Methods of treating cancer using antibodies and molecules that immunospecifically bind to BTN1A1

Abstract

Provided herein are methods of treating cancer using molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1, e.g., anti-BTN1A1 antibodies. These molecules include those having an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1, e.g., anti-glycosylated BTN1A1 antibodies. Also included are molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1 dimers, e.g., anti-BTN1A1 dimer antibodies. Also provided are methods of treating cancers resistant or refractory to anti-PD-1 or anti-PD-L1 therapy. [Selected Figure] Figure 1

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 513,393, filed May 31, 2017; the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Reference to sequence listing) This application has been filed with a computer readable form (CRF) copy of the Sequence Listing entitled 13532-019-228_ST25.txt, created on May 25, 2018, and having a size of May 25, 2018 bytes; which is incorporated herein by reference in its entirety.

[0003] (1. Field) The present invention relates generally to the fields of cancer immunology and molecular biology. Provided herein are methods of treating cancer using anti-BTN1A1 antibodies or other molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1. In some embodiments, the cancer is resistant or refractory to anti-PD-1 or anti-PD-L1 therapy. [Background technology]

[0004] (2.Background) The immune system of humans and other mammals protects them from infection and disease. Several stimulatory and inhibitory ligands and receptors provide a strict regulatory system that maximizes the immune response to infection while limiting autoimmunity. Recently, therapies that modulate the immune response, such as anti-PD1 or anti-PDL1 antibodies, have been found to be effective in treating some cancers. However, the development of new therapies that safely and effectively treat diseases by modulating the immune system remains a pressing need, particularly for cancers resistant or refractory to anti-PD1 or anti-PD-L1 therapy. The methods described herein fulfill these needs and offer other related advantages. Summary of the Invention

[0005] (3. Overview) In one aspect, provided herein is a method of treating anti-PD-1 therapy or anti-PD-L1 therapy resistant or refractory cancer in a subject, comprising administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0006] In another aspect, provided herein is a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 in combination with radiation therapy.

[0007] In some embodiments, the radiation therapy is high-dose radiation therapy.

[0008] In another aspect, provided herein is a method of killing or inhibiting the growth of cancer cells that are resistant to anti-PD-1 therapy or anti-PD-L1 therapy, comprising contacting the cells with an effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0009] In another aspect, provided herein is a method of treating cancer, the method comprising: (i) obtaining a sample comprising cancer cells from a subject having cancer; (ii) determining the level of BTN1A1 in the sample; (iii) diagnosing the subject as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 if the level of BTN1A1 in the sample is equal to or greater than a BTN1A1 reference level; and (iv) administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0010] In another aspect, provided herein is a method of treating cancer, the method comprising: (i) obtaining a sample comprising cancer cells from a subject with cancer; (ii) determining the level of PD-L1 in the sample; (iii) diagnosing the subject as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 if the level of PD-L1 in the sample is less than or equal to a PD-L1 reference level; and (iv) administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0011] In another aspect, provided herein is a method of treating an anti-PD1 or anti-PD-L1 therapy resistant or refractory cancer, the method comprising: (i) obtaining a sample comprising cancer cells from a subject with an anti-PD1 or anti-PD-L1 therapy resistant or refractory cancer; (ii) determining the level of BTN1A1 in the sample; (iii) diagnosing the subject as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 if the level of BTN1A1 in the sample is equal to or greater than a BTN1A1 reference level; and (iv) administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0012] In another aspect, provided herein is a method of treating an anti-PD1 or anti-PD-L1 therapy resistant or refractory cancer, the method comprising: (i) obtaining a sample comprising cancer cells from a subject with an anti-PD1 or anti-PD-L1 therapy resistant or refractory cancer; (ii) determining the level of BTN1A1 or PD-L1 in the sample; (iii) diagnosing the subject as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 if the level of BTN1A1 in the sample is equal to or greater than the BTN1A1 reference level, or if the level of PD-L1 in the sample is equal to or less than the PD-L1 reference level; and (iv) administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0013] In another aspect, provided herein is a method of treating cancer, the method comprising obtaining a sample comprising cancer cells from a subject with cancer; determining the level of BTN1A1 and / or PD-L1 in the sample; if the level of BTN1A1 in the sample is equal to or greater than a BTN1A1 reference level, and / or if the level of PD-L1 in the sample is equal to or less than a PD-L1 reference level, diagnosing the subject as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1; and administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0014] In some embodiments, the cancer is an anti-PD-1 therapy or anti-PD-L1 therapy resistant or refractory cancer.

[0015] In some embodiments, the cancer is breast cancer or lung cancer.

[0016] In some embodiments, the cancer is breast cancer or Lewis lung carcinoma.

[0017] In some embodiments, the method comprises determining the level of BTN1A1 in the sample.

[0018] In some embodiments, the method comprises determining the level of PD-L1 in the sample.

[0019] In some embodiments, the method comprises determining the levels of BTN1A1 and PD-L1 in the sample.

[0020] In some embodiments, if the level of BTN1A1 in the sample is greater than the BTN1A1 reference level, the subject is diagnosed as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0021] In some embodiments, if the level of PD-L1 in the sample is lower than the PD-L1 reference level, the subject is diagnosed as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0022] In some embodiments, if the level of BTN1A1 in the sample is higher than the BTN1A1 reference level, and if the level of PD-L1 in the sample is lower than the PD-L1 reference level, the subject is diagnosed as likely to respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1.

[0023] In some embodiments, determining the level of BTN1A1 or PD-L1 in the sample comprises analyzing the level of BTN1A1 or PD-L1 protein in the tissue sample by immunohistochemistry.

[0024] In some embodiments, an antigen-binding fragment that immunospecifically binds to BTN1A1 preferentially binds to BTN1A1 dimers over BTN1A1 monomers.

[0025] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC810.

[0026] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC2714.

[0027] In another aspect, provided herein is a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 and a therapeutically effective amount of an anti-PD-1 therapy or an anti-PD-L1 therapy.

[0028] In some embodiments, the method comprises administering an anti-PD-1 therapy.

[0029] In some embodiments, the method comprises administering an anti-PD-L1 therapy.

[0030] In some embodiments, the methods comprise administering an anti-PD-1 therapy and an anti-PD-L1 therapy.

[0031] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 and the anti-PD-1 therapy or anti-PD-L1 therapy are formulated together.

[0032] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 and the anti-PD-1 therapy or anti-PD-L1 therapy are formulated separately.

[0033] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 and the anti-PD-1 therapy or anti-PD-L1 therapy are independently administered simultaneously or separately within a time interval, optionally followed by repeated administration for one or more cycles.

[0034] In some embodiments, an antigen-binding fragment that immunospecifically binds to BTN1A1 preferentially binds to BTN1A1 dimers over BTN1A1 monomers.

[0035] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC810.

[0036] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC2714.

[0037] In some embodiments, the treatment results in at least one therapeutic effect, such as a decrease in tumor size, a decrease in the number of metastatic lesions over time, a complete response, a partial response, or stable disease.

[0038] In some embodiments, the cancer is breast cancer, neuroendocrine prostate cancer (NEPC), diffuse large B-cell lymphoma, melanoma, cancer from the National Cancer Institute Cancer Panel (NCI 60), uveal melanoma, pancreatic cancer, ovarian cancer, uterine cancer, lung adenocarcinoma, desmoplastic small round cell tumor, bladder cancer, colorectal cancer, lung squamous cell carcinoma, liver cancer, lung cancer, gastric cancer, cholangiocarcinoma, esophageal squamous cell carcinoma, head and neck cancer, sarcoma, prostate cancer, liver cancer, pancreatic cancer, pheochromocytoma or paraganglioma (PCPG), cervical cancer, glioma, or acute myeloid leukemia (AML).

[0039] In some embodiments, the anti-PD-1 or anti-PD-L1 therapy comprises an anti-PD-1 or anti-PD-L1 antibody or antibody fragment, or a soluble PD-1 or PD-L1 ligand, or an Fc-fusion protein thereof.

[0040] In some embodiments, the anti-PD-1 therapy comprises nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-514, or AMP-224.

[0041] In some embodiments, the anti-PD-1 therapy comprises an anti-PD-1 antibody provided in International Application No. PCT / US2016 / 64394.

[0042] In some embodiments, the anti-PD-L1 therapy comprises YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

[0043] In some embodiments, the anti-PD-L1 therapy comprises an antibody provided in International Application No. PCT / US2016 / 024691 and International Application No. PCT / US2017 / 024027.

[0044] In some embodiments, the antigen-binding fragment that immunospecifically binds to BTN1A1 preferentially binds glycosylated over unglycosylated BTN1A1.

[0045] In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 dimers over BTN1A1 monomers.

[0046] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC810.

[0047] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC2714.

[0048] In some embodiments, the antigen-binding fragment comprises: (a) (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, and 72; H CDR1; (2) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, and 73 H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, and 74. H Heavy chain variable (V) containing CDR3 H ) region; or (b)(1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, and 84. L CDR1; (2) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, and 85 L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, and 86. L The light chain variable (V) L ) area.

[0049] In some embodiments, the antigen-binding fragment comprises: (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, and 72; H CDR1; (2) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, and 73 H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, and 74. H Heavy chain variable (V) containing CDR3 H ) area.

[0050] In some embodiments, the heavy chain variable (V H ) region, (a) (1) a V having the amino acid sequence of SEQ ID NO: 7, 35, or 63; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 8, 36, or 64 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 9, 37, or 65. H CDR3; (b)(1) V having the amino acid sequence of SEQ ID NO: 10, 38, or 66 H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 11, 39, or 67 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 12, 40, or 68. H CDR3; (c) (1) V having the amino acid sequence of SEQ ID NO: 13, 41, or 69 H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 14, 42, or 70 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 15, 43, or 71. H or (d)(1) a V having the amino acid sequence of SEQ ID NO: 16, 44, or 72. H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 17, 45, or 73 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 18, 46, or 74. H Includes CDR3.

[0051] In some embodiments, the heavy chain variable (V H ) region comprises the amino acid sequence of SEQ ID NO: 3, 31, or 59.

[0052] In some embodiments, the antigen-binding fragment comprises: (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, and 84; L CDR1; (2) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, and 85 L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, and 86. L Light chain variable (V) containing CDR3: L ) area.

[0053] In some embodiments, the light chain variable (V L ) region, (a) (1) a V having the amino acid sequence of SEQ ID NO: 19, 47, or 75; L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 20, 48, or 76 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 21, 49, or 77. L CDR3; (b)(1) a V having the amino acid sequence of SEQ ID NO: 22, 50, or 78 L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 23, 51, or 79 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 24, 52, or 80. L CDR3; (c) (1) a V having the amino acid sequence of SEQ ID NO: 25, 53, or 81 L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 26, 54, or 82 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 27, 55, or 83. Lor (d)(1) a V having the amino acid sequence of SEQ ID NO: 28, 56, or 84. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 29, 57, or 85 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 30, 58, or 86. L Includes CDR3.

[0054] In some embodiments, the light chain variable (V L ) region comprises the amino acid sequence of SEQ ID NO: 5, 35, 61, 89, 117, or 145.

[0055] In some embodiments, the antigen-binding fragment comprises: (a) (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, and 72; H CDR1; (2) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, and 73 H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, and 74. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84. L CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85 L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86. L The light chain variable (V L ) area.

[0056] In some embodiments, the antigen-binding fragment comprises (i)(a)(1) a V having an amino acid sequence of SEQ ID NO: 7, 35, or 63 H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 8, 36, or 64 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 9, 37, or 65. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 19, 47, or 75. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 20, 48, or 76 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 21, 49, or 77. L The light chain variable (V) L ) region; (ii)(a)(1) a V region having the amino acid sequence of SEQ ID NO: 10, 38, or 66; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 11, 39, or 67 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 12, 40, or 68. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 22, 50, or 78. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 23, 51, or 79 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 24, 52, or 80. L The light chain variable (V) L ) region; (iii)(a)(1) a V region having the amino acid sequence of SEQ ID NO: 13, 41, or 69; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 14, 42, or 70 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 15, 43, or 71. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 25, 53, or 81. LCDR1; (2) V having the amino acid sequence of SEQ ID NO: 26, 54, or 82 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 27, 55, or 83. L The light chain variable (V) L ) region; or (iv)(a)(1) a V region having the amino acid sequence of SEQ ID NO: 16, 44, or 72. H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 17, 45, or 73 H CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 18, 46, or 74. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 28, 56, or 84. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 29, 57, or 85 L CDR2; and (3) a V having the amino acid sequence of SEQ ID NO: 30, 58, or 86. L The light chain variable (V) L ) area.

[0057] In some embodiments, the V H The region comprises the amino acid sequence of SEQ ID NO: 3, L The region comprises the amino acid sequence of SEQ ID NO:5.

[0058] In some embodiments, the V H The region comprises the amino acid sequence of SEQ ID NO: 31, L The region comprises the amino acid sequence of SEQ ID NO:33.

[0059] In some embodiments, the V H The region comprises the amino acid sequence of SEQ ID NO: 59, L The region comprises the amino acid sequence of SEQ ID NO:61.

[0060] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC703, STC810, or STC820, or a humanized variant thereof.

[0061] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC703 or STC81, or a humanized variant thereof.

[0062] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC810 ​​or a humanized variant thereof.

[0063] In some embodiments, the antigen-binding fragment comprises (a)(1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 228, 231, and 234. H CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 226, 229, 232, and 235 H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 227, 230, 233, and 236. H Heavy chain variable (V) containing CDR3 H ) region; or (b)(1) a V region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 237, 240, 243, and 246. L CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 238, 241, 244, and 247 L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 239, 242, 245, and 248. L The light chain variable (V) L ) area.

[0064] In some embodiments, the antigen-binding fragment comprises: (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 228, 231, and 234; H CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 226, 229, 232, and 235 H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 227, 230, 233, and 236. HHeavy chain variable (V) containing CDR3 H ) area.

[0065] In some embodiments, the heavy chain variable (V H ) region includes (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227; (b) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 228; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 229; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 230; c) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 231; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 232; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 233; or (d) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 235; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 236.

[0066] In some embodiments, the heavy chain variable (V H ) region comprises the amino acid sequence of SEQ ID NO:221.

[0067] In some embodiments, the antigen-binding fragment comprises: (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 237, 240, 243, and 246; L CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 238, 241, 244, and 247 L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 239, 242, 245, and 248. L Light chain variable (V) containing CDR3: L ) area.

[0068] In some embodiments, the light chain variable (V L) region includes (a)(1) a VL CDR1 having the amino acid sequence of SEQ ID NO:237; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:238; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:239; (b)(1) a VL CDR1 having the amino acid sequence of SEQ ID NO:240; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:241; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:242; (c)(1) a VL CDR1 having the amino acid sequence of SEQ ID NO:243; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:244; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:245; or (d)(1) a VL CDR1 having the amino acid sequence of SEQ ID NO:246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:247; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:248.

[0069] In some embodiments, the light chain variable (V L ) region comprises the amino acid sequence of SEQ ID NO:223.

[0070] In some embodiments, the antigen-binding fragment comprises (a)(1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 228, 231, and 234. H CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 226, 229, 232, and 235 H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 227, 230, 233, and 236. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 237, 240, 243, and 246. L CDR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 238, 241, 244, and 247 L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 239, 242, 245, and 248. L The light chain variable (V L ) area.

