Anti-TIGIT Antibodies

Abstract

Isolated antibodies that bind to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains) are provided. In some embodiments, the antibody has a binding affinity (KD) for human TIGIT of less than 5 nM. In some embodiments, the anti-TIGIT antibody blocks binding of CD155 and/or CD112 to TIGIT. In some embodiments, the antibodies are afucosylated.

1 .- 184 . (canceled) 
     
     
         185 . A method of treating cancer in a subject, comprising administering to the subject a therapeutic amount of an antibody that binds to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
 (a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or   (b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or   (c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or   (d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or   (e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.   
     
     
         186 . The method of  claim 185 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, or SEQ ID NO: 249 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64. 
     
     
         187 . The method of  claim 185 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64. 
     
     
         188 . The method of  claim 185 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 260, SEQ ID NO: 262, SEQ ID NO: 264, SEQ ID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, or SEQ ID NO: 272; and a light chain comprising the amino acid sequence of SEQ ID NO: 274. 
     
     
         189 . The method of  claim 185 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274. 
     
     
         190 . The method of  claim 185 , wherein the antibody is an IgG1 antibody. 
     
     
         191 . The method of  claim 187 , wherein the antibody is an IgG1 antibody. 
     
     
         192 . The method of  claim 185 , wherein the antibody is afucosylated. 
     
     
         193 . The method of  claim 187 , wherein the antibody is afucosylated. 
     
     
         194 . The method of  claim 189 , wherein the antibody is afucosylated. 
     
     
         195 . The method of  claim 191 , wherein the antibody is afucosylated. 
     
     
         196 . The method of  claim 194 , wherein the antibody binds with increased affinity to FcγRIIIa and binds with decreased affinity to FcγRIIa and FcγRIIb, compared to the same antibody that is not afucosylated. 
     
     
         197 . The method of  claim 189 , wherein the antibody has a binding affinity (K D ) for human TIGIT of less than 5 nM. 
     
     
         198 . The method of  claim 185 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         199 . The method of  claim 198 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         200 . The method of  claim 187 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         201 . The method of  claim 200 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         202 . The method of  claim 189 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         203 . The method of  claim 202 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         204 . The method of  claim 194 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         205 . The method of  claim 204 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         206 . The method of  claim 185 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         207 . The method of  claim 206 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         208 . The method of  claim 189 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         209 . The method of  claim 208 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         210 . The method of  claim 194 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         211 . The method of  claim 210 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         212 . The method of  claim 204 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         213 . The method of  claim 212 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         214 . A method of treating cancer in a subject, comprising administering to the subject a therapeutic amount of a composition comprising isolated antibodies that bind to human TIGIT, wherein at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the antibodies in the composition are afucosylated, and wherein each of the antibodies in the composition comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
 (a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or   (b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or   (c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or   (d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or   (e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.   
     
     
         215 . The method of  claim 214 , wherein each of the antibodies comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, or SEQ ID NO: 249 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64. 
     
     
         216 . The method of  claim 214 , wherein each of the antibodies comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64. 
     
     
         217 . The method of  claim 214 , wherein each of the antibodies comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 260, SEQ ID NO: 262, SEQ ID NO: 264, SEQ ID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, or SEQ ID NO: 272; and a light chain comprising the amino acid sequence of SEQ ID NO: 274. 
     
     
         218 . The method of  claim 214 , wherein each of the antibodies comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274. 
     
     
         219 . The method of  claim 214 , wherein each of the antibodies is an IgG1 antibody. 
     
     
         220 . The method of  claim 216 , wherein each of the antibodies is an IgG1 antibody. 
     
     
         221 . The method of  claim 218 , wherein the antibodies in the composition that are afucosylated bind with increased affinity to FcγRIIIa and bind with decreased affinity to FcγRIIa and FcγRIIb, compared to the antibodies in the composition that are not afucosylated. 
     
     
         222 . The method of  claim 218 , wherein each of the antibodies has a binding affinity (K D ) for human TIGIT of less than 5 nM. 
     
     
         223 . The method of  claim 214 , wherein at least 95% of the antibodies in the composition are afucosylated. 
     
     
         224 . The method of  claim 216 , wherein at least 95% of the antibodies in the composition are afucosylated. 
     
     
         225 . The method of  claim 218 , wherein at least 95% of the antibodies in the composition are afucosylated. 
     
