Combination therapies with BTN1a1 binding proteins and chemotherapeutic agents

Abstract

Provided herein are combination treatments comprising molecules having an antigen binding fragment that immunospecifically binds to BTN1A1, such as anti-BTN1A1 antibodies, and chemotherapeutic agents for treating cancer. These molecules include those having an antigen binding fragment that immunospecifically binds to BTN1A1. These methods of treatment include eliminating the cancer cells and / or sensitizing the cancer cells for treatment with the chemotherapeutic agent.

Description

Attorney Docket No.: 13532-031-228 COMBINATION THERAPIES WITH BTN1A1 BINDING PROTEINS AND CHEMOTHERAPEUTIC AGENTS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Serial No.63 / 554,067 filed February 15, 2024, the contents of which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “13532-031-228_SEQLISTING.xml”, was created on February 13, 2025, and is 76,084 bytes in size. 1. FIELD

[0003] The present invention relates in general to the field of cancer immunology and molecular biology. Provided herein are combination therapies with chemotherapeutic agents and molecules comprising an antigen binding fragment that immunospecifically binds to BTN1A1, and related therapeutic agents, compositions, kits, and uses and applications thereof. 2. SUMMARY

[0004] The present disclosure provides methods of treating cancer comprising a combination treatment that includes binding proteins that bind to BTN1A1 and a chemotherapy. Such binding proteins, including antibodies, can bind to a BTN1A1 polypeptide, a BTN1A1 fragment, and / or a BTN1A1 epitope. Such binding proteins, including antibodies, can be antagonist (e.g., inhibiting BTN1A1 mediated signaling). In some embodiments, the combination treatment is effective in treating small cell lung cancer. In some embodiments, the combination treatment is effective in treating colorectal cancer.

[0005] In one aspect, provided herein is a method of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering to the subject a combination therapy, wherein the combination therapy comprises a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 NAI-1543197688v1 1Attorney Docket No.: 13532-031-228 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA), and a therapeutic effective amount of a first chemotherapy suitable for treating said cancer.

[0006] In some embodiments, BTN1A1 is expressed on at least about 60% of cancer cells in a sample taken from the subject.

[0007] In some embodiments, at least about 70% of cancer cells in the sample express BTN1A1 and are Ki-67 negative.

[0008] In some embodiments, PD-L1 is expressed on less than about 20% of cancer cells in a sample taken from the subject.

[0009] In some embodiments, at least about 50% of cancer cells in a sample taken from the subject are Ki-67 negative.

[0010] In some embodiments, at least about 50% of cancer cells in a sample taken from the subject are slow reproduction cells; optionally, a doubling time the cancer cells is longer than about 40 hours.

[0011] In some embodiments, the subject has been previously treated with a second chemotherapy; optionally wherein the first chemotherapy and the second chemotherapy are the same or different.

[0012] In some embodiments, the subject has been previously treated for cancer with a radiation therapy.

[0013] In some embodiments, the subject has been previously treated for cancer with an anti- PD-1 therapy or anti-PD-L1 therapy.

[0014] In some embodiments, the anti-PD-1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).

[0015] In some embodiments, the cancer is resistant to or relapsed from prior treatment with the second chemotherapy, radiation therapy, anti-PD-1 or anti-PD-L1 therapy.

[0016] In some embodiments, the cancer is small cell lung cancer, and the first chemotherapy comprises one or more agents selected from carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, NAI-1543197688v1 2Attorney Docket No.: 13532-031-228 methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

[0017] In some embodiments, the cancer is small cell lung cancer, and wherein the first chemotherapy comprises paclitaxel.

[0018] In some embodiments, the cancer is colorectal cancer, and wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv-Aflibercept.

[0019] In some embodiments, the cancer is colorectal cancer, wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.

[0020] In some embodiments, the cancer is colorectal cancer, and wherein the first chemotherapy comprises: (a) folinic acid, fluorouracil and oxaliplatin (FOLFOX); (b) folinic acid, fluorouracil and irinotecan (FOLFIRI); or (c) capecitabine.