[0071] In some embodiments, the antigen-binding fragment comprises: (i)(a)(1) a V having an amino acid sequence of SEQ ID NO: 225; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 226 H and (3) a V having the amino acid sequence of SEQ ID NO: 227. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 237. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 238 L and (3) a V having the amino acid sequence of SEQ ID NO: 239. L The light chain variable (V L ) region; (ii)(a)(1) a V region having the amino acid sequence of SEQ ID NO: 228; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 229 H and (3) a V having the amino acid sequence of SEQ ID NO: 230. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 240. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 241 L and (3) a V having the amino acid sequence of SEQ ID NO: 242. L The light chain variable (V L ) region; (iii)(a)(1) a V region having the amino acid sequence of SEQ ID NO: 231; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 232 H and (3) a V having the amino acid sequence of SEQ ID NO: 233. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 243. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 244 L and (3) a V having the amino acid sequence of SEQ ID NO: 245. L The light chain variable (V L) region; or (iv)(a)(1) a V region having the amino acid sequence of SEQ ID NO: 234. H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 235 H and (3) a V having the amino acid sequence of SEQ ID NO: 236. H Heavy chain variable (V) containing CDR3 H ) region; and (b)(1) a V region having the amino acid sequence of SEQ ID NO: 246. L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 247 L and (3) a V having the amino acid sequence of SEQ ID NO: 248. L The light chain variable (V L ) area.

[0072] In some embodiments, the V H The region comprises the amino acid sequence of SEQ ID NO: 221, L The region comprises the amino acid sequence of SEQ ID NO:223.

[0073] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is STC2714 or a humanized variant thereof.

[0074] In some embodiments, the binding to BTN1A1 competitively blocks the binding of a molecule provided herein to BTN1A1 in a dose-dependent manner.

[0075] In some embodiments, molecules comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 have a dissociation constant (K D ) binds to glycosylated BTN1A1.

[0076] In some embodiments, molecules comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 have a dissociation constant (K D ) binds to glycosylated BTN1A1.

[0077] In some embodiments, molecules comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 have a dissociation constant (K D ) binds to the BTN1A1 dimer.

[0078] In some embodiments, molecules comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 have a dissociation constant (K D ) binds to the BTN1A1 dimer.

[0079] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is an antibody.

[0080] In some embodiments, the antibody is a monoclonal antibody.

[0081] In some embodiments, the antibody is a human antibody or a humanized antibody.

[0082] In some embodiments, the antibody is an IgG, IgM, or IgA.

[0083] In some embodiments, the molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is a Fab', F(ab')2, F(ab')3, monovalent scFv, bivalent scFv, or single domain antibody.

[0084] In some embodiments, molecules comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 are recombinantly produced. [Brief explanation of the drawings]

[0085] (4. Brief description of the drawings) The following drawings form part of the present specification and are included to further demonstrate certain embodiments of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0086] [Figure 1] Figure 1 - BTN1A1 expression across human cancers. Figure 1 shows a bar graph depicting BTN1A1 expression across various human cancer types according to cBioPortal. The frequency of mutations (green), deletions (blue), amplifications (red), or multiple aberrations (gray) is plotted by cancer type. CAN = copy number aberrations.

[0087] [Figure 2] Figure 2A-D - Mutually exclusive expression of BTN1A1 and PD-L1 in cancer tissues. Figures 2A-D show exemplary images of paraffin-embedded tissue samples from lung squamous cell carcinoma (Figure 2A), prostate adenocarcinoma (Figure 2B), pancreatic adenocarcinoma (Figure 2C), and hepatocellular carcinoma (Figure 2D). Two samples are shown for each tissue type (top and bottom rows in Figures 2A-D). Different slices from each sample were stained with PD-L1 (left row in Figures 2A-D) or BTN1A1 (right row in Figures 2A-D).

[0088] [Figure 3] Figures 3A-D - Mutually exclusive expression of BTN1A1 and PD-L1 in cancer tissues. Figures 3A-D show fluorescent microscopy images of exemplary human lung squamous cell carcinoma tissue slices. Figure 3A shows fluorescent staining for PD-L1 (green). Figure 3B shows fluorescent staining for BTN1A1 (red). Figure 3C shows fluorescent staining for cytokeratin (purple). Figure 3D shows a composite image of overlapping images from Figures 3A-C.

[0089] [Figure 4]Figures 4A-D - Mutually exclusive expression of BTN1A1 and PD-L1 in cancer tissues. Figures 4A-D show additional fluorescent microscopy images of additional exemplary human lung squamous cell carcinoma tissue slices. Figure 4A shows fluorescent staining for PD-L1 (green). Figure 4B shows fluorescent staining for BTN1A1 (red). Figure 4C shows fluorescent staining for cytokeratin (purple). Figure 4D shows a merged image of overlapping images from Figures 4A-C. DAPI = fluorescent dye (4',6-diamidino-2-phenylindole).

[0090] [Figure 5] Figures 5A and 5B - STC810 ​​synergizes with anti-PD-1 antibodies to induce IL-2 and IFNγ secretion in a mixed lymphocyte reaction. Figures 5A and 5B show bar graphs depicting the effect of the indicated antibody treatments on mixed lymphocyte cultures on IL-2 (Figure 5A) or IFNγ (Figure 5B) secretion.

[0091] [Figure 6] Figures 6A-C - Surface plasmon resonance analysis of BTN1A1-Fc binding to immobilized STC1011, STC1012, or STC1029 MAbs. Figures 6A, 6B, and 6C: Sensorgrams showing real-time binding of soluble BTN1A1-Fc protein (2-fold dilutions, 2-64 nM) to STC1011 (Figure 6A), STC1012 (Figure 6B), or STC1029 (Figure 6C) immobilized on a Protein A-CM5 chip (BIAcore). A flow cell without immobilized protein was used as a control for nonspecific binding and was subtracted from the test flow cell.

[0092] [Figure 7]Figures 7A-C—Fluorescently labeled STC1012 is internalized by cells overexpressing glycosylated murine BTN1A1 WT or nonglycosylated murine BTN1A1 2NQ. Figure 7A shows representative images from IncuCyte ZOOM® live-cell analysis. Red fluorescence, indicating internalized phRodo™-labeled STC1012, is visible in the middle panel (293T mBTN1A1(WT)) and the top right panel (293T mBTN1A1(2NQ)) of the top row, but not in the control panel. Figure 7B shows a graph plotting internalized STC1012-phRodo™ fluorescence over time. An increase in internalized STC810-phRodo™ fluorescence is observed in cells expressing glycosylated BTN1A1 WT and nonglycosylated BTN1A1 2NQ. FIG. 7C shows the results of a control experiment using pHRodo™-labeled control mIgG1.

[0093] [Figure 8] Figures 8A and 8B—Anti-mBTN1A1 antibodies promote proliferation of T cells cocultured with mBTN1A1-overexpressing 4T1 cells. Figures 8A and 8B show the results of a 4T1-BTN1A1-mouse spleen cell coculture experiment. 4T1 cells overexpressing BTN1A1 were cocultured with mouse spleen cells and the indicated anti-mouse BTN1A1 antibodies. Figure 8A shows the results of flow cytometry analysis of proliferating T cells in the coculture. Figure 8B shows a bar graph depicting the effects of STC1011, STC1012, and STC1029 on T cell proliferation in the coculture. CFSE = fluorescent dye (5(6)-carboxyfluorescein N-hydroxysuccinimidyl ester).

[0094] [Figure 9] Figure 9 - Dosing schedule for PD-1 / PD-L1 therapy refractory cancer models. Figure 9 shows a graph depicting the dosing schedule for anti-BTN1A1 antibody administration to Balb / c mice bearing breast cancer (4T1) xenografts or C57BL / 6 mice bearing Lewis lung carcinoma (LLC) xenografts. Sac = time at which mice were sacrificed.

[0095] [Figure 10] Figure 10 - STC1012 is effective in a PD-1 / PD-L1 therapy-refractory breast cancer model. Figure 10 shows scatter plots showing the progression of 4T1 tumor growth in Balb / c mice treated with the anti-mouse BTN1A1 antibody STC1012 or an IgG antibody control. Tumor volumes for individual animals are plotted over time.

[0096] [Figure 11] Figure 11 - STC1012 is effective in a PD-1 / PD-L1 therapy-refractory lung cancer model (days 6-16). Figure 11 shows scatter plots showing the progression of LLC tumor growth in C57BL / 6 mice treated with the anti-mouse BTN1A1 antibody STC1012 or an IgG antibody control. Tumor volumes for individual animals are plotted over time (days 6-16).

[0097] [Figure 12] Figure 12 - STC1012 is effective in a PD-1 / PD-L1 therapy-refractory lung cancer model (days 6-29). Figure 12 shows scatter plots showing the progression of LLC tumor growth in C57BL / 6 mice treated with the anti-mouse BTN1A1 antibody STC1012 or an IgG antibody control. Tumor volumes for individual animals are plotted over time (days 6-29).

[0098] [Figure 13] Figure 13A - Epitope mapping of BTN1A1-Fc. STC810 ​​and BTN1A1(ECD)-Fc were subjected to Ag-Ab cross-linking and analyzed by high-mass MALDI. Figure 13A shows the amino acid residues of BTN1A1(ECD)-Fc cross-linked to STC810, including R41, K42, K43, T185, and K188.

[0099] Figure 13B - Epitope mapping of BTN1A1-His. STC810 ​​and BTN1A1(ECD)-His were subjected to Ag-Ab cross-linking and analyzed by high-mass MALDI. Figure 13B shows the amino acid residues of BTN1A1(ECD)-His cross-linked to STC810, including R68, K78, T175, S179, and T185.

[0100] [Figure 14] Figure 14 - T cell killing effect of BTN1A1 antibody. Figure 14 shows a graph plotting T cell-mediated apoptosis of PC3 human prostate cancer cells in the presence of STC810, STC2602, STC2714, or STC2781 BTN1A1 antibodies, along with a negative control.

[0101] [Figure 15] Figure 15 - Dimer-specific binding of BTN1A1 antibodies. The leftmost panel of Figure 15 is an image of a Coomassie blue-stained SDS-PAGE gel showing the location of the monomeric and dimeric forms of BTN1A1 protein under both native and reduced conditions, along with size standards. Panels 2 through 5 show Western blots visualizing the monomeric and dimeric forms of BTN1A1 protein under both native and reduced conditions using the STC810, STC2602, STC2714, and STC2781 antibodies, respectively.

[0102] [Figure 16] Figure 16-B - Binding affinity (KD) of STC2714 for monomeric and dimeric forms of BTN1A1. Figure 16A: Sensorgram showing real-time binding of soluble BTN1A1-Fc protein (Figure 16A) (2-fold dilution, 2-64 nM) to STC2714 immobilized on a Protein A-CM5 chip (Biacore). Figure 16B: Sensorgram showing real-time binding of soluble BTN1A1-His protein (2-fold dilution, 2-64 nM) to STC2714 immobilized on a Protein A-CM5 chip (Biacore). DETAILED DESCRIPTION OF THE INVENTION

[0103] (5. Detailed Description) B7 family costimulatory molecules can promote immune cell activation and inhibition. A related family of molecules, buryrophilin, also has immunomodulatory functions similar to those of B7 family members. Butyrophilin, subfamily 1, member A1 ("BTN1A1"), a type I membrane glycoprotein and a major component of the milk fat globule membrane, shares structural similarity with the B7 family. BTN1A1 is known as a key protein regulating the formation of lipid droplets in milk (Ogg et al., PNAS, 101(27):10084-10089 (2004)). BTN1A1 is expressed in immune cells, including T cells. Treatment with recombinant BTN1A1 has been found to inhibit T cell activation and protect against EAE in animal models (Stefferl et al., J. Immunol. 165(5):2859-65 (2000)).

[0104] BTN1A1 is specifically and highly expressed in cancer cells. BTN1A1 expressed in cancer cells is usually glycosylated. BTN1A1 expression can be used to aid in cancer diagnosis and to evaluate the effectiveness of cancer treatments.

[0105] The present disclosure is based, at least in part, on the surprising discovery that BTN1A1 is expressed across a variety of cancer cells. See, e.g., Example 1.

[0106] The present disclosure is based, at least in part, on the surprising discovery that expression of BTN1A1 and PD-L1 is mutually exclusive in certain cancers. See, e.g., Example 2.

[0107] The present disclosure is based, at least in part, on the surprising discovery that anti-BTN1A1 antibodies can synergize with anti-PD1 antibodies in the activation of certain lymphocytes. See, e.g., Example 3.

[0108] The present disclosure is based, at least in part, on the surprising discovery that molecules capable of immunospecifically binding to BTN1A1 are effective in treating cancers that are refractory to anti-PD1 and anti-PD-L1 therapy. See, e.g., Example 4.

[0109] Provided herein are methods for treating cancer using anti-BTN1A1 antibodies and other molecules capable of immunospecifically binding to BTN1A1. In some embodiments, the cancer is a cancer refractory to anti-PD-1 therapy or anti-PD-L1 therapy. Also provided are methods for diagnosing cancer and selecting patients using anti-BTN1A1 antibodies and other molecules capable of immunospecifically binding to BTN1A1.

[0110] (5.1.Definition) As used herein, and unless otherwise specified, the articles "a," "an," and "the" refer to one or to more than one of the grammatical objects of the article. By way of example, an antibody refers to one antibody or to more than one antibody.

[0111] As used herein, and unless otherwise specified, the term "butyrophilin, subfamily 1, member A1" or "BTN1A1" refers to BTN1A1 from any vertebrate source, including mammals, e.g., primates (e.g., humans, cynomolgus monkeys (cynos)), dogs, and rodents (e.g., mice and rats). Unless otherwise specified, BTN1A1 also includes various BTN1A1 isoforms, related BTN1A1 polypeptides, including SNP variants thereof, and various modified forms of BTN1A1, including, but not limited to, phosphorylated BTN1A1, glycosylated BTN1A1, and ubiquitinated BTN1A1. As used herein, glycosylated BTN1A1 includes BTN1A1 with N55, N215, and / or N449 glycosylation.

[0112] An exemplary amino acid sequence of human BTN1A1 (BC096314.1 GI: 64654887) is provided below, with potential glycosylation sites bolded and underlined:

[0113] [ka]

[0114] An exemplary coding nucleic acid sequence for human BTN1A1 (BC096314.1 GI: 64654887) is provided below:

[0115] [ka]

[0116] An exemplary amino acid sequence of an exemplary dimeric BTN1A1 extracellular domain construct (BTN1A1-ECD-Fc) is provided below. [ka]

[0117] An exemplary amino acid sequence of an exemplary monomeric BTN1A1 extracellular domain construct (BTN1A1-His6) is provided below. [ka]

[0118] An exemplary amino acid sequence of mouse BTN1A1 (GenBank: AAH11497.1) is provided below, with potential glycosylation sites bolded and underlined:

[0119] [ka]

[0120] An exemplary coding nucleic acid sequence for mouse BTN1A1 (GenBank: BC011497.1) is provided below:

[0121] [ka]

[0122] As used herein, and unless otherwise specified, the terms "programmed death 1," "programmed cell death 1," "protein PD-1," "PD-1," "PD-1 polypeptide," or "PD1" encompass polypeptides ("polypeptide" and "protein" are used interchangeably herein), including any naturally occurring polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynomolgus)), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. In certain embodiments, these terms include "related PD-1 polypeptides," including SNP variants thereof. The term "PD-1" also encompasses "full-length," unprocessed PD-1 and any form of PD-1 that results from intracellular processing. NCBI Reference Sequence NP_005009.2 provides an exemplary human PD-L1 amino acid sequence. GenBank™ Accession Number L27440.1 provides an exemplary human PD-1 nucleic acid sequence.

[0123] As used herein, and unless otherwise specified, the term "anti-PD-1 therapy" includes any inhibitor of PD-1. In some embodiments, the anti-PD-1 therapy can include an anti-PD-1 antibody or antigen-binding fragment thereof, an inhibitory nucleic acid, or a soluble PD-1 ligand (e.g., soluble PD-L1), or a fusion protein thereof (e.g., an Fc-fusion protein). In some embodiments, the anti-PD-1 therapy includes nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-514, or AMP-224.