     
         226 . The method of  claim 214 , wherein at least 97% of the antibodies in the composition are afucosylated. 
     
     
         227 . The method of  claim 216 , wherein at least 97% of the antibodies in the composition are afucosylated. 
     
     
         228 . The method of  claim 218 , wherein at least 97% of the antibodies in the composition are afucosylated. 
     
     
         229 . The method of  claim 214 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         230 . The method of  claim 229 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         231 . The method of  claim 216 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         232 . The method of  claim 231 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         233 . The method of  claim 218 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         234 . The method of  claim 233 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         235 . The method of  claim 214 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         236 . The method of  claim 235 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         237 . The method of  claim 216 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         238 . The method of  claim 237 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         239 . The method of  claim 218 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         240 . The method of  claim 239 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         241 . The method of  claim 233 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         242 . The method of  claim 241 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.   
     
     
         243 . A method of treating cancer in a subject, comprising administering to the subject a therapeutic amount of a composition of isolated antibodies that bind to human TIGIT, wherein the antibodies are produced by a method comprising (a) culturing a host cell in the presence of a fucose analogue under conditions suitable for producing afucosylated antibodies, or (b) culturing a host cell engineered to produce afucylated antibodies, wherein each of the antibodies in the composition comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
 (a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or   (b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or   (c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or   (d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or   (e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.   
     
     
         244 . The method of  claim 243 , wherein each of the antibodies comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64. 
     
     
         245 . The method of  claim 243 , wherein each of the antibodies comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274. 
     
     
         246 . The method of  claim 243 , wherein at least 95% of the antibodies in the composition are afucosylated. 
     
     
         247 . The method of  claim 243 , wherein the cancer is bladder cancer, breast cancer, uterine cancer, 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, Hodgkin lymphoma, or diffuse large B-cell lymphoma. 
     
     
         248 . The method of  claim 247 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, gastrointestinal cancer, lung cancer, stomach cancer, head and neck cancer, lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, or skin cancer. 
     
     
         249 . The method of  claim 243 , wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent. 
     
     
         250 . The method of  claim 249 ,
 a) wherein the additional therapeutic agent is an antagonist or an inhibitor of a T cell coinhibitor, an agonist of a T cell coactivator, an immune stimulatory cytokine, or SGN-2FF;   b) wherein the additional therapeutic agent binds a protein selected from CD25, PD-1, PD-L1, Tim3, Lag3, CTLA4, 41BB, OX40, CD3, CD40, CD47M, GM-CSF, CSF1R, TLR, STING, RIGI, TAM receptor kinase, NKG2A, NKG2D, GD2, HER2, EGFR, PDGFRα, SLAMF7, VEGF, CTLA-4, CD20, cCLB8, KIR, and CD52;   c) wherein the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, anti-TLR antibody, anti-STING antibody, anti-RIGI antibody, anti-TAM receptor kinase antibody, anti-NKG2A antibody, anti-NKG2D antibody, anti-GD2 antibody, anti-HER2 antibody, anti-EGFR antibody, anti-PDGFR-α-antibody, anti-SLAMF7 antibody, anti-VEGF antibody, anti-CTLA-4 antibody, anti-CD20 antibody, anti-cCLB8 antibody, anti-KIR antibody, and anti-CD52 antibody;   d) wherein the additional therapeutic agent comprises a cytokine selected from IL-15, IL-21, IL-2, GM-CSF, M-CSF, G-CSF, IL-1, IL-3, IL-12, and IFNγ; or   e) wherein the additional therapeutic agent is selected from SEA-CD40, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A, Hu3F8, dinutuximab, trastuzumab, cetuximab, olaratumab, necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, lirilumab, and alemtuzumab; or wherein the additional therapeutic agent is selected from an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, or temozolomide), an anthracycline (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, or mitoxantrone), a cytoskeletal disruptor (e.g., paclitaxel or docetaxel), a histone deacetylase inhibitor (e.g., vorinostat or romidepsin), an inhibitor of topoisomerase (e.g., irinotecan, topotecan, amsacrine, etoposide, or teniposide), a kinase inhibitor (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib), a nucleoside analog or precursor analog (e.g., azacitidine, azathioprine, capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine), a peptide antibiotic (e.g., actinomycin or bleomycin), a platinum-based agent (e.g., cisplatin, oxaliplatin, or carboplatin), a plant alkaloid (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, or docetaxel), galardin, thalidomide, lenalidomide, and pomalidomide.