[0021] In some embodiments, the cancer is colorectal cancer, and wherein the first chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).

[0022] In some embodiments, the method further comprises administering to the subject an antibody or antigen binding fragment thereof that specifically binds to VEGF. In some embodiments, the antibody that binds to VEGF is bevacizumab.

[0023] In some embodiments, the colorectal cancer is a colon cancer of Stage I, Stage II, Stage III, or Stage IV.

[0024] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutic effective amount of a combination therapy, wherein the combination therapy comprises Lonsurf (Trifluridine and Tipiracil), bevacizumab, and a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA); wherein the cancer is a Stage IV colon cancer, NAI-1543197688v1 3Attorney Docket No.: 13532-031-228 and wherein the cancer is resistant to or relapsed from prior treatment with anti-PD-1 or anti-PD- L1 therapy. In some embodiments, the molecule is hSTC810.

[0025] In some embodiments, the molecule is administered intravenously.

[0026] In some embodiments, the molecule is administered at a dosage in the range of from about 0.1 mg / kg body weight to about 30 mg / kg body weight.

[0027] In some embodiments, the molecule is administered at a dosage in the range of from about 400 mg to about 800mg.

[0028] In one aspect, provided herein is a method of preparing a subject suffering from cancer for a chemotherapy or a radiation therapy. In some embodiments, the method comprises administering to the subject a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL- 9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) prior to treating the subject with the chemotherapy or the radiation therapy.

[0029] In some embodiments, BTN1A1 is expressed on at least about 60% of cancer cells in a sample taken from the subject.

[0030] In some embodiments, PD-L1 is expressed on less than about 20% of cancer cells in a sample taken from the subject.

[0031] In some embodiments, the subject has been previously treated with the chemotherapy or the radiation therapy.

[0032] In some embodiments, the cancer is resistant to or relapsed from the chemotherapy or the radiation therapy.

[0033] In some embodiments, the cancer is small cell lung cancer, and the chemotherapy comprises one or more agents selected from carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

[0034] In some embodiments, the cancer is small cell lung cancer, and wherein the chemotherapy comprises paclitaxel.

[0035] In some embodiments, the cancer is colorectal cancer, and wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, NAI-1543197688v1 4Attorney Docket No.: 13532-031-228 irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv-Aflibercept.

[0036] In some embodiments, the cancer is colorectal cancer, wherein the chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.

[0037] In some embodiments, the cancer is colorectal cancer, and wherein the chemotherapy comprises: (a) folinic acid, fluorouracil and oxaliplatin (FOLFOX); (b) folinic acid, fluorouracil and irinotecan (FOLFIRI); or (c) capecitabine.

[0038] In some embodiments, the cancer is colorectal cancer, and wherein the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).

[0039] In some embodiments, the cancer is colorectal cancer, and wherein the chemotherapy comprises a combination of Lonsurf (Trifluridine and Tipiracil) and an antibody or antigen binding fragment thereof that specifically binds to VEGF. In some embodiments, the antibody that binds to VEGF is bevacizumab.

[0040] In some embodiments, the administering to the subject the therapeutic effective amount of the molecule is no more than 2 months, no more than 1 month, no more than 2 weeks, or no more than 1 week prior to treating the subject with the chemotherapy or the radiation therapy.

[0041] In one aspect, provided herein is a method of eliminating cancer cells from a cell population. In some embodiments, the method comprises contacting the cell population with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T- Lymphocyte Attenuator (BTLA) in the presence of immune effector cells and a first chemotherapeutic agent; wherein one or both of the cancer cells and the immune effector cells express BTN1A1; and wherein upon the contacting, a percentage of the cancer cells in the cell population is reduced.

