Anti-tnfrsf9 antibodies and uses thereof

Abstract

This disclosure relates to anti-TNFRSF9 (tumor necrosis factor receptor superfamily member 9) antibodies, antigen-binding fragments, and the uses thereof.

1 . An antibody or antigen-binding fragment thereof that binds to 4-1BB (TNF Receptor Superfamily Member 9) comprising:
 a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and   a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence,   wherein the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs, 1, 2, and 3 amino acid sequences are one of the following:   (1) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1, 2, 3, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4, 5, 6, respectively;   (2) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7, 8, 9, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10, 11, 12, respectively;   (3) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13, 14, 15, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16, 17, 18, respectively;   (4) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 19, 20, 21, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 22, 23, 24, respectively;   (5) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 25, 26, 27, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 28, 29, 30, respectively;   (6) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 31, 32, 33, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 34, 35, 36, respectively;   (7) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 37, 38, 39, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 40, 41, 42, respectively;   (8) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 43, 44, 45, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 46, 47, 48, respectively;   (9) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 49, 50, 51, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 52, 53, 54, respectively;   (10) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 55, 56, 57, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 58, 59, 60, respectively;   (11) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 61, 62, 63, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 64, 65, 66, respectively;   (12) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 67, 68, 69, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 70, 71, 72, respectively;   (13) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 73, 74, 75, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 76, 77, 78, respectively;   (14) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 79, 80, 81, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 82, 83, 84, respectively;   (15) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 85, 86, 87, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 88, 89, 90, respectively;   (16) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 91, 92, 93, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 94, 95, 96, respectively;   (17) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 97, 98, 99, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 100, 101, 102, respectively;   (18) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 103, 104, 105, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 106, 107, 108, respectively;   (19) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 109, 110, 111, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 112, 113, 114, respectively;   (20) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 115, 116, 117, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 118, 119, 120, respectively;   (21) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 121, 122, 123, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 124, 125, 126, respectively;   (22) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 127, 128, 129, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 130, 131, 132, respectively;   (23) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 133, 134, 135, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 136, 137, 138, respectively;   (24) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 139, 140, 141, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 142, 143, 144, respectively;   (25) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 145, 146, 147, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 148, 149, 150, respectively;   (26) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 151, 152, 153, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 154, 155, 156, respectively;   (27) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 157, 158, 159, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 160, 161, 162, respectively;   (28) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 163, 164, 165, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 166, 167, 168, respectively;   (29) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 169, 170, 171, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 172, 173, 174, respectively;   (30) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 175, 176, 177, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 178, 179, 180, respectively;   (31) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 181, 182, 183, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 184, 185, 186, respectively;   (32) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 187, 188, 189, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 190, 191, 192, respectively;   (33) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 193, 194, 195, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 196, 197, 198, respectively;   (34) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 199, 200, 201, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 202, 203, 204, respectively;   (35) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 205, 206, 207, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 208, 209, 210, respectively; and   (36) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 211, 212, 213, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 214, 215, 216, respectively.   
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the VH comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3 respectively, and the VL comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. 
     
     
         3 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the VH comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and the VL comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively. 
     
     
         4 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the VH comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively, and the VL comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 16, 17, and 18, respectively. 
     
     
         5 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment specifically binds to human 4-1BB. 
     
     
         6 . The antibody or antigen-binding fragment thereof  claim 1 , wherein the antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment thereof. 
     
     
         7 . The antibody or antigen-binding fragment thereof  claim 1 , wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFv) or a multi-specific antibody. 
     
     
         8 . A nucleic acid comprising a polynucleotide encoding a polypeptide comprising:
 (1) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 225, 226, 227, 228, or 244 binds to 4-1BB;   (2) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 221, 222, 223, 224, or 243 binds to 4-1BB;   (3) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 232, 233, 234, 235, or 246 binds to 4-1BB;   (4) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 229, 230, 231, or 245 binds to 4-1BB;   (5) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 239, 240, 241, 242, or 248 binds to 4-1BB;   (6) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 16, 17, and 18, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 236, 237, 238, or 247 binds to 4-1BB;   (7) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 19, 20, 21, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 250 binds to 4-1BB;   (8) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 22, 23, 24, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 249 binds to 4-1BB;   (9) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 25, 26, 27, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 252 binds to 4-1BB;   (10) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 28, 29, 30, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 251 binds to 4-1BB;   (11) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 31, 32, 33, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 254 binds to 4-1BB;   (12) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 34, 35, 36, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 253 binds to 4-1BB;   (13) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 256 binds to 4-1BB;   (14) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 40, 41, 42, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 255 binds to 4-1BB;   (15) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 43, 44, 45, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 258 binds to 4-1BB;   (16) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 46, 47, 48, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 257 binds to 4-1BB;   (17) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 49, 50, 51, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 260 binds to 4-1BB;   (18) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 52, 53, 54, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 259 binds to 4-1BB;   (19) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 55, 56, 57, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 262 binds to 4-1BB;   (20) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 58, 59, 60, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 261 binds to 4-1BB;   (21) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 61, 62, 63, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 264 binds to 4-1BB;   (22) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 64, 65, 66, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 263 binds to 4-1BB;   (23) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 67, 68, 69, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 266 binds to 4-1BB;   (24) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 70, 71, 72, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 265 binds to 4-1BB;   (25) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 73, 74, 75, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 268 binds to 4-1BB;   (26) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 76, 77, 78, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 267 binds to 4-1BB;   (27) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 79, 80, 81, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 270 binds to 4-1BB;   (28) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 82, 83, 84, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 269 binds to 4-1BB;   (29) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 85, 86, 87, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 272 binds to 4-1BB;   (30) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 88, 89, 90, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 271 binds to 4-1BB;   (31) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 91, 92, 93, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 274 binds to 4-1BB;   (32) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 94, 95, 96, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 273 binds to 4-1BB;   (33) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 97, 98, 99, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 276 binds to 4-1BB;   (34) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 100, 101, 102, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 275 binds to 4-1BB;   (35) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 103, 104, 105, respectively, and wherein the VH, when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 278 binds to 4-1BB; or   (36) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 106, 107, 108, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 277 binds to 4-1BB.   
     