[0124] In some embodiments, the anti-PD-1 therapy comprises nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is also known as MDX-1 106, MDX-1 106-04, ONO-4538, or BMS-936558. Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449 and WO2006 / 121 168.

[0125] In some embodiments, the anti-PD-1 therapy includes pembrolizumab. Pembrolizumab is also known as KEYTRUDA®, lambrolizumab, Merck 3745, MK-3475, or SCH-900475. Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab is disclosed, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369(2): 134-44, WO2009 / 1 14335, and US 8,354,509.

[0126] In some embodiments, the anti-PD-1 therapy is pidilizumab. Pidilizumab, also known as CT-011 (CureTech), is a humanized IgG1 monoclonal antibody that binds to PD-1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009 / 101611.

[0127] In some embodiments, the anti-PD-1 therapy comprises an anti-PD-1 antibody provided in International Application No. PCT / US2016 / 64394.

[0128] Further anti-PD1 antibodies that may be useful for anti-PD1 therapy are disclosed in US 8,609,089, US 2010028330, and / or US 201201 14649.

[0129] In some embodiments, the anti-PD-1 therapy includes the fusion protein AMP 514 (Amplimmune). AMP-224, also known as B7-DCIg, is disclosed, for example, in WO 2010 / 027827 and WO 201 1 / 066342. AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.

[0130] In some embodiments, the anti-PD-1 therapy comprises an immunoadhesin (e.g., an immunoadhesin comprising the extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the anti-PD-1 therapy comprises the fusion protein AMP-224 (an Fc fusion of PD-L2).

[0131] As used herein, and unless otherwise specified, the terms "programmed death 1 ligand 1," "programmed cell death 1 ligand 1," "protein PD-L1," "PD-L1," "PD-L1 polypeptide," or "PD1-L1" encompass polypeptides ("polypeptide" and "protein" are used interchangeably herein), including any naturally occurring polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynomolgus)), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. In certain embodiments, these terms include "related PD-L1 polypeptides," including SNP variants thereof. The term "PD-L1" also encompasses "full-length," unprocessed PD-L1 and any form of PD-L1 that results from processing within cells. NCBI Reference Sequence NP_054862.1 provides an exemplary human PD-L1 amino acid sequence. GenBank™ Accession Number NM_014143 provides an exemplary human PD-1 nucleic acid sequence.

[0132] As used herein, and unless otherwise specified, the term "anti-PD-L1 therapy" includes any inhibitor of PD-L1. In some embodiments, the anti-PD-L1 therapy can include an anti-PD-L1 antibody or antigen-binding fragment thereof, an inhibitory nucleic acid, or a soluble PD-L1 ligand (e.g., soluble PD-1), or a fusion protein thereof (e.g., an Fc-fusion protein). In some embodiments, the anti-PD-L1 therapy includes YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

[0133] In some embodiments, the anti-PD-L1 therapy includes MDX-1105. MDX-1105 is also known as BMS-936559. See, e.g., WO2007 / 005874.

[0134] In some embodiments, the anti-PD-L1 therapy includes antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID NOs: 20 and 21, respectively), for example, as described in WO 2010 / 077634.

[0135] In some embodiments, the anti-PD-L1 therapy includes MDPL3280A (Genentech / Roche). MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are disclosed, for example, in U.S. Patent No. 7,943,743 and U.S. Publication No. 20120039906.

[0136] In some embodiments, the anti-PD-L1 therapy includes the antibody MSB0010718C (Merck Serono). MSB0010718C is also known as A09-246-2.

[0137] In some embodiments, the anti-PD-L1 therapy comprises MDPL3280A (Genentech / Roche), a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are disclosed in U.S. Patent No. 7,943,743 and U.S. Publication No. 20120039906.

[0138] In some embodiments, the anti-PD-L1 therapy comprises an antibody provided in International Application No. PCT / US2016 / 024691, published as WO 2016 / 160792 A1, and International Application No. PCT / US2017 / 024027.

[0139] As used herein, and unless otherwise specified, the term "antibody" refers to a polypeptide product of B cells within the immunoglobulin (or "Ig") class of polypeptides that is capable of binding to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, each pair having one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), the amino-terminal portion of each chain containing a variable region of about 100 to about 130 or more amino acids, and the carboxy-terminal portion of each chain containing a constant region (see Borrebaeck (ed.) (1995), Antibody Engineering, 2nd ed., Oxford University Press; Kuby (1997), Immunology, 3rd ed., W.H. Freeman and Company, New York). Here, the specific molecular antigen includes the target BTN1A1, which can be a BTN1A1 polypeptide, a BTN1A1 fragment, or a BTN1A1 epitope. The antibodies provided herein include, but are not limited to, monoclonal antibodies, synthetic antibodies, recombinantly produced antibodies, bispecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, and anti-idiotypic (anti-Id) antibodies.

[0140] As used herein, and unless otherwise specified, the term "monoclonal antibody" refers to an antibody that is the product of a single cell clone or hybridoma, or a population of cells derived from a single cell. Monoclonal antibody is also intended to refer to an antibody produced by recombinant methods from heavy and light chain encoding immunoglobulin genes to produce a single immunoglobulin species. The amino acid sequences of antibodies within a monoclonal antibody preparation are substantially homogeneous, and the binding activity of antibodies within such a preparation exhibits substantially the same antigen-binding activity. In contrast, polyclonal antibodies are obtained from various B cells within a population and are a combination of immunoglobulin molecules that bind to a specific antigen. Each immunoglobulin in a polyclonal antibody can bind to a different epitope of the same antigen. Methods for producing both monoclonal and polyclonal antibodies are well known in the art (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989) and Borrebaeck (ed.), Antibody Engineering: A Practical Guide, W.H. Freeman and Co., Publishers, New York, pp. 103-120 (1991)).

[0141] As used herein, and unless otherwise specified, the term "human antibody" refers to an antibody having human variable regions and / or human constant regions, or portions thereof that correspond to human germline immunoglobulin sequences. Such human germline immunoglobulin sequences are described in Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242. Herein, human antibodies can include antibodies that bind to BTN1A1 and are encoded by nucleic acid sequences that are naturally occurring somatic variants of human germline immunoglobulin nucleic acid sequences.

[0142] As used herein, and unless otherwise specified, the term "chimeric antibody" refers to antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, and to fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

[0143] As used herein, and unless otherwise specified, the term "humanized antibody" refers to a chimeric antibody comprising a human immunoglobulin (e.g., recipient antibody) in which native complementarity-determining region ("CDR") residues are replaced by residues from a corresponding CDR of a non-human species (e.g., donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and capacity. In some cases, one or more FR region residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. The heavy or light chain of a humanized antibody can comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. A humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992); Carter et al., Proc. Natl. Acad. Sci. USA 89:4285-4289 (1992); and U.S. Patent Nos. 6,800,738, 6,719,971, 6,639,055, 6,407,213, and 6,054,297.

[0144] As used herein, and unless otherwise specified, the term "recombinant antibody" refers to an antibody that is prepared, expressed, produced, or isolated by recombinant means. A recombinant antibody can be an antibody expressed using a recombinant expression vector transfected into a host cell, an antibody isolated from a recombinant combinatorial antibody library, an antibody isolated from an animal (e.g., a mouse or a cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see, e.g., Taylor, LD et al., Nucl. Acids Res. 20:6287-6295 (1992)), or an antibody prepared, expressed, produced, or isolated by any other means involving splicing of immunoglobulin gene sequences into other DNA sequences. Such recombinant antibodies can have variable and constant regions, including those derived from human germline immunoglobulin sequences (see Kabat, EA et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Recombinant antibodies can also be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used) so that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but can be sequences that do not naturally occur in the human antibody germline repertoire in vivo.

[0145] As used herein, and unless otherwise specified, a "neutralizing antibody" refers to an antibody that blocks the binding of BTN1A1 to its natural ligand and inhibits signal transduction pathways and / or other physiological activities mediated by BTN1A1. The IC50 of a neutralizing antibody refers to the concentration of antibody required to neutralize 50% of BTN1A1 in a neutralization assay. The IC50 of a neutralizing antibody can range from 0.01 to 10 μg / ml in a neutralization assay.

[0146] As used herein, and unless otherwise specified, the term "antigen-binding fragment" and similar terms refer to a portion of an antibody that immunospecifically binds to an antigen and contains amino acid residues that confer on the antibody its specificity and affinity for the antigen. An antigen-binding fragment can be referred to as a functional fragment of an antibody. An antigen-binding fragment can be monovalent, bivalent, or multivalent.

[0147] Examples of molecules having an antigen-binding fragment include Fd, Fv, Fab, F(ab'), F(ab)2, F(ab')2, single-chain Fv (scFv), diabodies, triabodies, tetrabodies, minibodies, and single-domain antibodies. An scFv can be a monovalent scFv or a divalent scFv. Other molecules having an antigen-binding fragment can include, for example, heavy or light chain polypeptides, variable region polypeptides, or CDR polypeptides, or portions thereof, so long as such antigen-binding fragments retain binding activity. Such antigen-binding fragments can be found described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publishers; Huston et al., Cell Biophysics, 22:189-224 (1993); Pluckthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, ED, Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990).An antigen-binding fragment can be a polypeptide having an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino acid residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues.

[0148] The heavy chain of an antibody refers to a polypeptide chain of approximately 50 to 70 kDa, the amino-terminal portion of which contains a variable region of approximately 120 to 130 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The constant region can be one of five different types, called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. Different heavy chains vary in size: α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with light chains, these different types of heavy chains give rise to the five known classes of antibodies: IgA, IgD, IgE, IgG, and IgM, respectively, including the four subclasses of IgG, namely, IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0149] The light chain of an antibody refers to a polypeptide chain of approximately 25 kDa, the amino-terminal portion of which contains a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types, called kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. The light chain can be a human light chain.

[0150] The variable domain or variable region of an antibody is typically located at the amino terminus of the light or heavy chain, approximately 120-130 amino acids in length for heavy chains and approximately 100-110 amino acids in length for light chains. It refers to the portion of the light or heavy chain of an antibody that is used for the binding and specificity of each particular antibody to its specific antigen. Variable domains vary significantly in sequence among different antibodies. Sequence variability is concentrated in the CDRs, while less variable portions of the variable domain are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with the antigen. The numbering of amino acid positions used herein is according to the EU index, as found in Kabat et al. (1991), Sequences of Proteins of Immunological Interest (US Department of Health and Human Services, Washington, DC), 5th ed. The variable region can be a human variable region.

[0151] CDR refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of the antibody VL β-sheet framework. Thus, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art and have been defined, for example, by Kabat as the most hypervariable region within an antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have also been structurally defined by Chothia as residues that are not part of a conserved β-sheet framework and therefore can adopt a variety of conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terminologies are well recognized in the art. The positions of CDRs within standard antibody variable domains have been determined by comparison of numerous structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Because the number of residues within hypervariable regions varies among different antibodies, standard variable domain numbering schemes conventionally number additional residues relative to the standard positions with a, b, c, etc. next to the residue number (Al-Lazikani et al., supra (1997)). Such nomenclature is also well known to those skilled in the art.

[0152] For example, CDRs defined according to standard notation are shown in Table 1 below. Table 1: CDR definition [Table 1]

[0153] One or more CDRs can also be incorporated covalently or noncovalently into a molecule to make it an immunoadhesin. Immunoadhesins can incorporate the CDR(s) as part of a larger polypeptide chain, can covalently link the CDR(s) to another polypeptide chain, or can incorporate the CDR(s) noncovalently. The CDR(s) enable the immunoadhesin to bind to a specific antigen of interest.

[0154] "Framework" or "FR" residues refer to variable domain residues that flank the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are variable domain residues other than the hypervariable region residues as defined herein.

[0155] As used herein, and unless otherwise specified, the term "isolated" when used in the context of an antibody means that the antibody is substantially free of cellular material or other contaminating proteins from the cell or tissue source and / or other contaminating components from which the antibody is derived, or, if chemically synthesized, substantially free of chemical precursors or other chemicals. The language "substantially free of cellular material" includes preparations of antibodies in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, an antibody that is substantially free of cellular material includes preparations of antibodies having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as "contaminating protein"). In certain embodiments, when the antibody is recombinantly produced, it is substantially free of culture medium; for example, culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. In certain embodiments, when an antibody is produced by chemical synthesis, it is substantially free of chemical precursors or other chemicals, e.g., it is separated from chemical precursors or other chemicals involved in protein synthesis. Thus, such antibody preparations have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. Contaminating components may include, but are not limited to, substances that would interfere with therapeutic use of the antibody, and may also include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In certain embodiments, antibodies are prepared by (1) the Lowry method (Lowry et al., J. Bio. Chem. 193:265-275, 192);

[0156] The antibody is purified to greater than 95% by weight, e.g., 99% by weight, as determined by (1), (2) sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue staining or preferably silver staining. Isolated antibodies include antibodies in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. However, isolated antibodies are usually prepared by at least one purification step. In specific embodiments, the antibodies provided herein are isolated.

[0157] As used herein, and unless otherwise specified, the terms "polynucleotide," "nucleotide," "nucleic acid," "nucleic acid molecule," and other similar terms are used interchangeably and include DNA, RNA, mRNA, etc.

[0158] As used herein, and unless otherwise specified, the term "isolated" when used in connection with a nucleic acid molecule means that the nucleic acid molecule is separated from other nucleic acid molecules that are present in the natural source of the nucleic acid molecule. Furthermore, an "isolated" nucleic acid molecule, e.g., a cDNA molecule, can be substantially free of other cellular material, or culture medium if produced by recombinant techniques, or substantially free of chemical precursors or other chemicals if chemically synthesized. In a specific embodiment, the nucleic acid molecules encoding the antibodies provided herein are isolated or purified.

[0159] As used herein, and unless otherwise specified, the terms "bind" or "binding" refer to interactions between molecules. The interactions can be non-covalent interactions, including, for example, hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. The strength of the overall non-covalent interactions between an antibody and a single epitope of a target molecule, e.g., BTN1A1, is the affinity of the antibody for that epitope. "Binding affinity" typically refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a binding protein, e.g., an antibody) and its binding partner (e.g., an antigen).

[0160] The affinity of a binding molecule X, e.g., an antibody, for its binding partner Y, e.g., an antibody's cognate antigen, is usually determined by the dissociation constant (K D ) Low affinity antibodies usually bind antigens slowly and tend to dissociate quickly, whereas high affinity antibodies usually bind antigens faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of this disclosure. "K D " or "K D The "K value" can be measured by assays known in the art, for example, by binding assays. D can be measured, for example, by a radiolabeled antigen binding assay (RIA) performed using the Fab form of the antibody of interest and its antigen (Chen et al. (1999) J. Mol Biol 293:865-881). D or K D Values ​​can also be measured by using surface plasmon resonance assays by Biacore, e.g., using a BIAcore™-2000 or BIAcore™-3000 (BIAcore, Inc., Piscataway, NJ), or by biolayer interferometry, e.g., using an OctetQK384 system (ForteBio, Menlo Park, CA).

[0161] As used herein, and unless otherwise specified, a molecule is said to be capable of "immunospecifically binding" to a second molecule if such binding exhibits the specificity and affinity of the antibody for its cognate antigen. An antibody immunospecifically binds to a target region or conformation ("epitope") of an antigen if such binding involves the antibody's antigen recognition site. An antibody that immunospecifically binds to a particular antigen may bind other antigens with lower affinity if the other antigens share a degree of sequence or conformational similarity recognized by the antigen recognition site, as determined, for example, by immunoassays, BIACORE® assays, or other assays known in the art. Antibodies generally do not bind to completely unrelated antigens. Some antibodies (and antigen-binding fragments thereof) do not cross-react with other antigens. Antibodies can also bind other molecules in a non-immunospecific manner, for example, to FcR receptors, by virtue of other regions / domains of the antibody that do not contain the antigen recognition site, such as binding domains in the Fc region.

