Anti-gitr antibodies and methods of use thereof

Abstract

The present disclosure provides antibodies that specifically bind to human glucocorticoid-induced TNFR family related receptor (GITR) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human GITR and modulate GITR activity, e.g., enhance, activate or induce GITR activity, utilizing such antibodies. The present disclosure also provides methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity e.g., enhances, activates or induces GITR activity.

1 - 205 . (canceled) 
     
     
         206 . An isolated nucleic acid molecule encoding a VH comprising the VH CDR1, VH CDR2, and VH CDR3 amino acid sequences of the VH amino acid sequence of SEQ ID NO: 203, and/or a VL comprising the VL CDR1, VL CDR2, and VL CDR3 amino acid sequences of the VL amino acid sequence of SEQ ID NO: 204 or 205. 
     
     
         207 . The isolated nucleic acid molecule of  claim 206 , wherein the isolated nucleic acid molecule encodes a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18; 19, 24, 34, 101, 105, and 106; 19, 25, 34, 102, 105, and 107; 19, 26, 34, 102, 105, and 107; 20, 27, 34, 103, 105, and 108; 21, 28, 34, 101, 105, and 107; 22, 29, 34, 103, 105, and 109; 21, 24, 34, 101, 105, and 109; 21, 177, 34, 103, 105, and 107; 23, 31, 34, 104, 105, and 107; 19, 32, 34, 103, 105, and 107; 22, 29, 34, 102, 105, and 107; 22, 29, 34, 101, 105, and 107; 22, 29, 34, 103, 105, and 107; 22, 33, 34, 102, 105, and 107; 22, 33, 34, 101, 105, and 107; 22, 33, 34, 103, 105, and 107; 19, 24, 34, 102, 105, and 107; 19, 144, 34, 102, 105, and 109; 119, 162, 34, 102, 105, and 107; 22, 121, 34, 103, 105, and 109; 23, 187, 34, 102, 105, and 107; 22, 148, 34, 101, 105, and 108; 119, 181, 34, 101, 105, and 109; 23, 124, 34, 104, 105, and 107; 22, 151, 34, 103, 105, and 108; 23, 135, 34, 101, 105, and 107; 20, 132, 34, 104, 105, and 108; 116, 152, 34, 102, 105, and 106; 19, 144, 34, 102, 105, and 109; 23, 148, 34, 104, 105, and 107; 117, 148, 34, 104, 105, and 109; 19, 164, 34, 101, 105, and 109; 19, 127, 34, 103, 105, and 109; 119, 146, 34, 101, 105, and 107; 21, 162, 34, 101, 105, and 107; 19, 140, 34, 102, 105, and 107; 23, 157, 34, 101, 105, and 108; 19, 130, 34, 103, 105, and 107; 19, 145, 34, 104, 105, and 109; 21, 114, 34, 102, 105, and 107; 119, 162, 34, 102, 105, and 107; 19, 25, 34, 101, 105 and 191; 19, 127, 34, 101, 105, and 192; 117, 151, 34, 103, 105, and 109; 23, 138, 34, 102, 105, and 109; 22, 123, 34, 102, 105, and 108; 21, 148, 34, 104, 105, and 109; 21, 32, 34, 101, 105, and 109; 21, 172, 34, 104, 105, and 107; 35, 165, 34, 101, 105, and 107; 23, 133, 34, 103, 105, and 107; 21, 171, 34, 102, 105, and 107; 21, 32, 34, 103, 105, and 107; 21, 168, 34, 103, 105, and 109; 23, 129, 34, 102, 105, and 106; 23, 174, 34, 101, 105, and 106; 35, 170, 34, 102, 105, and 107; 23, 123, 34, 102, 105, and 107; 22, 142, 34, 102, 105, and 108; 23, 147, 34, 101, 105, and 109; 23, 122, 34, 101, 105, and 107; 21, 188, 189, 101, 105, and 109; 21, 149, 34, 101, 105, and 108; 19, 179, 34, 102, 105, and 109; 21, 134, 34, 103, 105, and 107; 23, 172, 34, 102, 105, and 192; 21, 27, 34, 102, 105, and 109; 22, 182, 34, 101, 105, and 107; 22, 147, 34, 103, 105, and 109; 21, 177, 34, 104, 105, and 107; 19, 143, 34, 104, 105, and 107; 21, 186, 34, 101, 105, and 107; 21, 153, 34, 102, 105, and 106; 22, 115, 34, 101, 105, and 109; 116, 167, 34, 102, 105, and 108; 23, 163, 34, 101, 105, and 109; 21, 180, 34, 104, 105, and 106; 23, 26, 34, 104, 105, and 108; 35, 183, 34, 104, 105, and 109; 23, 156, 34, 102, 105, and 109; 19, 151, 34, 102, 105, and 107; 118, 169, 34, 103, 105, and 109; 19, 178, 34, 101, 105, and 109; 19, 32, 34, 103, 105, and 107; 19, 175, 34, 102, 105, and 108; 119, 120, 34, 102, 105, and 109; 21, 154, 34, 101, 105, and 107; 19, 187, 34, 101, 105, and 107; 117, 125, 34, 101, 105, and 109; 22, 121, 34, 103, 105, and 109; 21, 155, 34, 102, 105, and 107; 22, 150, 34, 102, 105, and 107; 22, 126, 34, 103, 105, and 109; 21, 128, 34, 104, 105, and 107; 119, 170, 34, 104, 105, and 107; 19, 161, 34, 103, 105, and 109; 19, 127, 34, 103, 105, and 109; 23, 185, 34, 104, 105, and 107; 23, 188, 34, 102, 105, and 107; 19, 159, 34, 102, 105, and 107; 22, 177, 34, 102, 105, and 109; 19, 25, 34, 102, 105, and 109; 23, 141, 34, 101, 105, and 193; 22, 115, 34, 101, 105, and 108; 23, 139, 34, 102, 105, and 107; 117, 158, 34, 103, 105, and 107; 19, 173, 34, 102, 105, and 107; 21, 148, 34, 102, 105, and 109; 23, 184, 34, 104, 105, and 107; 22, 131, 34, 102, 105, and 108; 20, 166, 34, 101, 105, and 107; 117, 122, 34, 102, 105, and 109; 22, 167, 34, 101, 105, and 192; 117, 136, 34, 103, 105, and 109; 19, 194, 34, 104, 105, and 107; 19, 177, 34, 104, 105, and 192; 21, 137, 34, 101, 105, and 106; 23, 135, 34, 101, 105, and 107; 21, 160, 34, 103, 105, and 107; 19, 176, 34, 101, 105, and 107, respectively. 
     