[0042] In some embodiments, the immune effector cells comprise CD8+ cells. NAI-1543197688v1 5Attorney Docket No.: 13532-031-228

[0043] In some embodiments, the immune effector cells are infiltrating lymphocytes in a tumor microenvironment.

[0044] In some embodiments, the immune effector cells comprise CD8+ T cells.

[0045] In some embodiments, (a) the cancer cells lack expression of PD-L1; and / or (b) the immune effector cells lack expression of PD-1.

[0046] In some embodiments, the cancer cells have been previously treated with a second chemotherapeutic agent; optionally wherein the first therapeutic agent and the second therapeutic agent are the same or different.

[0047] In some embodiments, the cancer cells have been previously treated with radiation.

[0048] In some embodiments, the first chemotherapeutic agent does not induce apoptosis or inhibit proliferation of the cancer cells when contacted with the cancer cells alone.

[0049] In one aspect, provided herein is a method of sensitizing a response of cancer cells to a chemotherapeutic agent. In some embodiments, the method comprises contacting the cancer cells with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

[0050] In some embodiments, the response is apoptosis of the cancer cells; optionally wherein apoptosis of the cancer cells is increased for at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% comparing to cancer cells contacted with the chemotherapeutic agent in the absence of the molecule.

[0051] In some embodiments, the response is proliferation of the cancer cells; optionally wherein proliferation of the cancer cells is reduced for at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% comparing to cancer cells contacted with the chemotherapeutic agent in the absence of the molecule.

[0052] In one aspect, provided herein is a method of removing slow-reproduction cancer cells in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand NAI-1543197688v1 6Attorney Docket No.: 13532-031-228 selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

[0053] In some embodiments, the slow-reproduction cancer cells divide at a doubling time of longer than about 40 hours, longer than about 45 hours, longer than about 50 hours, longer than about 55 hours, longer than about 60 hours, longer than about 70 hours, longer than about 80 hours, longer than about 90 hours, longer than about 100 hours, longer than about 110 hours, longer than about 120 hours, longer than about 130 hours, longer than about 140 hours, longer than about 150 hours, or longer than about 160 hours.

[0054] In some embodiments, the slow-reproduction cancer cells are lung cancer cells dividing at a doubling time of longer than about 40 hours.

[0055] In some embodiments, the slow-reproduction cancer cells express BTN1A1.

[0056] In some embodiments, the slow-reproduction cancer cells comprise cancer stem cells.

[0057] In some embodiments, the subject has been previously treated with a chemotherapy or a radiation therapy.

[0058] In some embodiments, the subject has been previously treated for cancer with an anti- PD-1 therapy or anti-PD-L1 therapy.

[0059] In some embodiments, the anti-PD-1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).

[0060] In some embodiments, the cancer is resistant to or relapsed from prior treatment with the second chemotherapy, radiation therapy, anti-PD-1 or anti-PD-L1 therapy.

[0061] In some embodiments, the molecule is administered intravenously.

[0062] In some embodiments, the molecule is administered at a dosage in the range of from about 0.1 mg / kg body weight to about 30 mg / kg body weight.

[0063] In some embodiments, the molecule is administered at a dosage in the range of from about 400 mg to about 800mg.

[0064] In any of the method described herein, in some embodiments, the molecule preferentially binds to dimeric BTN1A1 relative to monomeric BTN1A1.

[0065] In some embodiments, the molecule preferentially binds to glycosylated BTN1A1 relative to non-glycosylated BTN1A1. NAI-1543197688v1 7Attorney Docket No.: 13532-031-228

[0066] In some embodiments, the antigen binding fragment is a Fab’, a F(ab’)2, a F(ab’)3, a monovalent scFv, or a bivalent scFv.

[0067] In some embodiments, the molecule is an antibody.

[0068] In some embodiments, the antibody is a monoclonal antibody.

[0069] In some embodiments, the antibody is a humanized antibody.

[0070] In some embodiments, the antibody is an IgG, IgM, or IgA.