[0162] Antibodies or antigen-binding fragments that immunospecifically bind to an antigen or epitope of an antigen that contains a glycosylation site can bind to both the glycosylated and non-glycosylated forms of the antigen or epitope. In some embodiments, the antibody or antigen-binding fragment preferentially binds to the glycosylated antigen or epitope over the non-glycosylated antigen or epitope. Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 over non-glycosylated BTN1A1 has a K of 100 or less exhibited for non-glycosylated BTN1A1. D Less than K D In some embodiments, the antibody or antigen-binding fragment can bind to glycosylated BTN1A1 at a K D Less than half of K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 10 times smaller than K DIn some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K is about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of D It binds to glycosylated BTN1A1.

[0163] An antibody or antigen-binding fragment that immunospecifically binds to BTN1A1 can bind to a BTN1A1 monomer or a BTN1A1 dimer. In some embodiments, the antibody or antigen-binding fragment preferentially binds to a BTN1A1 dimer over a BTN1A1 monomer. BTN1A1 binding can occur, for example, to cell-surface-expressed BTN1A1 or to a soluble BTN1A1 domain construct, such as a BTN1A1 extracellular domain (ECD) construct (e.g., a flag-tagged BTN1A1-ECD or BTN1A1-CED-Fc fusion construct). In some embodiments, the BTN1A1 monomer or dimer is glycosylated at one or more positions. In some embodiments, the antibody or antigen-binding fragment exhibits a K α - ... D Less than half of K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer with a K D At least 10 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer with a K D about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of K D binds to the BTN1A1 dimer at

[0164] Preferential binding can be determined by binding assays and can be demonstrated, for example, by mean fluorescence intensity ("MFI"). For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 can bind to glycosylated BTN1A1 with an MFI that is higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least two-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least three-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least five-fold, at least ten-fold, at least fifteen-fold, or at least twenty-fold higher than the MFI exhibited for unglycosylated BTN1A1.

[0165] As used herein, and unless otherwise specified, a molecule is said to "immunospecifically mask" the glycosylation of an antigen or epitope, or at specific glycosylation sites thereof, and refers to its ability to either (1) block the glycosylation sites of a non-glycosylated antigen or epitope, so that the antigen or epitope cannot be glycosylated, or (2) bind to a glycosylated antigen or epitope or at a specific glycosylation site of a glycosylated antigen or epitope and prevent the physiological effects of glycosylation, e.g., downstream signaling mediated by glycosylation. For example, an antibody or antigen-binding fragment that immunospecifically masks BTN1A1 glycosylation refers to an antibody or antigen-binding fragment that either (1) blocks the glycosylation site of unglycosylated BTN1A1, preventing its glycosylation, or (2) binds to glycosylated BTN1A1 and prevents the physiological effects of glycosylation, e.g., immunosuppressive effects mediated by glycosylation. As another example, an antibody or antigen-binding fragment that immunospecifically masks BTN1A1 glycosylation at N55 and N215 refers to an antibody or antigen-binding fragment that either (1) blocks N55 and N215 of unglycosylated BTN1A1, preventing glycosylation at N55 and N215, or (2) binds to BTN1A1 glycosylated at N55 and N215, preventing the physiological effects of glycosylation, e.g., immunosuppressive effects mediated by glycosylation.

[0166] As used herein, and unless otherwise specified, the term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), excipient, stabilizer, or vehicle with which the therapeutic is administered. A "pharmaceutically acceptable carrier" is a carrier that is nontoxic to cells or mammals exposed to it at the dosages and concentrations employed, and can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like.

[0167] As used herein, and unless otherwise specified, the term "vector" refers to a substance used to introduce a nucleic acid molecule into a host cell. Suitable vectors for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which may contain selectable sequences or markers operable for stable integration into a host cell chromosome. Furthermore, a vector may contain one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that may be included provide, for example, resistance to antibiotics or toxins, complement autotrophic deficiencies, or supply critical nutrients not present in the culture medium. Expression control sequences may include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, which are well known in the art. When two or more nucleic acid molecules (e.g., both the heavy and light chains of an antibody) are to be coexpressed, both nucleic acid molecules can be inserted, for example, into a single expression vector or into separate expression vectors. For single vector expression, the encoding nucleic acids can be operably linked to a common expression control sequence or can be linked to different expression control sequences, e.g., one inducible promoter and one constitutive promoter. Introduction of nucleic acid molecules into host cells can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis, e.g., Northern blot or polymerase chain reaction (PCR) amplification of mRNA, or immunoblotting for expression of gene products, or other suitable analytical methods for testing expression of the introduced nucleic acid sequence or its corresponding gene product. It will be understood by those skilled in the art that the nucleic acid molecule will be expressed in an amount sufficient to produce the desired product (e.g., the anti-BTN1A1 antibody provided herein), and it will further be understood that expression levels can be optimized using methods well known in the art to obtain sufficient expression.

[0168] As used herein, and unless otherwise specified, the term "host cell" refers to a particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. The progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in subsequent generations or due to integration of the nucleic acid molecule into the host cell genome.

[0169] As used herein, and unless otherwise specified, the term "subject" refers to an animal that is the object of treatment, observation, and / or experiment. "Animal" includes vertebrates and invertebrates, such as fish, crustaceans, reptiles, and birds, particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and humans.

[0170] As used herein, and unless otherwise specified, the terms "cancer" or "cancerous" refer to the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, blood cancers and solid tumors.

[0171] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" when used in reference to a cancer patient refer to the act of reducing the severity of cancer or preventing or slowing the progression of cancer, including (a) inhibiting the growth of cancer or halting the development of cancer, and (b) causing regression of cancer or delaying or minimizing one or more symptoms associated with the presence of cancer.

[0172] As used herein, and unless otherwise specified, the terms "resistant" or "refractory" refer to a situation in which a patient has residual cancer cells (e.g., lung or breast cancer cells) in a tissue or organ (e.g., lung or chest) even after intensive treatment.

[0173] The term "responsiveness" or "responsive" when used in reference to a treatment refers to the degree of effectiveness of a treatment in alleviating or reducing the symptoms of the disease being treated, e.g., a cancer resistant or refractory to anti-PD1 therapy or anti-PD-L1 therapy. For example, the term "increased responsiveness" when used in reference to the treatment of a cell or subject refers to increased effectiveness in alleviating or reducing the symptoms of the disease compared to a reference treatment (e.g., of the same cell or subject, or of a different cell or subject) as measured using any method known in the art. In certain embodiments, the increased effectiveness is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0174] As used herein, the terms "effective subject response," "effective patient response," and "effective patient tumor response" refer to any increase in therapeutic benefit to a patient. An "effective patient tumor response" can be, for example, about a 5%, about 10%, about 25%, about 50%, or about 100% reduction in the rate of tumor progression. An "effective patient tumor response" can be, for example, about a 5%, about 10%, about 25%, about 50%, or about 100% reduction in physical symptoms of cancer. An "effective patient tumor response" can also be about a 5%, about 10%, about 25%, about 50%, about 100%, about 200%, or greater increase in patient response as measured by any suitable means, such as, for example, gene expression, cell count, assay results, tumor size, etc.

[0175] Improvement in cancer or cancer-related disease can be characterized as a complete or partial response. A "complete response" refers to the absence of clinically detectable disease, accompanied by normalization of any previous abnormal radiographic examinations, bone marrow, and cerebrospinal fluid (CSF), or abnormal monoclonal protein measurements. A "partial response" refers to a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in all measurable tumor burden (i.e., the number of malignant cells present in the subject or the size of the measured tumor mass or the amount of abnormal monoclonal protein) in the absence of new lesions. The term "treatment" contemplates both complete and partial responses.

[0176] The term "likelihood" generally refers to an increased probability of an event. When used in relation to the efficacy of a patient tumor response, the term "likelihood" generally contemplates an increased probability that the rate of tumor progression or tumor cell growth will decrease. When used in relation to the efficacy of a patient tumor response, the term "likelihood" generally can also refer to an increase in indicators, such as mRNA or protein expression, that may be evidence of increased progress in treating a tumor.

[0177] The term "predict" generally means to determine or refer in advance. When used to "predict" the effectiveness of a cancer treatment, for example, the term "predict" means that the likelihood of a cancer treatment outcome can be initially determined before treatment begins or before the treatment period has substantially progressed.

[0178] The term "monitoring" as used herein generally refers to the oversight, supervision, regulation, observation, tracking, or investigation of an activity. For example, the term "monitoring the effectiveness of a compound" refers to tracking the effectiveness of a cancer treatment in a patient or in a tumor cell culture. Similarly, the term "monitoring," when used in the context of patient compliance, either individually or in a clinical trial, refers to tracking or verifying that a patient is actually taking the test drug as prescribed. Monitoring can be performed, for example, by tracking the expression of mRNA or protein biomarkers.

[0179] As used herein, "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. As used herein, "neoplastic" refers to all forms of dysregulated or unregulated cell growth, whether malignant or benign, that result in abnormal tissue growth. Thus, "neoplastic cells" include malignant and benign cells that have dysregulated or unregulated cell growth.

[0180] As used herein, and unless otherwise specified, the term "therapeutically effective amount" refers to an amount of an agent (e.g., an antibody described herein or any other agent described herein) sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder, or condition, and / or its associated symptoms. A therapeutically effective amount of an agent, including a therapeutic agent, can be the amount necessary to (i) reduce or ameliorate the development or progression of a given disease, disorder, or condition; (ii) reduce or ameliorate the recurrence, onset, or occurrence of a given disease, disorder, or condition; and / or (iii) improve or enhance the prophylactic or therapeutic effects of another therapy (e.g., a therapy other than administration of an antibody provided herein). A therapeutically effective amount of a substance / molecule / agent of the present disclosure (e.g., an anti-BTN1A1 antibody) can vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the substance / molecule / agent to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects.

[0181] As used herein, and unless otherwise specified, the terms "administer" or "administration" refer to the act of injecting or otherwise physically delivering a substance from its external state to a patient, for example, by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When treating a disease, disorder, or condition, or a symptom thereof, administration of the substance typically occurs after the onset of the disease, disorder, or condition, or a symptom thereof. When preventing a disease, disorder, or condition, or a symptom thereof, administration of the substance typically occurs before the onset of the disease, disorder, or condition, or a symptom thereof.

[0182] A "biological marker" or "biomarker" is a substance whose detection indicates a particular biological state, such as, for example, the presence of cancer. In some embodiments, biomarkers can be determined individually. In other embodiments, several biomarkers can be measured simultaneously. In some embodiments of the methods provided herein, BTN1A1 is a biomarker that indicates the presence of cancer. In some embodiments, PD-L1 is a biomarker that indicates the presence of cancer. In some embodiments, BTN1A1 and PD-L1 can be used in combination to indicate the presence of cancer (e.g., anti-PD1 or anti-PD-L1 therapy-resistant or refractory cancers that respond to treatment with an anti-BTN1A1 antibody).

[0183] In some embodiments, a "biomarker" indicates changes in the level of mRNA expression that may correlate with the risk or progression of a disease, or the susceptibility of a disease to a given treatment. In some embodiments, a biomarker is a nucleic acid, such as an mRNA or cDNA (e.g., an mRNA or cDNA of BTN1A1 or PD-L1).

[0184] In further embodiments, a "biomarker" indicates a change in the level of polypeptide or protein expression that may correlate with the risk or progression of a disease, or with a patient's susceptibility to a treatment. In some embodiments, a biomarker can be a polypeptide or protein, or a fragment thereof (e.g., BTN1A1 or PD-L1 protein). The relative levels of particular proteins can be determined by methods known in the art. For example, antibody-based methods, such as immunoblot, enzyme-linked immunosorbent assay (ELISA), or other methods can be used.

[0185] As used herein, the term "expressed" or "expression" refers to transcription from a gene, resulting in an RNA nucleic acid molecule that is at least partially complementary to a region of one of the gene's two nucleic acid strands. As used herein, the term "expressed" or "expression" also refers to translation from an RNA molecule, resulting in a protein, polypeptide, or portion thereof.

[0186] The term "level" refers to the amount, accumulation, or proportion of a biomarker molecule (e.g., BTN1A1 or PD-L1). The level can be expressed, for example, by the amount or synthesis rate of messenger RNA (mRNA) encoded by a gene, the amount or synthesis rate of a polypeptide or protein encoded by a gene, or the amount or synthesis rate of a biomolecule accumulated in a cell or biological fluid. The term "level" refers to the absolute amount of a molecule in a sample determined under steady-state or non-steady-state conditions or the relative amount of the molecule.

[0187] As used herein, the terms "determining," "measuring," "evaluating," "assessing," and "assaying" generally refer to any form of measurement, and include determining whether an element is present or absent. These terms include both quantitative and / or qualitative determinations. Assessing can be relative or absolute. "Assessing the presence of" can include determining the amount of something present, as well as determining whether it is present or absent.

[0188] The term "sample" as used herein relates to a material or mixture of materials, usually, although not necessarily, in fluid form, containing one or more components of interest.

[0189] As used herein, a "biological sample" refers to a sample obtained from a biological subject, including samples of biological tissue or fluid origin obtained, touched, or collected in vivo or in situ. Biological samples include samples derived from regions of a biological subject containing precancerous or cancerous cells or tissue. Such samples can be, but are not limited to, organs, tissues, and cells isolated from a mammal. Exemplary biological samples include, but are not limited to, cell lysates, cell cultures, cell lines, tissues, oral tissues, gastrointestinal tissues, organs, organelles, biological fluids, blood samples, urine samples, skin samples, and the like. Preferred biological samples include, but are not limited to, whole blood, partially purified blood, PBMCs, tissue biopsies, and the like.

[0190] 5.2 Molecules Having Antigen-Binding Fragments That Immunospecifically Bind to BTN1A1 Molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 that are useful in the methods provided herein are described, for example, in International Patent Application No. PCT / US2016 / 064436 and U.S. Provisional Application No. PCT / US2016 / 064436, filed May 31, 2017, entitled "ANTIBODIES AND MOLECULES THAT IMMUNOSPECIFICALLY BIND TO BTN1A1 AND THERAPEUTIC USES THEREOF" (Attorney Docket No. 13532-018-888), which are incorporated herein by reference in their entireties.

[0191] Provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1, including anti-BTN1A1 antibodies. In some embodiments, the antigen-binding fragments that immunospecifically bind to BTN1A1 bind to a fragment or epitope of BTN1A1. In some embodiments, the antigen-binding fragments immunospecifically bind to a BTN1A1 dimer. In some embodiments, the BTN1A1 epitope can be a linear epitope. In some embodiments, the BTN1A1 epitope can be a conformational epitope. In some embodiments, the BTN1A1 epitope is found in a BTN1A1 dimer and not in a BTN1A1 monomer. In some embodiments, the molecules provided herein having antigen-binding fragments that immunospecifically bind to BTN1A1 inhibit the immunosuppressive function of BTN1A1.

[0192] N-glycosylation is a post-translational modification that is initiated in the endoplasmic reticulum (ER) and subsequently processed in the Golgi (Schwarz and Aebi, Curr. Opin. Struc. Bio., 21(5): 576-582 (2011)). This type of modification is primarily catalyzed by membrane-associated oligosaccharyltransferase (OST) complexes that transfer preformed glycans composed of oligosaccharides to asparagine (Asn) side chain acceptors located within the NXT motif (-Asn-X-Ser / Thr-) (Cheung and Reithmeier, Methods, 41: 451-459 2007); Helenius and Aebi, Science, 291(5512):2364-9 (2001). The addition or removal of saccharides from preformed glycans is mediated by a group of glycosyltransferases and glycosidases, respectively, that tightly regulate the N-glycosylation cascade in a cell- and location-dependent manner.