     
         208 . The isolated nucleic acid molecule of  claim 206 , wherein the antibody is agonistic. 
     
     
         209 . The isolated nucleic acid molecule of  claim 206 , wherein the isolated nucleic acid molecule encodes:
 (a) a VH having human derived framework regions;   (b) a VH framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein said amino acid sequence is selected from the group consisting of IGHV1-2*02 (SEQ ID NO: 601), IGHV1-3*01 (SEQ ID NO: 602), IGHV1-46*01 (SEQ ID NO: 603), IGHV1-18*01 (SEQ ID NO: 604), IGHV1-69*01 (SEQ ID NO: 605), and IGHV7-4-1*02 (SEQ ID NO: 606); and/or   (c) a VH framework region that is derived from amino acid sequence SEQ ID NO: 601 and wherein at least one amino acid in amino acid sequence SEQ ID NO: 601 is substituted with an amino acid in an analogous position in a corresponding non-human heavy chain variable framework region, optionally wherein the amino acid substitution is at an amino acid position selected from the group consisting of 24, 48, 67, 71, 73, and 94, according to Kabat numbering.   
     
     
         210 . The isolated nucleic acid molecule of  claim 206 , wherein the isolated nucleic acid molecule encodes:
 (a) a VL having human derived framework regions;   (b) a VL framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein said amino acid sequence is selected from the group consisting of IGKV4-1*01 (SEQ ID NO: 607) and IGKV3-7*02 (SEQ ID NO: 608); and/or   (c) a VL framework region that is derived from an amino acid sequence selected from the group consisting of IGKV4-1*01 (SEQ ID NO: 607) and IGKV3-7*02 (SEQ ID NO: 608) and at least one amino acid in amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 is substituted with an amino acid in an analogous position in a corresponding non-human light chain variable framework region, optionally wherein the amino acid substitution is at amino acid position 87, according to Kabat numbering.   
     
     
         211 . The isolated nucleic acid molecule of  claim 206 , wherein the isolated nucleic acid molecule encodes a VH comprising the VH CDR1, VH CDR2, and VH CDR3 amino acid sequences of an amino acid sequence selected from the group consisting of SEQ ID NOs: 201, 206, and 215, 217-234, 236-256, 258-259, 261-265, 267-268, 270-273, 276-277, 280-281, 283-285, 287-288, 290-291, 294, 296-299, 301, 304-306, 308, 313-316, 319-320, 322-325, 327-328, 333, 336, 338-343, 345, 350, 354-356, 358-360, and 362-368, and/or the isolated nucleic acid molecule encodes a VL comprising the VL CDR1, VL CDR2, and VL CDR3 amino acid sequences of an amino acid sequence selected from the group consisting of SEQ ID NOs: 202, 207, 208, 400-411, 413-416, 418-421, 423-448, 450-464, 467-477, 481-486, 488-513, and 515-519. 
     
     
         212 . The isolated nucleic acid molecule of  claim 206 , wherein the isolated nucleic acid molecule also encodes a protein comprising a heavy and/or a light chain constant region, wherein:
 (a) the heavy chain constant region is a human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , or IgA 2  constant region; and/or   (b) the light chain constant region is a human kappa light chain constant region or a human lambda light chain constant region.   
     
     
         213 . The isolated nucleic acid molecule of  claim 212 , wherein:
 (a) the amino acid sequence of the IgG 1  constant region comprises an N297A or an N297Q mutation;   (b) the amino acid sequence of the IgG 4  constant region comprises an S228P mutation; or   (c) the amino acid sequence of the IgG 2  constant region comprises a C127S mutation.   
     
     
         214 . An isolated vector comprising the nucleic acid molecule of  claim 206 . 
     
     
         215 . A host cell comprising the isolated nucleic acid molecule of  claim 206 . 
     
     
         216 . The host cell of  claim 215 , wherein the first and second nucleic acid molecules further encode a human IgG1 heavy chain constant region and/or a human kappa light chain constant region, respectively. 
     
     
         217 . The host cell of  claim 215 , wherein the first nucleic acid molecule and the second nucleic acid molecule are comprised within a single vector. 
     
     
         218 . The host cell of  claim 215 , wherein the first nucleic acid molecule and the second nucleic acid molecule are comprised within separate vectors. 
     
     
         219 . The host cell of  claim 215 , wherein the host cell is a CHO cell. 
     
     
         220 . A method of producing an antibody that specifically binds to human GITR comprising culturing the host cell of  claim 215  so that the nucleic acid molecule is expressed and the antibody is produced.