[0071] In some embodiments, the antibody is STC810 or hSTC810.

[0072] In any of the method described herein, in some embodiments, the antigen-binding fragment comprises: (i) (a) a heavy chain variable region (VH) comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3 having an amino acid sequence of a VH CDR1, a VH CDR2, and a VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO:31; and (b) a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of a VL CDR1, a VL CDR2, and a VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:32; or (ii) (a) a VH comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO:15; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO:16; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO:17; and (b) a VL comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:18; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:19; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:20; or (iii) (a) a VH comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO:21; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO:22; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO:17; and (b) a VL comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:18; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:19; (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:20; or (iv) (a) a VH comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO:23; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO:24; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO:17; and (b) a VL comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:18; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:19; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:20; or (v) (a) a VH comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO:25; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO:26; and (3) a VH CDR3 having the NAI-1543197688v1 8Attorney Docket No.: 13532-031-228 amino acid sequence of SEQ ID NO:27; and (b) a VL 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.

[0073] In some embodiments, the antigen-binding fragment comprises a VH comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31.

[0074] In some embodiments, the antigen-binding fragment comprises a VH comprising the amino acid sequence of SEQ ID NO:31.

[0075] In some embodiments, the antigen-binding fragment comprises a VL comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.

[0076] In some embodiments, the antigen-binding fragment comprises a VL comprising the amino acid sequence of SEQ ID NO:32.

[0077] In some embodiments, the antigen-binding fragment comprises a VH comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31; and a VL comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.

[0078] In some embodiments, the antigen-binding fragment comprises a VH comprising the amino acid sequence of SEQ ID NO:31; and a VL comprising the amino acid sequence of SEQ ID NO:32.

[0079] In some embodiments, the antigen-binding fragment comprises a VH consisting of the amino acid sequence of SEQ ID NO:31; and a VL consisting of the amino acid sequence of SEQ ID NO:32.

[0080] In some embodiments, the antigen-binding fragment comprises a heavy chain comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:33.

[0081] In some embodiments, the antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of the amino acid sequence of SEQ ID NO:33.

[0082] In some embodiments, the antigen-binding fragment comprises a light chain comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:34.

[0083] In some embodiments, the antigen-binding fragment comprises a light chain comprising the amino acid sequence of the amino acid sequence of SEQ ID NO:34. NAI-1543197688v1 9Attorney Docket No.: 13532-031-228

[0084] In some embodiments, the antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:33; and a light chain comprising the amino acid sequence of SEQ ID NO:34.

[0085] In some embodiments, the antigen-binding fragment comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:33; and a light chain consisting of the amino acid sequence of SEQ ID NO:34.

[0086] In one aspect, provided herein is an antibody or antigen binding fragment thereof that binds to human BTN1A1, wherein the antibody or the antigen binding fragment thereof comprises: (i) a heavy chain variable region (VH) comprising a VH complementarity- determining region (CDR) 1, a VH CDR2, and a VH CDR3 having an amino acid sequence of a VH CDR1, a VH CDR2, and a VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO:31; and (b) a light chain variable region (VL) comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.

[0087] In one aspect, provided herein is an antibody or antigen binding fragment thereof that binds to human BTN1A1, wherein the antibody or the antigen binding fragment thereof comprises: (i) a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31; and (b) a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of a VL CDR1, a VL CDR2, and a VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:32.

[0088] In some embodiments of the antibody or antigen binding fragment provided herein, the VH comprises the amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31, and the VL comprises the amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.

[0089] In some embodiments of the antibody or antigen binding fragment provided herein, the VH comprises the amino acid sequence of SEQ ID NO:31, and the VL comprises the amino acid sequence of SEQ ID NO:32.

