring human heavy chain constant regions, under conditions that allow for formation of a complex between the antibody and GITR, and detecting the formation of a complex.