[0193] In some embodiments, the molecule comprises an antigen-binding fragment that selectively binds to one or more glycosylation motifs of BTN1A1. In some embodiments, the antigen-binding fragment immunospecifically binds to a glycopeptide having a glycosylation motif and an adjacent peptide. In some embodiments, the antigen-binding fragment immunospecifically binds to a peptide sequence that is located three-dimensionally near one or more of the glycosylation motifs. In some embodiments, the antigen-binding fragment preferentially binds to one or more glycosylation motifs of a BTN1A1 dimer over one or more glycosylation motifs of a BTN1A1 monomer.

[0194] In some embodiments, the antigen-binding fragment has a K D At least 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than D In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) at a K D K less than 50% of D In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 at a K D Less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of K D In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 10 times smaller than K D It binds to glycosylated BTN1A1.

[0195] The specific glycosylation site of a particular BTN1A1 isoform or variant can vary from amino acid positions 55, 215, or 449 of that particular BTN1A1 isoform or variant. In these circumstances, one of skill in the art would be able to determine the glycosylation site of any particular BTN1A1 isoform or variant corresponding to N55, N215, and N449 of the human BTN1A1 exemplified above based on sequence alignment and other common knowledge in the art. Accordingly, provided herein are also molecules having antigen-binding fragments that immunospecifically bind to the glycosylated form of a BTN1A1 isoform or variant relative to the unglycosylated BTN1A1 isoform or variant. The glycosylation site of a BTN1A1 isoform or variant can be the corresponding site of N55, N215, and N449 of the human BTN1A1 sequence provided above.

[0196] In some embodiments, the molecule comprises an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer). In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at positions N55, N215, and / or N449. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at position N55. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at position N215. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at position N449. In some embodiments, the antigen-binding fragment immunospecifically binds to one or more glycosylation motifs. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at positions N55 and N215. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at positions N215 and N449. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at positions N55 and N449. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at positions N55, N215, and N449.

[0197] In some embodiments, the molecule has an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer), wherein the antigen-binding fragment preferentially binds glycosylated BTN1A1 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds BTN1A1 that is glycosylated at positions N55, N215, and / or N449 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds BTN1A1 that is glycosylated at position N55 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds BTN1A1 that is glycosylated at position N215 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N449 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to one or more glycosylation motifs. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55 and N215 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N215 and N449 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55 and N449 over unglycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at positions N55, N215, and N449 over unglycosylated BTN1A1.

[0198] Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) will have a K that is lower than that shown for unglycosylated BTN1A1. D Less than K DIn some embodiments, the antibody or antigen-binding fragment can bind to glycosylated BTN1A1 at a K D Less than half of K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least two times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 5 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 10 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 15 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 20 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 25 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 30 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 40 times smaller than K DIn some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D At least 50 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 75% of D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 50% of D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 25% of D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 10% of D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 5% of D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 2.5% of D In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 at a K D K, which is about 1% of D It binds to glycosylated BTN1A1.

[0199] Preferential binding can also be determined in binding assays, e.g., as indicated by fluorescence intensity ("MFI"). For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) can bind to glycosylated BTN1A1 with an MFI that is higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least two-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least two-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least three-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 5-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 10-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 15-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 20-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 25-fold higher than the MFI exhibited for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 30-fold higher than the MFI shown for unglycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 40-fold higher than the MFI shown for unglycosylated BTN1A1.In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 50-fold higher than the MFI shown for unglycosylated BTN1A1.

[0200] In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55, N215, and / or N449 (e.g., in a glycosylated BTN1A1 dimer). In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N55. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N215. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N449. In some embodiments, the antigen-binding fragment immunospecifically masks one or more glycosylation motifs of BTN1A1. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55 and N215. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N215 and N449. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55 and N449. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55, N215, and N449.

[0201] In some embodiments, the molecule has an antigen-binding fragment that selectively binds to a BTN1A1 dimer over a BTN1A1 monomer. In some embodiments, the BTN1A1 dimer is expressed on the cell surface. In some embodiments, the BTN1A1 dimer is a soluble protein fragment of BTN1A1, e.g., an extracellular domain construct of BTN1A1, e.g., an Fc-fusion protein construct (e.g., BTN1A1-ECD-Fc). In some embodiments, the BTN1A1 monomer is an extracellular domain construct of BTN1A1, e.g., a Flag-tagged or His6-tagged BTN1A1-ECD construct. In some embodiments, the molecule that selectively binds to a BTN1A1 dimer is a molecule provided herein that selectively binds to glycosylated BTN1A1. In some embodiments, preferential binding to a BTN1A1 dimer relative to a BTN1A1 monomer is determined, for example, by determining preferential binding to a BTN1A1-ECD-Fc construct relative to a BTN1A1-ECD-His6 or BTN1A1-ECD-Flag construct using a surface plasmon resonance assay (e.g., BIAcore).

[0202] In some embodiments, the antigen-binding fragment has a K D At least 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than D In certain embodiments, the antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K less than 50% of D In some embodiments, the antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K DLess than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of K D In some embodiments, the antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 10 times smaller than K D binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at

[0203] Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) will have a K that is lower than that exhibited by a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). D Less than K D In some embodiments, the antibody or antigen-binding fragment can bind to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D Less than half of K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least two times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 5 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 10 times smaller than KD In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 15 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 20 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 25 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 30 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 40 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D At least 50 times smaller than K D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 75% ofD In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 50% of D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 25% of D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 10% of D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 5% of D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 2.5% of D In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) at a K D K, which is about 1% of D binds to the BTN1A1 dimer at

[0204] Preferential binding can also be determined in binding assays, e.g., as indicated by fluorescence intensity ("MFI"). For example, an antibody or antigen-binding fragment that preferentially binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) can bind to the BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) with a higher MFI than the MFI displayed for the BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to the BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least two-fold higher than the MFI displayed for the BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 3-fold higher than the MFI displayed for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 5-fold higher than the MFI displayed for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 10-fold higher than the MFI displayed for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 15-fold higher than the MFI shown for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 20-fold higher than the MFI shown for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer).In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 25-fold higher than the MFI exhibited for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 30-fold higher than the MFI exhibited for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 40-fold higher than the MFI exhibited for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antibody or antigen-binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with an MFI that is at least 50-fold higher than the MFI shown for a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer).

[0205] In some embodiments, the antibody or antigen-binding fragment preferentially binds glycosylated dimeric BTN1A1 over glycosylated monomeric BTN1A1. The two BTN1A1 monomers in a glycosylated BTN1A1 dimer may be independently glycosylated at the same position or at different positions. In some embodiments, one of the monomers in a BTN1A1 dimer is not glycosylated. The glycosylated BTN1A1 monomer in a glycosylated BTN1A1 dimer may be glycosylated at positions N55, N215, and / or N449. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at position N55. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at position N215. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at position N449. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at positions N55 and N215. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at positions N55 and N449. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at positions N215 and N449. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at positions N55, N215, and N449.

[0206] 5.2.1. Antibodies and Other Molecules Having Antigen-Binding Fragments In some embodiments, the anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimer antibody can be IgG, IgM, IgA, IgD, or IgE. The anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimer antibody can also be a chimeric antibody, affinity matured antibody, humanized antibody, or human antibody. The anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimer antibody can also be a camelized antibody, intrabody, or anti-idiotype (anti-Id) antibody. In some embodiments, the anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimer antibody can be a polyclonal or monoclonal antibody. In some embodiments, the anti-BTN1A1 antibody is STC703, STC810, STC820, or a humanized variant thereof.

[0207] Antibodies can be produced from any animal source, including birds and mammals. In some embodiments, the antibodies are from sheep, murine (e.g., mouse and rat), rabbit, goat, guinea pig, camel, horse, or chicken. Furthermore, newer technologies allow for the development and screening of human antibodies from human combinatorial antibody libraries. For example, bacteriophage antibody expression technology allows specific antibodies to be produced in the absence of animal immunization, as described in U.S. Pat. No. 6,946,546, which is incorporated herein by reference in its entirety. These techniques are further described in Marks (1992); Stemmer (1994); Gram et al. (1992); Barbas et al. (1994); and Schier et al. (1996), which are incorporated herein by reference in their entirety.

[0208] Methods for producing polyclonal antibodies in various animal species, as well as methods for producing various types of monoclonal antibodies, including humanized, chimeric, and fully human, are well known in the art. For example, the following U.S. patents provide enabling descriptions of such methods and are incorporated herein by reference: U.S. Patent Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,196,265; 4,275,149; 4,277,437; 4,366,241; 4,469,797; 4,472 ,509;No.4,606,855;No.4,703,003;No.4,742,159;No.4,767,720;No.4,816,567;No.4,867,973;No.4,938,9 No. 48; No. 4,946,778; No. 5,021,236; No. 5,164,296; No. 5,196,066; No. 5,223,409; No. 5,403,484; No. 5,420,253 ;No.5,565,332;No.5,571,698;No.5,627,052;No.5,656,434;No.5,770,376;No.5,789,208;No.5,821,337;No. No. 5,844,091; No. 5,858,657; No. 5,861,155; No. 5,871,907; No. 5,969,108; No. 6,054,297; No. 6,165,464; No. 6, 365,157; ​​6,406,867; 6,709,659; 6,709,873; 6,753,407; 6,814,965; 6,849,259; 6,861,572; 6,875,434; 6,891,024; 7,407,659; and 8,178,098, which are incorporated herein by reference in their entireties.

[0209] Molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or specifically bind to glycosylated BTN1A1 or specifically bind to BTN1A1 dimers, including anti-BTN1A1 antibodies or anti-glycosylated BTN1A1 antibodies or anti-BTN1A1 dimer antibodies (e.g., STC703, STC810, STC2714), can also be produced by any method known in the art useful for producing polypeptides, such as in vitro synthesis, recombinant DNA production, etc. Humanized antibodies can be produced by recombinant DNA technology. The antibodies described herein can also be produced using recombinant immunoglobulin expression technology. Recombinant production of immunoglobulin molecules, including humanized antibodies, is described in U.S. Pat. No. 4,816,397 (Boss et al.), U.S. Pat. Nos. 6,331,415 and 4,816,567 (both to Cabilly et al.), British Patent GB 2,188,638 (Winter et al.), and British Patent GB 2,209,757; these references are incorporated herein by reference in their entireties. Techniques for the recombinant expression of immunoglobulins, including humanized immunoglobulins, can also be found in Goeddel et al., Gene Expression Technology, Methods in Enzymology, Vol. 185, Academic Press (1991), and Borreback, Antibody Engineering, W.H. Freeman (1992); these references are incorporated herein by reference in their entireties. Further information regarding the generation, design, and expression of recombinant antibodies can be found in Mayforth, Designing Antibodies, Academic Press, San Diego (1993).

[0210] In some embodiments, the anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimeric antibody is a human antibody. Human antibodies can be produced by various methods known in the art, including the above-mentioned phage display method using antibody libraries derived from human immunoglobulin sequences (see U.S. Patent Nos. 4,444,887 and 4,716,111; and International Publication Nos. WO 98 / 46645, WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 33735, and WO 91 / 10741). Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins but can express human immunoglobulin genes. For example, human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, human variable, constant, and diversity regions can be introduced into mouse embryonic stem cells in addition to human heavy and light chain genes. Mouse heavy and light chain immunoglobulin genes can be rendered nonfunctional, individually or simultaneously, by the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to generate chimeric mice. The chimeric mice are then bred to produce homozygous offspring expressing human antibodies. The transgenic mice are immunized using conventional methods with all or part of a selected antigen, such as a BTN1A1 polypeptide, a glycosylated BTN1A1 polypeptide, or a BTN1A1 polypeptide dimer. Monoclonal antibodies against the antigen can be obtained from immunized transgenic mice using conventional hybridoma technology (see, e.g., U.S. Patent No. 5,916,771). The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation and subsequently undergo class switching and somatic mutation. Thus, such techniques can be used to produce therapeutically useful IgG, IgA, IgM, and IgE antibodies.For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93, incorporated herein by reference in its entirety. For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., International Publication Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Patent Nos. 5,413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,939,598, incorporated herein by reference in their entireties. Additionally, companies such as Abgenix (Freemont, Calif.) and Medarex (Princeton, NJ) can be contracted to provide human antibodies directed against a selected antigen using technology similar to that described above.

[0211] In some embodiments, the anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimeric antibody is a chimeric antibody, e.g., an antibody in which an antigen-binding sequence from a non-human donor has been grafted onto heterologous non-human, human, or humanized sequences (e.g., framework and / or constant domain sequences). In one embodiment, the non-human donor is a rat. In one embodiment, the antigen-binding sequence is synthetic, e.g., obtained by mutagenesis (e.g., phage display screening of a human phage library). In one embodiment, the chimeric antibody can have a mouse V region and a human C region. In one embodiment, the mouse light chain V region is fused to a human kappa light chain. In one embodiment, the mouse heavy chain V region is fused to a human IgG1 C region.

[0212] Methods for producing chimeric antibodies are known in the art (see, e.g., Morrison, 1985, Science 229:1202; Oi et al., 1986, BioTechniques 4:214; Gillies et al., 1989, J. Immunol. Methods 125:191-202; and U.S. Patent Nos. 6,311,415, 5,807,715, 4,816,567, and 4,816,397, all of which are incorporated herein by reference in their entirety). Chimeric antibodies comprising one or more CDRs from a non-human species and a framework region from a human immunoglobulin molecule have been described, for example, by CDR-grafting (EP 239,400; WO 91 / 09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka et al., 1994, Protein Engineering 7:805; and Roguska et al., 1994, Proc. Natl. Acad. Sci. USA). 91:969), as well as chain shuffling (U.S. Pat. No. 5,565,332); all of which are incorporated herein by reference in their entireties.

[0213] An exemplary process for producing a recombinant chimeric anti-BTN1A1 antibody can include: a) constructing, by conventional molecular biology methods, an expression vector encoding and expressing an antibody heavy chain in which the CDRs and variable region of a mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) monoclonal antibody are fused to an Fc region derived from a human immunoglobulin, thereby producing a vector for expressing the chimeric antibody heavy chain; b) constructing, by conventional molecular biology methods, an expression vector encoding and expressing the antibody light chain of a mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) monoclonal antibody, thereby producing a vector for expressing the chimeric antibody light chain; c) transferring these expression vectors into host cells by conventional molecular biology methods to produce transfected host cells for expression of the chimeric antibody; and d) culturing the transfected cells by conventional cell culture techniques to produce the chimeric antibody.

[0214] An exemplary process for producing a recombinant humanized anti-BTN1A1 antibody involves: a) constructing, by conventional molecular biology methods, an expression vector encoding and expressing an antibody heavy chain in which the CDRs and the minimum portion of the variable region framework required to retain donor antibody binding specificity are derived from a non-human immunoglobulin, such as a mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) monoclonal antibody, and the remainder of the antibody is derived from a human immunoglobulin, thereby producing a vector for expressing the humanized antibody heavy chain; b) constructing, by conventional molecular biology methods, an expression vector encoding and expressing an antibody light chain in which the minimum portion of the variable region framework required to retain CDRs and donor antibody binding specificity are derived from a non-human immunoglobulin, such as a mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) monoclonal antibody, and the remainder of the antibody is derived from a human immunoglobulin, thereby producing a vector for expressing the humanized antibody light chain; c) transferring these expression vectors into host cells by conventional molecular biology methods to produce transfected host cells for expression of the humanized antibody; and d) culturing the transfected cells by conventional cell culture techniques to produce the humanized antibody.