[0090] In some embodiments of the antibody or antigen binding fragment provided herein, the VH consists of the amino acid sequence of SEQ ID NO:31, and the VL consists of the amino acid sequence of SEQ ID NO:32. NAI-1543197688v1 10Attorney Docket No.: 13532-031-228

[0091] In one aspect, provided herein is an antibody that binds to human BTN1A1 comprising a heavy chain having the amino acid sequence of SEQ ID NO:33, and a light chain having the amino acid sequence of SEQ ID NO:34. 3. BRIEF DESCRIPTION OF THE FIGURES

[0092] FIGS.1A-1B show BTN1A1 expression levels and doubling time in lung cancer cell lines.

[0093] FIG.2 show BTN1A1 and PD-L1 expression of SCLC patients’ tumors. SCLC patients’ specimen were processed for IHC and IF analysis and stained (A, C, E) with anti- BTN1A1 (STC43H11-1, 0.5 µg / ml) and (B, D, F) with anti-PD-L1 (1:200) antibodies. Strong positive BTN1A1 staining was observed in panels A, C, and E. In contrast, panels B, D, and F showed faint staining for PD-L1 in small cell lung carcinoma.

[0094] FIG.3 shows a confocal single-optical section images showing BTN1A1 (red) and PD-L1 (green) in SCLC patient specimen. Arrows point to BTN1A1+ / PD-L1- SCLCs; arrowheads point to BTN1A1- / PD-L1+SCLC.

[0095] FIG.4 shows automated digital analysis of fluorescent multiplexing using InForm software in two different SCLC tumor tissues (40X magnification). Panel A and D show Multiparametric fluorescent staining: BTN1A1 (green), PD-L1 (cyan), CD8 (orange), Ki-67 (magenta), and Pan-Keratin (red). Panel B and E show individual cells identification and segmentation: with nuclear, membranous, and cytoplasmic segmentation. Panel C and F show phenotyping: identification of the cells on the slide, with their phenotypes, among all the cells present in the image, or among the cells stained.

[0096] FIG.5 shows BTN1A1-relevant phenotypic counts of the cell segmentation analysis from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) tumor tissues. Based on the three markers (CK, BTN1A1, and Ki-67), cancer cells were counted and classified into 4 different groups. Both tissues expressed BTN1A1 at high levels (92.5% in NSCLC and 70% in SCLC tissues, respectively). In contrast, the percentage of CK+BTN1A1+Ki-67- cells showed significant differences in the two types of tissues.

[0097] FIGS.6A to 6D show NCI-H345 SCLC spheroid formation and efficacy of hSTC810 in combination with Paclitaxel. Particularly, FIG.6A shows spheroids formation over the course of 8 days when no treatment was applied. FIG.6B shows change of shape and volume of NAI-1543197688v1 11Attorney Docket No.: 13532-031-228 spheroids treated with PBMCs alone. FIG.6C shows change of shape and volume of spheroids treated with the combination of PBMCs and hSTC810. FIG.6C shows change of shape and volume of spheroids treated with the triple combination of PBMC, hSTC810 and Paclitaxel. As shown, immune cells in the subsets contacted the spheroids at 2 days 18 hours (FIG.6B), 3 days 18 hours (FIG.6C) and 2 days 6 hours (FIG.6D), respectively. After the attachment, the shape and volume of the spheroids were subsequently monitored for another 5 days.

[0098] FIGS.7A and 7B show efficacy of hSTC810 in combination with Paclitaxel for NCI- H345 SCLC spheroids. Particularly, FIG.7A shows change of volume of spheroids receiving no treatment (control) or with hSTC810 alone. FIG.7B shows change of volume of spheroids receiving treatment of either PBMC alone, the combination of PBMC and Paclitaxel, the combination of PBMC and hSTC810, or the triple combination of PBMC, hSTC810, and Paclitaxel. An initial contact between PBMCs and spheroids were set to 0 hour and the size and shape of spheroids were subsequently monitored for 5 days.

[0099] FIG.8 shows immunohistochemistry staining of BTN1A1 and PD-L1 in samples taken from human SCLC patients treated with 6 mg / kg hSTC810 in a Phase I clinical study.