     
         9 .- 18 . (canceled) 
     
     
         19 . A vector comprising one or more of the nucleic acids of  claim 8 . 
     
     
         20 .- 21 . (canceled) 
     
     
         22 . A cell comprising one or more of the nucleic acids of  claim 8 . 
     
     
         23 .- 26 . (canceled) 
     
     
         27 . A method of producing an antibody or an antigen-binding fragment thereof, the method comprising
 culturing the cell of  claim 22  under conditions sufficient for the cell to produce the antibody or the antigen-binding fragment.   
     
     
         28 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the
 VH comprises an amino acid sequence that is at least 90% identical to a selected VH sequence, and the VL comprises an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:   (1) the selected VH sequence is SEQ ID NOs: 221, 222, 223, 224, or 243, and the selected VL sequence is SEQ ID NOs: 225, 226, 227, 228, or 244;   (2) the selected VH sequence is SEQ ID NOs: 229, 230, 231, or 245, and the selected VL sequence is SEQ ID NOs: 232, 233, 234, 235, or 246;   (3) the selected VH sequence is SEQ ID NO: 236, 237, 238, or 247, and the selected VL sequence is SEQ ID NO: 239, 240, 241, 242, or 248;   (4) the selected VH sequence is SEQ ID NO: 249, and the selected VL sequence is SEQ ID NO: 250;   (5) the selected VH sequence is SEQ ID NO: 251, and the selected VL sequence is SEQ ID NO: 252;   (6) the selected VH sequence is SEQ ID NO: 253, and the selected VL sequence is SEQ ID NO: 254;   (7) the selected VH sequence is SEQ ID NO: 255, and the selected VL sequence is SEQ ID NO: 256;   (8) the selected VH sequence is SEQ ID NO: 257, and the selected VL sequence is SEQ ID NO: 258;   (9) the selected VH sequence is SEQ ID NO: 259, and the selected VL sequence is SEQ ID NO: 260;   (10) the selected VH sequence is SEQ ID NO: 261, and the selected VL sequence is SEQ ID NO: 262;   (11) the selected VH sequence is SEQ ID NO: 263, and the selected VL sequence is SEQ ID NO: 264;   (12) the selected VH sequence is SEQ ID NO: 265, and the selected VL sequence is SEQ ID NO: 266;   (13) the selected VH sequence is SEQ ID NO: 267, and the selected VL sequence is SEQ ID NO: 268;   (14) the selected VH sequence is SEQ ID NO: 269, and the selected VL sequence is SEQ ID NO: 270;   (15) the selected VH sequence is SEQ ID NO: 271, and the selected VL sequence is SEQ ID NO: 272;   (16) the selected VH sequence is SEQ ID NO: 273, and the selected VL sequence is SEQ ID NO: 274;   (17) the selected VH sequence is SEQ ID NO: 275, and the selected VL sequence is SEQ ID NO: 276; and   (18) the selected VH sequence is SEQ ID NO: 277, and the selected VL sequence is SEQ ID NO: 278.   
     
     
         29 .- 33 . (canceled) 
     
     
         34 . An antibody-drug conjugate comprising the antibody or antigen-binding fragment thereof of  claim 1  covalently bound to a therapeutic agent. 
     
     
         35 . (canceled) 
     
     
         36 . A method of treating a subject having cancer, the method comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof of  claim 1  to the subject. 
     
     
         37 . The method of  claim 36 , wherein the subject has a solid tumor, breast cancer, oropharyngeal cancer, ovarian cancer, B cell lymphoma, Non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), melanoma, B-cell non-Hodgkin lymphoma, colorectal cancer, hematologic malignancy, head and neck cancer, bladder cancer, or multiple myeloma. 
     
     
         38 .- 39 . (canceled) 
     
     
         40 . A method of decreasing the rate of tumor growth, the method comprising
 administering to a subject in need thereof an effective amount of a composition comprising an antibody or antigen-binding fragment thereof of  claim 1 .   
     
     
         41 . A method of killing a tumor cell, the method comprising administering to a subject in need thereof an effective amount of a composition comprising the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         42 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         43 .- 45 . (canceled) 
     
     
         46 . The method of  claim 52 , wherein the anti-4-1BB IgG1 antibody or antigen-binding fragment thereof comprises:
 (1) a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and   a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, wherein the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs, 1, 2, and 3 amino acid sequences are selected from one of the antibodies as set forth in Table 3; or   (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are selected from one of the antibodies as set forth in Table 3.   
     
     
         47 .- 51 . (canceled) 
     
     
         52 . A method of treating a subject having cancer, the method comprising administering to the subject a therapeutically effective amount of an anti-4-1BB IgG1 antibody or antigen-binding fragment thereof and
 (1) a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof; or   (2) a therapeutically effective amount of an anti-CTLA4 antibody or antigen-binding fragment thereof.   
     
     
         53 .- 57 . (canceled)