[0215] For either exemplary method, host cells can be co-transfected with such expression vectors; these expression vectors can contain different selectable markers, but are preferably identical except for the heavy and light chain coding sequences. This procedure results in equal expression of heavy and light chain polypeptides. Alternatively, a single vector encoding both heavy and light chain polypeptides can be used. The coding sequences for the heavy and light chains can comprise cDNA or genomic DNA, or both. Host cells used to express recombinant antibodies can be either bacterial cells, such as Escherichia coli, or, more preferably, eukaryotic cells (e.g., Chinese hamster ovary (CHO) cells or HEK-293 cells). The choice of expression vector depends on the choice of host cell and can be selected to have the desired expression and regulatory characteristics in the selected host cell. Other cell lines that can be used include, but are not limited to, CHO-K1, NSO, and PER.C6 (Crucell, Leiden, Netherlands). Furthermore, codon usage can be optimized when host cells are selected to account for species-specific codon usage biases and enhance protein expression. For example, for CHO cell expression, the antibody-encoding DNA can incorporate codons preferentially used by Cricetulus griseus (from which Chinese hamster ovary cells are derived).Codon optimization methods can be used to facilitate improved expression by desired host cells (see, e.g., Wohlgemuth, I. et al., Philos. Trans. R. Soc. Lond. B Biol. Sci. 366(1580):2979-2986(2011); Jestin, JL et al., J. Mol. Evol. 69(5):452-457(2009); Bollenbach, T. et al., Genome Res. 17(4):401-404(2007); Kurland, C. G. et al., Prog. Nucleic Acid Res. Mol. Biol. 31:191-219(1984); Grosjean, H. et al., Gene 18(3): 199-209(1982)).

[0216] In some embodiments, the anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimer antibody can be a monoclonal antibody. In some embodiments, the anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibody, or anti-BTN1A1 dimer antibody can be a polyclonal antibody. To produce antibodies specific for a BTN1A1 polypeptide, glycosylated BTN1A1 polypeptide, or BTN1A1 dimer, an animal can be inoculated with an antigen, such as a BTN1A1 polypeptide, glycosylated BTN1A1 polypeptide, or BTN1A1 dimer polypeptide. Often, the antigen is linked or conjugated to another molecule to enhance the immune response. The conjugate can be any peptide, polypeptide, protein, or non-proteinaceous substance linked to the antigen used to elicit an immune response in the animal. The antibodies produced in the animal in response to antigen inoculation comprise a variety of non-identical molecules (polyclonal antibodies) produced by different individual antibody-producing B lymphocytes. Given the correct conditions for polyclonal antibody production in an animal, most of the antibodies in the animal's serum will recognize a collective epitope on the antigenic compound against which the animal was immunized.

[0217] This specificity can be further enhanced by affinity purification to select only those antibodies that recognize the antigen or epitope of interest. The method for generating monoclonal antibodies (MAbs) can begin similarly to the method for preparing polyclonal antibodies. In some embodiments, rodents such as mice and rats are used in generating monoclonal antibodies. In some embodiments, rabbit, sheep, or frog cells are used in generating monoclonal antibodies. The use of rats is well known and can offer certain advantages. Mice (e.g., BALB / c mice) are routinely used and typically produce a high percentage of stable fusions.

[0218] Hybridoma technology involves the fusion of a single B lymphocyte from a mouse previously immunized with a BTN1A1 polypeptide, a glycosylated BTN1A1 polypeptide, or a BTN1A1 dimeric polypeptide with an immortal myeloma cell (usually a mouse myeloma). This technology provides a method for propagating a single antibody-producing cell for an unlimited number of generations so that unlimited quantities of structurally identical antibodies (monoclonal antibodies) with the same antigen or epitope specificity can be produced.

[0219] In one embodiment, the antibody is an immunoglobulin single variable domain derived from a camelid antibody, preferably derived from a heavy chain camelid antibody, devoid of light chains, which is V H H domain sequences or known as Nanobodies™. Nanobodies™ (Nbs) are the smallest functional fragments or single variable domains (VH domains) of naturally occurring single-chain antibodies. HH), and are well known to those skilled in the art. They are derived from heavy chain-only antibodies found in camelids (Hamers-Casterman et al., Nature, 363(6428):446-8 (1993); Desmyter et al., Nat Struct Biol., 3(9):803-11 (1996)). In the family "camelids," immunoglobulins that lack light polypeptide chains are found. "Camelids" includes Old World camelids (Camelus bactrianus and Camelus dromedarius) and New World camelids (e.g., alpacas, Lama glama, guanacos, and vicunas). Single variable domain heavy chain antibodies are referred to herein as Nanobodies™ or VHCs. H These antibodies are designated H antibodies. The small size and unique biophysical properties of Nbs allow them to surpass conventional antibody fragments in recognizing unusual or hidden epitopes and binding within cavities or active sites of protein targets. Furthermore, Nbs can be engineered as multispecific and multivalent antibodies, conjugated to reporter molecules, or humanized. Nbs are stable, persist in the gastrointestinal system, and can be easily manufactured.

[0220] By combining two antigen-binding sites with different specificities into a single construct, bispecific antibodies can unite two separate antigens with excellent specificity and therefore have great potential as therapeutic agents. Bispecific antibodies can be generated by fusing two hybridomas, each capable of producing a different immunoglobulin. Bispecific antibodies can also be produced by connecting two scFv antibody fragments while simultaneously deleting the Fc portion present in the intact immunoglobulin. Each scFv unit in such a construct can consist of one variable domain from each of the heavy (VH) and light (VL) antibody chains connected to each other by a synthetic polypeptide linker, the latter of which is often genetically modified to maximize resistance to proteolysis while minimizing immunogenicity. Individual scFv units can be connected by several techniques, including the incorporation of a short (usually less than 10 amino acids) polypeptide spacer that bridges the two scFv units, thereby generating bispecific single-chain antibodies. The resulting bispecific single-chain antibodies are thus species containing two VH / VL pairs of different specificities on a single polypeptide chain, in which the VH and VL domains in each scFv unit are separated by a polypeptide linker long enough to allow intramolecular association between these two domains, and in which the scFv units thus formed are tethered in close proximity to each other by a polypeptide spacer that is kept short enough to prevent, for example, undesired association between the VH domain of one scFv unit and the VL of another scFv unit.

[0221] Examples of molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 or a BTN1A1 dimer include: (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an "Fd" fragment consisting of the VH and CH1 domains; (iii) an "Fv" fragment consisting of the VL and VH domains of a single antibody; (iv) a "dAb" fragment consisting of the VH domain; (v) an isolated CDR region; and (vi) an F(ab') fragment, which is a bivalent fragment comprising two linked Fab fragments. (vii) single-chain Fv molecules ("scFv"), in which the VH and VL domains are linked by a peptide linker that allows the two domains to associate and form a binding domain; (viii) bispecific single-chain Fv dimers (see U.S. Pat. No. 5,091,513); and (ix) diabodies, which are multivalent or multispecific fragments constructed by gene fusion (U.S. Patent Application Publication No. 20050214860). Fv, scFv, or diabody molecules can be stabilized by the incorporation of disulfide bridges linking the VH and VL domains. Minibodies can also be made in which an scFv is connected to a CH3 domain (Hu et al., Cancer Res., 56(13):3055-61 (1996)).

[0222] Antibody-like binding peptidomimetics are also contemplated in embodiments. Murali et al., Cell Mol. Biol., 49(2):209-216 (2003), describes "antibody-like binding peptidomimetics" (ABiPs), which are peptides that act as light-loaded antibodies and have the particular advantages of a longer serum half-life and less cumbersome synthesis methods, and is incorporated herein by reference in its entirety.

[0223] (5.2.2. Anti-BTN1A1 antibody) A total of 68 murine monoclonal antibodies that immunospecifically bind to human BTN1A1 were cloned and characterized (Table 7). Additionally, three murine monoclonal antibodies that immunospecifically bind to murine BTN1A1 were cloned and characterized (see Example 4). For example, antibodies designated STC703, STC810, and STC820 exhibited glycosylation-specific binding with high affinity (K between STC703 and hBTN1A1-Fc). D was determined to be 286 nM by Biacore, the K between STC810 ​​and hBTN1A1-Fc D was determined to be 0.92 nM by Biacore, the K between STC820 and hBTN1A1-His D (The binding affinity was determined to be 16.2 nM by Biacore). STC703 and STC810 ​​were found to preferentially bind to BTN1A1 dimers over BTN1A1 monomers. STC703, STC810, and STC820 were found to preferentially bind to human BTN1A1 over mouse BTN1A1. STC1011, STC1012, and STC1029 were found to preferentially bind to mouse BTN1A1 over human BTN1A1. Treatment with monoclonal anti-BTN1A1 antibodies enhanced T cell-dependent apoptosis of cancer cells, inhibited cancer cell proliferation, and resulted in glycosylation-dependent internalization of BTN1A1 into lysosomes. Thus, anti-BTN1A1 antibodies with specific sequence characteristics, anti-BTN1A1 antibodies that immunospecifically bind to specific epitopes, and their uses in cancer treatment are also provided herein.

[0224] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof. In certain embodiments, the anti-BTN1A1 antibodies can further comprise a VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0225] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof. In certain embodiments, the anti-BTN1A1 antibodies can further comprise a VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0226] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC703 or STC810 ​​described herein, or a humanized variant thereof. In certain embodiments, the anti-BTN1A1 antibodies can further comprise the VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0227] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC820 or a humanized variant thereof described herein. In certain embodiments, the anti-BTN1A1 antibodies can further comprise the VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0228] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC1011, STC1012, or STC1029 described herein, or a humanized variant thereof. In certain embodiments, the anti-BTN1A1 antibodies can further comprise the VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0229] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof. In certain embodiments, the anti-BTN1A1 antibodies can further comprise the VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0230] In some embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC2714 described herein or a humanized variant thereof. In certain embodiments, the anti-BTN1A1 antibodies can further comprise the VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0231] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof. In a specific embodiment, the antibody further comprises VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0232] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof. In a specific embodiment, the antibody further comprises VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0233] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of STC703 or STC810, or a humanized variant thereof, described herein. In a specific embodiment, the antibody further comprises a VH FR1, a VH FR2, a VH FR3, a VH FR4, a VL FR1, a VL FR2, a VL FR3, and / or a VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0234] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of STC820 or a humanized variant thereof described herein. In a specific embodiment, the antibody further comprises a VH FR1, a VH FR2, a VH FR3, a VH FR4, a VL FR1, a VL FR2, a VL FR3, and / or a VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0235] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of STC1011, STC1012, or STC1029, or a humanized variant thereof, described herein. In a specific embodiment, the antibody further comprises a VH FR1, a VH FR2, a VH FR3, a VH FR4, a VL FR1, a VL FR2, a VL FR3, and / or a VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0236] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In specific embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of STC2602, STC2714, STC2739, STC2778, or STC2781, or a humanized variant thereof, as described herein. In a specific embodiment, the antibody further comprises a VH FR1, a VH FR2, a VH FR3, a VH FR4, a VL FR1, a VL FR2, a VL FR3, and / or a VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0237] In some embodiments, the anti-BTN1A1 antibody comprises fewer than six CDRs. In some embodiments, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody comprises or consists of one, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of STC2714 or a humanized variant thereof described herein. In a specific embodiment, the antibody further comprises a VH FR1, a VH FR2, a VH FR3, a VH FR4, a VL FR1, a VL FR2, a VL FR3, and / or a VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0238] In some embodiments, the antibody is a humanized antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding fragment, or any combination thereof. In some embodiments, the antibody is a humanized monoclonal antibody or an antigen-binding fragment thereof.

[0239] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof, to a BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to the BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein.

[0240] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively interfere (e.g., in a dose-dependent manner) with the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof, to a BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to the BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein.

[0241] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC703 or STC810 ​​described herein, or a humanized variant thereof, to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to a BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein.

[0242] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC820 or a humanized variant thereof described herein to a BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to a BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein.

[0243] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC1011, STC1012, or STC1029 described herein, or a humanized variant thereof, to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to a BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein.

[0244] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC2602, STC2714, STC2739, STC2778, or STC2781 described herein, or a humanized variant thereof, to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to a BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein.

[0245] In some embodiments, provided herein are antibodies, including humanized antibodies, that (i) competitively block (e.g., in a dose-dependent manner) the binding of an anti-BTN1A1 antibody provided herein to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope, and / or (ii) bind to a BTN1A1 epitope bound by an anti-BTN1A1 antibody provided herein (e.g., a humanized anti-BTN1A1 antibody). In some embodiments, the antibody competitively blocks (e.g., in a dose-dependent manner) the binding of monoclonal antibody STC2714 or a humanized variant thereof described herein to a BTN1A1 polypeptide (e.g., cell-surface-expressed or soluble BTN1A1), a BTN1A1 fragment, or a BTN1A1 epitope. In other embodiments, the antibody binds to a BTN1A1 epitope bound (e.g., recognized) by monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein. Table 2a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-human BTN1A1 antibody STC703 [Table 2] Table 2b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC703 [Table 3] Table 3a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-human BTN1A1 antibody STC810 [Table 4] Table 3b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC810 [Table 5] Table 4a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-human BTN1A1 antibody STC820 [Table 6] Table 4b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC820 [Table 7] Table 5a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC1011 [Table 8] Table 5b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC1011 [Table 9] Table 6a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC1012 [Table 10] Table 6b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC1012 [Table 11] Table 7a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC1029 [Table 12] Table 7b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC1029 [Table 13] Table 8a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC2602 [Table 14] Table 8b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2602 [Table 15] Table 9a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC2714 [Table 16] Table 9b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2714 [Table 17] Table 10a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC2739 [Table 18] Table 10b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2739 [Table 19] Table 11a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC2778 [Table 20] Table 11b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2778 [Table 21] Table 12a: Sequences of the heavy chain variable (VH) and light chain variable (VL) regions of the mouse monoclonal anti-mouse BTN1A1 antibody STC2781 [Table 22] Table 12b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2781 [Table 23]

[0246] Thus, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise a heavy chain variable (VH) region comprising: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, or 72; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74; and / or (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84. (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86.

[0247] In some embodiments, provided herein are heavy chain variable (VH) regions comprising: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, or 72; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74; and (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84. (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86. The antibody may be a monoclonal antibody. The antibody may be a humanized antibody.

[0248] In another aspect, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157; and (3) a VH CDR2 having the amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158. and / or (b) an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170.

[0249] In some embodiments, provided herein are (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157; and (3) a VH CDR2 having the amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158. and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170. The antibody may be a monoclonal antibody. The antibody may be a humanized antibody.

[0250] Thus, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209, 212, 215, or 218; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210, 213, 216, or 219; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220.

[0251] In some embodiments, provided herein is an antibody having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209, 212, 215, or 218; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210, 213, 216, or 219; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0252] Thus, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237, 240, 243, or 246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238, 241, 244, or 247; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248.

[0253] In some embodiments, provided herein is an antibody having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237, 240, 243, or 246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238, 241, 244, or 247; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0254] Thus, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265, 268, 271, or 274; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266, 269, 272, or 275; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276.

[0255] In some embodiments, provided herein is an antibody having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265, 268, 271, or 274; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266, 269, 272, or 275; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0256] Thus, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293, 296, 299, or 302; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294, 297, 300, or 303; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304.

[0257] In some embodiments, provided herein is an antibody having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293, 296, 299, or 302; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294, 297, 300, or 303; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0258] Thus, provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321, 324, 327, or 330; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322, 325, 328, or 331; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332.

[0259] In some embodiments, provided herein is an antibody having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321, 324, 327, or 330; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322, 325, 328, or 331; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0260] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, or 72; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74. In some embodiments, the heavy chain variable (VH) region comprises (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, or 72; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73. In some embodiments, the heavy chain variable (VH) region comprises (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, or 72; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74.

[0261] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158. In some embodiments, the heavy chain variable (VH) region comprises (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157. In some embodiments, the heavy chain variable (VH) region comprises (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158.

[0262] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208.

[0263] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236.

[0264] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264.

[0265] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292.

[0266] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320.

[0267] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, 72, 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, 156, 197, 200, 203, 206, 225, 228, 231, 234, 253, 256, 259, 262, 281, 284, 287, 290, 309, 312, 315, or 318. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 7. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 10. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 13. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 16. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 35. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 38. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 41. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 44. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 63. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 66. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 69. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 72. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 91. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 94. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 97. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 100. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 119. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 122. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 125. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 128. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 147. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 150.The VH CDR1 can have the amino acid sequence of SEQ ID NO: 153. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 156. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 197. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 200. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 203. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 206. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 225. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 228. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 231. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 234. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 253. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 256. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 259. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 262. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 281. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 284. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 287. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 290. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 309. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 312. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 315. The VH CDR1 can have the amino acid sequence of SEQ ID NO: 318.

[0268] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, 73, 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, 157, 198, 201, 204, 207, 226, 229, 232, 235, 254, 257, 260, 263, 282, 285, 288, 291, 310, 313, 316, or 319. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 8. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 11. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 14. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 17. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 36. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 39. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 42. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 45. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 64. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 67. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 70. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 73. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 92. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 95. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 98. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 101. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 120. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 123. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 126. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 129. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 148. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 151.The VH CDR2 can have the amino acid sequence of SEQ ID NO: 154. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 157. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 198. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 201. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 204. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 207. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 226. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 229. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 232. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 235. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 254. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 257. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 260. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 263. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 282. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 285. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 288. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 291. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 310. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 313. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 316. The VH CDR2 can have the amino acid sequence of SEQ ID NO: 319.

[0269] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, 74, 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, 158, 199, 202, 205, 208, 227, 230, 233, 236, 255, 258, 261, 264, 283, 286, 289, 292, 311, 314, 317, or 320. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 9. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 12. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 15. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 20. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 37. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 40. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 43. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 46. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 65. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 68. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 71. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 74. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 93. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 96. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 99. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 102. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 121. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 124. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 127. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 130. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 149. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 152.The VH CDR3 can have the amino acid sequence of SEQ ID NO: 155. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 158. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 199. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 202. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 205. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 208. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 227. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 230. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 233. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 236. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 255. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 258. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 261. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 264. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 283. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 286. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 289. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 292. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 311. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 314. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 317. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 320.

[0270] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO:7; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO:8; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO:9.

[0271] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 10; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 11; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 12.

[0272] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 15.

[0273] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18.

[0274] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 35; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 36; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 37.

[0275] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 38; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 39; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 40.

[0276] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 41; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 42; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 43.

[0277] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 44; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 45; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 46.

[0278] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 63; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 64; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 65.

[0279] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 66; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 67; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 68.

[0280] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 69; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 70; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 71.

[0281] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 72; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 73; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 74.

[0282] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 93.

[0283] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 94; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 95; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 96.

[0284] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 97; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 98; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 99.

[0285] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 100; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 101; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 102.

[0286] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 119; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 120; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 121.

[0287] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 122; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 123; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 124.

[0288] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 125; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 126; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 127.

[0289] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 128; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 129; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 130.

[0290] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 147; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 148; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 149.

[0291] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 150; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 151; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 152.

[0292] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 153; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 154; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 155.

[0293] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 156; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 157; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 158.

[0294] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199.

[0295] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 200; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 201; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 202.

[0296] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 203; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 204; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 205.

[0297] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 206; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 207; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 208.

[0298] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227.

[0299] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 228; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 229; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 230.

[0300] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 231; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 232; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 233.

[0301] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 235; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 236.

[0302] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255.

[0303] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 256; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 257; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 258.

[0304] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 259; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 260; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 261.

[0305] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 262; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 263; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 264.

[0306] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283.

[0307] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 284; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 285; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 286.

[0308] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 287; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 288; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 289.

[0309] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 290; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 291; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 292.

[0310] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311.

[0311] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 312; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 313; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 314.

[0312] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 315; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 316; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 317.

[0313] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 318; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 319; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 320.

[0314] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 3. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0315] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 31. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0316] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 59. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0317] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 87. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0318] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 115. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0319] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 143. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0320] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 193. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0321] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 221. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0322] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 249. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0323] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 277. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0324] In some embodiments, the molecules provided herein have an antigen-binding fragment having a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 305. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0325] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86.

[0326] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170.

[0327] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209, 212, 215, or 218; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210, 213, 216, or 219; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220.

[0328] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237, 240, 243, or 246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238, 241, 244, or 247; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248.

[0329] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265, 268, 271, or 274; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266, 269, 272, or 275; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276.

[0330] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293, 296, 299, or 302; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294, 297, 300, or 303; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304.

[0331] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321, 324, 327, or 330; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322, 325, 328, or 331; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332.

[0332] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86.

[0333] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170.

[0334] In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209, 212, 215, or 21; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210, 213, 216, or 219. In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209, 212, 215, or 21; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210, 213, 216, or 219; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220.

[0335] In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237, 240, 243, or 246; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238, 241, 244, or 247. In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237, 240, 243, or 246; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238, 241, 244, or 247; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248.

[0336] In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265, 268, 271, or 274; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266, 269, 272, or 275. In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265, 268, 271, or 274; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266, 269, 272, or 275; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276.

[0337] In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293, 296, 299, or 302; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294, 297, 300, or 303. In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293, 296, 299, or 302; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294, 297, 300, or 303; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304.

[0338] In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321, 324, 327, or 330; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322, 325, 328, or 331. In some embodiments, the molecules provided herein have antigen-binding fragments having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321, 324, 327, or 330; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332. In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322, 325, 328, or 331; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332.

[0339] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, 84, 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, 168, 209, 212, 215, 218, 237, 240, 243, 246, 265, 268, 271, 274, 293, 296, 299, 302, 321, 324, 327, or 330. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 19. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 22. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 25. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 28. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 47. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 50. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 53. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 56. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 75. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 78. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 81. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 84. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 103. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 106. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 109. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 112. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 131. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 134. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 137. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 140. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 159. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 162.The VL CDR1 can have the amino acid sequence of SEQ ID NO: 165. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 168. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 209. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 212. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 215. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 218. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 237. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 162408. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 243. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 246. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 265. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 268. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 271. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 274. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 293. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 296. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 299. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 302. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 321. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 324. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 327. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 330.

[0340] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, 85, 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, 169, 210, 213, 216, 219, 238, 241, 244, 247, 266, 269, 272, 275, 294, 297, 300, 303, 322, 325, 328, or 331. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 20. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 23. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 26. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 29. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 48. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 51. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 54. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 57. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 76. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 79. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 82. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 85. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 104. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 107. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 110. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 113. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 132. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 135. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 138. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 141. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 160. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 163.The VL CDR2 can have the amino acid sequence of SEQ ID NO: 166. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 169. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 210. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 213. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 216. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 219. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 238. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 241. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 244. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 247. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 266. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 269. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 272. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 275. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 294. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 297. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 300. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 303. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 322. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 325. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 328. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 331.

[0341] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a light chain variable (VL) region comprising a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, 86, 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, 170, 211, 214, 217, 220, 239, 242, 245, 248, 267, 270, 273, 276, 295, 298, 301, 304, 323, 326, 329, or 332. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 21. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 24. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 27. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 30. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 49. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 52. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 55. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 58. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 77. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 80. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 83. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 86. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 105. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 108. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 111. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 114. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 133. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 136. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 139. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 142. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 161. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 164.The VL CDR3 can have the amino acid sequence of SEQ ID NO: 167. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 170. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 211. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 214. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 217. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 220. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 239. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 242. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 245. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 248. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 267. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 270. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 273. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 276. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 295. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 298. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 301. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 304. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 323. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 326. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 329. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 332.

[0342] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21.

[0343] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 22; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 23; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 24.

[0344] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 25; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 27.

[0345] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 30.

[0346] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 47; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 48; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 49.

[0347] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 50; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 51; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 52.

[0348] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 53; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 54; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 55.

[0349] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 56; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 57; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 58.

[0350] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 75; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 76; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 77.

[0351] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 78; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 79; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 80.

[0352] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 81; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 82; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 83.

[0353] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 84; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 85; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 86.

[0354] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105.

[0355] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 106; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 107; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 108.

[0356] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 109; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 110; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 111.

[0357] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 112; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 113; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 114.

[0358] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 131; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 132; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 133.

[0359] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 134; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 135; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 136.

[0360] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 137; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 138; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 139.

[0361] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 140; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 141; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 142.

[0362] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 159; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 160; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 161.

[0363] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 162; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 163; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 164.

[0364] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 165; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 166; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 167.

[0365] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 168; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 169; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 170.

[0366] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211.

[0367] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 212; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 213; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 214.

[0368] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 215; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 216; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 217.

[0369] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 218; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 219; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 220.

[0370] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239.

[0371] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 240; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 241; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 242.

[0372] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 243; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 244; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 245.

[0373] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 247; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 248.

[0374] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267.

[0375] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 268; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 269; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 270.

[0376] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 271; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 272; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 273.

[0377] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 274; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 275; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 276.

[0378] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295.

[0379] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 296; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 297; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 298.

[0380] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 299; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 300; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 301.

[0381] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 302; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 303; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 304.

[0382] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323.

[0383] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 324; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 325; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 326.

[0384] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 327; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 328; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 329.

[0385] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 330; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 331; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 332.

[0386] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0387] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 33. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0388] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 61. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0389] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 89. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0390] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 117. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0391] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 145. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0392] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 195. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0393] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 223. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0394] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 251. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0395] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 279. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0396] In some embodiments, the molecules provided herein have an antigen-binding fragment having a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 307. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0397] In some embodiments, the molecules provided herein comprise a heavy chain variable (VH) region comprising: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, 16, 35, 38, 41, 44, 63, 66, 69, or 72; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74; and (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, or 84. The antigen-binding fragment has a light chain variable (VL) region comprising: (1) a CDR1; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0398] In some embodiments, the molecules provided herein comprise: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157; and / or (3) a VH CDR2 having the amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158. and (b) an antigen-binding fragment having a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0399] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209, 212, 215, or 218; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210, 213, 216, or 219; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0400] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237, 240, 243, or 246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238, 241, 244, or 247; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0401] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265, 268, 271, or 274; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266, 269, 272, or 275; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0402] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293, 296, 299, or 302; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294, 297, 300, or 303; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0403] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321, 324, 327, or 330; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322, 325, 328, or 331; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0404] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO:7; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO:8; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO:9; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:19; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:20; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:21. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0405] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 10; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 11; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 12; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 22; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 23; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 24. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0406] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 15; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 25; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 27. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0407] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 30. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0408] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 35; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 36; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 37; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 47; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 48; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 49. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0409] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 38; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 39; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 40; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 50; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 51; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 52. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0410] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 41; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 42; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 43; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 53; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 54; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 55. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0411] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 44; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 45; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 46; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 56; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 57; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 58. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0412] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 63; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 64; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 65; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 75; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 76; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 77. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0413] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 66; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 67; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 68; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 78; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 79; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 80. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0414] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 69; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 70; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 71; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 81; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 82; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 83. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0415] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 72; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 73; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 74; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 84; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 85; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 86. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0416] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 91; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 92; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 93; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 103; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 104; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 105. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0417] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 94; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 95; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 96; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 106; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 107; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 108. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0418] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 97; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 98; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 99; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 109; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 110; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 111. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0419] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 100; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 101; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 102; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 112; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 113; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 114. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0420] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 119; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 120; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 121; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 131; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 132; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 133. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0421] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 122; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 123; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 124; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 134; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 135; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 136. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0422] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 125; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 126; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 127; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 137; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 138; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 139. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0423] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 128; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 129; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 130; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 140; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 141; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 142. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0424] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 147; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 148; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 149; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 159; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 160; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 161. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0425] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 150; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 151; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 152; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 162; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 163; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 164. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0426] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 153; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 154; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 155; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 165; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 166; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 167. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0427] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 156; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 157; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 158; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 168; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 169; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 170. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0428] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 197; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 198; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 209; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 210; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 211. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0429] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 200; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 201; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 202; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 212; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 213; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 214. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0430] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 203; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 204; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 205; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 215; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 216; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 217. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0431] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 206; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 207; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 208; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 218; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 219; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 220. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0432] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 225; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 226; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 237; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 238; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 239. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0433] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 228; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 229; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 230; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 240; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 241; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 242. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0434] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 231; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 232; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 233; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 243; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 244; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 245. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0435] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 234; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 235; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 236; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 246; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 247; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 248. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0436] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 254; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 265; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 266; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 267. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0437] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 256; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 257; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 258; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 268; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 269; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 270. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0438] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 259; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 260; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 261; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 271; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 272; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 273. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0439] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 262; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 263; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 264; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 274; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 275; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 276. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0440] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 282; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 293; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 294; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 295. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0441] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 284; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 285; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 286; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 296; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 297; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 298. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0442] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 287; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 288; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 289; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 299; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 300; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 301. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0443] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 290; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 291; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 292; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 302; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 303; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 304. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0444] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 310; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 321; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 322; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 323. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0445] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 312; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 313; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 314; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 324; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 325; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 326. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0446] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 315; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 316; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 317; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 327; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 328; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 329. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0447] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having: (a) a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 318; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 319; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 320; and (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 330; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 331; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 332. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0448] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 3 and a VL region having the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0449] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 31 and a VL region having the amino acid sequence of SEQ ID NO: 33. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0450] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 59 and a VL region having the amino acid sequence of SEQ ID NO: 61. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0451] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 87 and a VL region having the amino acid sequence of SEQ ID NO: 89. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0452] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 115 and a VL region having the amino acid sequence of SEQ ID NO: 117. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0453] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 143 and a VL region having the amino acid sequence of SEQ ID NO: 145. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0454] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 193 and a VL region having the amino acid sequence of SEQ ID NO: 195. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0455] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 221 and a VL region having the amino acid sequence of SEQ ID NO: 223. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0456] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 249 and a VL region having the amino acid sequence of SEQ ID NO: 251. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0457] In some embodiments, the molecules provided herein have an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 277 and a VL region having the amino acid sequence of SEQ ID NO: 279. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0458] In some embodiments, the molecules provided herein comprise an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 305 and a VL region having the amino acid sequence of SEQ ID NO: 307. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0459] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC703 or a humanized version thereof. The humanized STC703 antibody can have the VH region, VL region, or both the VH and VL regions of STC703 described herein. The humanized STC703 antibody can also have the six CDR regions of STC703 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC703 antibody can also have fewer than six CDR regions of STC703. In some embodiments, the humanized STC703 antibody can have one, two, three, four, or five CDR regions of STC703 (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0460] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC810 ​​or a humanized version thereof. The humanized STC810 ​​antibody can have the VH region, the VL region, or both the VH and VL regions of STC810 ​​described herein. The humanized STC810 ​​antibody can also have the six CDR regions of STC810 ​​described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC810 ​​antibody can also have fewer than six CDR regions of STC810. In some embodiments, the humanized STC810 ​​antibody can have one, two, three, four, or five CDR regions of STC810 ​​(VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0461] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC820 or a humanized version thereof. The humanized STC820 antibody can have the VH region, VL region, or both the VH and VL regions of STC820 described herein. The humanized STC820 antibody can also have the six CDR regions of STC820 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC820 antibody can also have fewer than six CDR regions of STC820. In some embodiments, the humanized STC820 antibody can have one, two, three, four, or five CDR regions of STC820 (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0462] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC1011 or a humanized version thereof. The humanized STC1011 antibody can have the VH region, the VL region, or both the VH and VL regions of STC1012 described herein. The humanized STC1011 antibody can also have the six CDR regions of STC1011 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC1011 antibody can also have fewer than six CDR regions of STC1011. In some embodiments, the humanized STC1011 antibody may have one, two, three, four, or five CDR regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC1011.

[0463] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC1012 or a humanized version thereof. The humanized STC1012 antibody can have the VH region, the VL region, or both the VH and VL regions of STC1012 described herein. The humanized STC1012 antibody can also have the six CDR regions of STC1012 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC1012 antibody can also have fewer than six CDR regions of STC1012. In some embodiments, the humanized STC1012 antibody may have one, two, three, four, or five CDR regions of STC1012 (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0464] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC1029 or a humanized version thereof. The humanized STC1029 antibody can have the VH region, VL region, or both the VH and VL regions of STC1029 described herein. The humanized STC1029 antibody can also have the six CDR regions of STC1029 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC1029 antibody can also have fewer than six CDR regions of STC1029. In some embodiments, the humanized STC1029 antibody may have one, two, three, four, or five CDR regions of STC1029 (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0465] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC2602 or a humanized version thereof. The humanized STC2602 antibody can have the VH region, VL region, or both the VH and VL regions of STC2602 described herein. The humanized STC2602 antibody can also have the six CDR regions of STC2602 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC2602 antibody can also have fewer than six CDR regions of STC2602. In some embodiments, the humanized STC2602 antibody may have one, two, three, four, or five CDR regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC2602.

[0466] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC2714 or a humanized version thereof. The humanized STC2714 antibody can have the VH region, VL region, or both the VH and VL regions of STC2714 described herein. The humanized STC2714 antibody can also have the six CDR regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC2714 described herein. The humanized STC2714 antibody can also have fewer than the six CDR regions of STC2602. In some embodiments, the humanized STC2714 antibody may have one, two, three, four, or five CDR regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC2714.

[0467] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC2739 or a humanized version thereof. The humanized STC2739 antibody can have the VH region, VL region, or both the VH and VL regions of STC2739 described herein. The humanized STC2739 antibody can also have the six CDR regions of STC2739 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC2739 antibody can also have fewer than six CDR regions of STC2739. In some embodiments, the humanized STC2739 antibody may have one, two, three, four, or five CDR regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC2739.

[0468] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC2778 or a humanized version thereof. The humanized STC2778 antibody can have the VH region, the VL region, or both the VH and VL regions of STC2778 described herein. The humanized STC2778 antibody can also have the six CDR regions of STC2778 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC2778 antibody can also have fewer than six CDR regions of STC2778. In some embodiments, the humanized STC2778 antibody may have one, two, three, four, or five CDR regions of STC2778 (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0469] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC2781 or a humanized version thereof. The humanized STC2781 antibody can have the VH region, the VL region, or both the VH and VL regions of STC2781 described herein. The humanized STC2781 antibody can also have the six CDR regions of STC2781 described herein (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC2781 antibody can also have fewer than six CDR regions of STC2781. In some embodiments, the humanized STC2781 antibody may have one, two, three, four, or five CDR regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC2781.

[0470] For example, mutations can be introduced into the nucleotide sequence encoding the antigen-binding fragment or antibody provided herein using standard techniques known to those skilled in the art, including site-directed mutagenesis and PCR-mediated mutagenesis, which result in amino acid substitutions. In certain embodiments, a derivative contains fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, or fewer than 2 amino acid substitutions compared to the original molecule. In specific embodiments, a derivative has conservative amino acid substitutions made at one or more predicted non-essential amino acid residues. A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Families of amino acid residues with side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of a coding sequence, for example, by saturation mutagenesis, and the resulting mutants can be screened for biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed, and the activity of the protein can be determined.

[0471] In some embodiments, molecules provided herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 can have an amino acid sequence that is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of murine monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781, or an antigen-binding fragment thereof, e.g., the VH domain or VL domain. In one embodiment, a molecule provided herein can have an amino acid sequence that is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 3, 5, 31, 33, 59, 61, 87, 89, 115, 117, 143, 145, 193, 195, 221, 223, 249, 251, 277, 279, 305, or 307. In yet another embodiment, the molecules provided herein can have a VH CDR and / or VL CDR amino acid sequence that is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to a VH CDR and / or VL CDR amino acid sequence set forth in any one of Tables 2a-12b above.

[0472] In some embodiments, the molecules provided herein can have the amino acid sequence of a VH domain and / or the amino acid sequence of a VL domain encoded by a nucleotide sequence that hybridizes to the complement of a nucleotide sequence encoding any one of the VH and / or VL domains set forth in any one of Tables 2a-12b under stringent conditions (e.g., hybridization to filter-bound DNA in 6× sodium chloride / sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6× SSC at about 45° C., followed by one or more washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art (see, e.g., Ausubel, F.M. et al., eds., 1989, Current Protocols in Molecular Biology, vol. 1, pp. 111-112). (See, Biology, Vol. I, Green Publishing Associates and John Wiley & Sons, New York, pp. 6.3.1 to 6.3.6 and 2.10.3).

[0473] In another embodiment, the molecules provided herein can have a VH CDR amino acid sequence or a VL CDR amino acid sequence encoded by a nucleotide sequence that hybridizes to the complement of a nucleotide sequence encoding any one of the VH CDRs and / or VL CDRs set forth in any one of Tables 2a-12b under stringent conditions (e.g., hybridization to filter-bound DNA in 6×SSC at about 45° C., followed by one or more washes in 0.2×SSC / 0.1% SDS at about 50-65° C.), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6×SSC at about 45° C., followed by one or more washes in 0.1×SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art (see, e.g., Ausubel, FM et al., eds., 1989, Current Protocols in Molecular Biology, vol. 1, pp. 111-112). (See, Biology, Vol. I, Green Publishing Associates and John Wiley & Sons, New York, pp. 6.3.1 to 6.3.6 and 2.10.3).

[0474] In some embodiments, provided herein are isolated nucleic acids encoding the amino acid sequence of a VH CDR or the amino acid sequence of a VL CDR set forth in any one of Tables 2a-12b, or isolated nucleic acids that hybridize to the complement of a nucleic acid sequence encoding any one of the VH CDRs and / or VL CDRs set forth in any one of Tables 2a-12b under stringent conditions (e.g., hybridization to filter-bound DNA in 6× sodium chloride / sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC / 0.1% SDS at about 50-65° C.), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6×SSC at about 45° C., followed by one or more washes in 0.1×SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to one of skill in the art.

[0475] In some embodiments, provided herein is an isolated nucleic acid encoding the amino acid sequence of a VH domain and / or the amino acid sequence of a VL domain set forth in any one of Tables 2a-12b, or an isolated nucleic acid that hybridizes to the complement of a nucleotide sequence encoding any one of the VH and / or VL domains set forth in any one of Tables 2a-12b under stringent conditions (e.g., hybridization to filter-bound DNA in 6× sodium chloride / sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6× SSC at about 45° C., followed by one or more washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to one of skill in the art.

[0476] In some embodiments, the isolated nucleic acid can have the sequence of SEQ ID NO: 4, or a sequence that hybridizes to the complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization to filter-bound DNA in 6x sodium chloride / sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2x SSC / 0.1% SDS at about 50-65°C), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6x SSC at about 45°C, followed by one or more washes in 0.1x SSC / 0.2% SDS at about 68°C), or other stringent hybridization conditions known to one of skill in the art.

[0477] In some embodiments, the isolated nucleic acid can have the sequence of SEQ ID NO: 6, or a sequence that hybridizes to the complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization to filter-bound DNA in 6x sodium chloride / sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2x SSC / 0.1% SDS at about 50-65°C), under highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6x SSC at about 45°C, followed by one or more washes in 0.1x SSC / 0.2% SDS at about 68°C), or other stringent hybridization conditions known to one of skill in the art.

[0478] In some embodiments, the isolated nucleic acid can have the sequence of SEQ ID NO: 32, or a sequence that hybridizes to the complement of the nucleotide sequence of SEQ ID NO: 32 under stringent conditions (e.g., hybridization to filter-bound DNA in 6× sodium chloride / sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC / 0.1% SDS at about 50-65° C.), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6×SSC at about 45° C., followed by one or more washes in 0.1×SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to one of skill in the art.

[0479] In some embodiments, the isolated nucleic acid can have the sequence of SEQ ID NO: 36, or a sequence that hybridizes to the complement of the nucleotide sequence of SEQ ID NO: 34 under stringent conditions (e.g., hybridization to filter-bound DNA in 6x sodium chloride / sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2x SSC / 0.1% SDS at about 50-65°C), highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6x SSC at about 45°C, followed by one or more washes in 0.1x SSC / 0.2% SDS at about 68°C), or other stringent hybridization conditions known to one of skill in the art.

[0480] In some embodiments, the isolated nucleic acid can have the sequence of SEQ ID NO: 60, or a sequence that hybridizes to the complement of the nucleotide sequence of SEQ ID NO: 60 under stringent conditions (e.g., h...

Claims

1. 1. A pharmaceutical composition comprising a molecule that is an antibody or antigen-binding fragment thereof and that immunospecifically binds to BTN1A1, wherein the molecule is an antagonist of activity that inhibits T cell activation, for treating cancer in a subject, wherein the cancer is resistant or refractory to anti-PD-1 therapy or anti-PD-L1 therapy.

2. Treatment is: (i) (a) determining the level of BTN1A1 in a sample comprising cancer cells from said subject; (b) diagnosing the subject as likely to respond to a molecule that immunospecifically binds to BTN1A1 if the level of BTN1A1 in the sample is equal to or greater than a BTN1A1 reference level; and (c) administering to the subject a therapeutically effective amount of the molecule; (ii) (a) determining the level of PD-L1 in a sample comprising cancer cells from the subject; (b) diagnosing the subject as likely to respond to the molecule that immunospecifically binds to BTN1A1 if the level of PD-L1 in the sample is less than or equal to a PD-L1 reference level; and (c) administering to the subject a therapeutically effective amount of the molecule; or (iii) (a) determining the level of BTN1A1 and / or PD-L1 in a sample comprising cancer cells from the subject; (b) diagnosing the subject as likely to respond to a molecule that immunospecifically binds to BTN1A1 if the level of BTN1A1 in the sample is equal to or greater than the BTN1A1 reference level, and / or if the level of PD-L1 in the sample is equal to or less than the PD-L1 reference level; and 10. The pharmaceutical composition of claim 1, comprising: (c) administering to said subject a therapeutically effective amount of said molecule.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the treatment comprises administering to the subject a therapeutically effective amount of the molecule in combination with radiation therapy, wherein the radiation therapy is high-dose therapy.

4. The cancer is (i) breast or lung cancer; or (ii) The pharmaceutical composition according to claim 1 or 2, wherein the cancer is breast cancer or Lewis lung cancer.

5. 3. The pharmaceutical composition of claim 2, wherein determining the level of BTN1A1 or PD-L1 in the sample comprises analyzing the level of BTN1A1 or PD-L1 protein in the tissue sample by immunocytochemistry.

6. (i) if the level of BTN1A1 in the sample is greater than a reference level of BTN1A1, the subject is diagnosed as likely to respond to a molecule that immunospecifically binds to BTN1A1; (ii) if the level of PD-L1 in the sample is lower than the reference level of PD-L1, the subject is diagnosed as likely to respond to the molecule that immunospecifically binds to BTN1A1; or (iii) if the level of BTN1A1 in the sample is higher than the BTN1A1 reference level, and if the level of PD-L1 in the sample is lower than the PD-L1 reference level, the subject is diagnosed as having a high likelihood of responding to a molecule that immunospecifically binds to BTN1A1.

7. The pharmaceutical composition of claim 1 or 2, wherein the molecule that immunospecifically binds to BTN1A1 preferentially binds to BTN1A1 dimers over BTN1A1 monomers, and the molecule that immunospecifically binds to BTN1A1 is STC810 ​​or STC2714, or a humanized variant thereof.

8. 3. The pharmaceutical composition of claim 1 or 2, wherein the treatment comprises administering to the subject a therapeutically effective amount of the molecule and a therapeutically effective amount of the anti-PD-1 therapy or anti-PD-L1 therapy.

9. (i) the molecule and the anti-PD-1 therapy or anti-PD-L1 therapy are formulated together, formulated separately, or administered simultaneously and independently or separately within a time interval, optionally thereafter repeatedly administered for one or more cycles; (ii) the molecule that immunospecifically binds to BTN1A1 preferentially binds to BTN1A1 dimers over BTN1A1 monomers; or (iii) The pharmaceutical composition of claim 8, wherein the molecule is STC810 ​​or STC2714.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the treatment results in at least one therapeutic effect selected from a reduction in tumor size, a reduction in the number of metastatic lesions over time, a complete response, a partial response, and stable disease.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the cancer is breast cancer, neuroendocrine prostate cancer (NEPC), diffuse large B-cell lymphoma, melanoma, cancer from the National Cancer Institute Cancer Panel (NCI 60), uveal melanoma, pancreatic cancer, ovarian cancer, uterine cancer, lung adenocarcinoma, desmoplastic small round cell tumor, bladder cancer, colorectal cancer, lung squamous cell carcinoma, liver cancer, lung cancer, gastric cancer, cholangiocarcinoma, esophageal squamous cell carcinoma, head and neck cancer, sarcoma, prostate cancer, pheochromocytoma or paraganglioma (PCPG), cervical cancer, glioma, or acute myeloid leukemia (AML).

12. the anti-PD-1 therapy or anti-PD-L1 therapy: (i) an anti-PD-1 or anti-PD-L1 antibody or antibody fragment, or a soluble PD-1 or PD-L1 ligand, or an Fc-fusion protein thereof; (ii) nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-514, or AMP-224; (iii) any one of the anti-PD-1 antibodies provided in International Publication No. WO2017096026; (iv) YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105; or (v) any one of the antibodies provided in International Publication Nos. WO2016160792 and WO2017172518.

13. the molecule that immunospecifically binds to BTN1A1 is: (i) glycosylated BTN1A1 over non-glycosylated BTN1A1; or (ii) preferentially binds to BTN1A1 dimers over BTN1A1 monomers; and The pharmaceutical composition of claim 12, wherein the molecule that immunospecifically binds to BTN1A1 is STC810 ​​or STC2714.

14. A pharmaceutical composition for killing or inhibiting the growth of cancer cells that are resistant to anti-PD-1 therapy or anti-PD-L1 therapy, comprising a molecule that is an antibody or antigen-binding fragment thereof and that immunospecifically binds to BTN1A1, wherein the molecule is capable of neutralizing the activity of inhibiting T cell activation.

15. An in vitro method for killing or inhibiting the growth of cancer cells that are resistant to anti-PD-1 therapy or anti-PD-L1 therapy, comprising contacting the cells with an effective amount of an antibody or antigen-binding fragment thereof that immunospecifically binds to BTN1A1 and neutralizes its activity of inhibiting T cell activation.

16. the molecule that immunospecifically binds to BTN1A1 is: (i) Intact antibodies; (ii) monoclonal antibodies; (iii) a human or humanized antibody; (iv) IgG, IgM, or IgA; (v) a Fab', F(ab')2, F(ab')3, monovalent scFv, bivalent scFv, or single domain antibody; or (vi) The pharmaceutical composition of any one of claims 1 to 14, which is a recombinant molecule.

17. the molecule that immunospecifically binds to BTN1A1 is: (i) Intact antibodies; (ii) monoclonal antibodies; (iii) a human or humanized antibody; (iv) IgG, IgM, or IgA; (v) a Fab', F(ab')2, F(ab')3, monovalent scFv, bivalent scFv, or single domain antibody; or (vi) The in vitro method of claim 15, wherein the molecule is a recombinant molecule.

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