[0100] FIGS.9A and 9B show the treatment history of two male colon cancer human patients, respectively.

[0101] FIG.10 shows reduction of tumor volume in a colon cancer patient who received 2 cycles of capecitabine within 1 month immediately following the end of treatment with a humanized version of STC810 antibody (hSTC810) in a clinical study. The first post-treatment scan showed about 32% tumor reduction in target lesions.

[0102] FIG.11 shows an image illustrating results of an exemplary plasma membrane protein array experiment to reconfirm Galectin-1 (GAL-1, “LGALS1”), Galectin-2 (GAL-2, “LGALS9”) and Neuropilin-2 (NRP-2) as BTN1A1 ligands. Expression vectors of indicated expressed proteins were spotted in duplicates on two slides each (“rep1,” “rep2”) and reverse transfected into HEK293T cells. The transfected cells were then fixed and probed with CTLA-4- Fc, BTN1A1-2NQ-Fc (unglycosylated), BTN1A1-Fc (glycosylated), or secondary antibody alone (cells expressing CD86 / ZsGreen1 positive control vector). Binding of probe protein to expressed proteins was detected following addition of a fluorescent labeled secondary antibody using fluorescence imaging. NAI-1543197688v1 12Attorney Docket No.: 13532-031-228

[0103] FIG.12A shows schematics of BTN1A1 and BTN1A1-ligand (GAL-1 or GAL-9) protein constructs used for immunoprecipitation. BTN1A1 included an extracellular domain (ECD), a transmembrane domain (TM), a cytosolic protein domain (CPD), and a Flag-tag. BTN1A1-ligands included Myc- and Flag-tags. FIG.12B shows a graph illustrating an immunoprecipitation experiment. BTN1A1 or BTN1A1-ligands were pulled down from HEK293T cell lysates using beads coated with anti-BTN1A1 antibodies or anti-Myc antibodies. FIG.12C shows images of western blots following immunoprecipitation. Asterisks indicate BTN1A1 bands (*) or BTN1A1-ligand bands (**).

[0104] FIGS.13A-13D show sensograms of exemplary SPR assays. GAL-1 protein was injected on a sensor chip with immobilized glycosylated wild-type BTN1A1-Fc (FIG.13A), unglycosylated BTN1A1-2NQ-Fc (FIG.13B), glycosylated wild-type BTN2A1 (FIG.13C), or glycosylated wild-type BTN3A2 (FIG.13D).

[0105] FIG.14A shows a schematic illustrating a β-galactosidase (β-gal) complementation assay, in which β-gal is split into enzyme donor (ED) and the enzyme acceptor (EA). Interaction of an ED-fusion protein with an EA-fusion protein results in reconstitution of functional β-gal that is detectable using a luminescent β-gal substrate. FIG.14B shows a bar diagram illustrating the results of an exemplary β-galactosidase (β-gal) complementation assay.

[0106] FIG.15 shows results of exemplary western blots following immunoprecipitation of BTN1A1-Flag or BTLA-Myc-Flag with an anti-Myc antibody or an anti-BTN1A1 antibody (STC810).

[0107] FIG.16A shows sensograms of SPR assays, in which GAL-1, BTLA or a control protein (Control 1, Control 2, or Control 3) was injected onto a sensor chip with immobilized glycosylated wild-type BTN1A1-Fc at a single concentration of 3.2 μM. FIG.16B shows sensograms of SPR assays in which BTLA was injected onto a sensor chip with immobilized glycosylated wild-type BTN1A1-Fc at indicated concentration.

[0108] FIG.17 shows sensograms of BLI experiments in which soluble BTLA was contacted at indicated concentrations with immobilized BTN1A1-Fc.

[0109] FIG.18 shows a graph plotting T cell mediated apoptosis of PC3 human prostate cancer cells in the presence of STC810, STC2602, STC2714 or STC2781 BTN1A1 antibody along with a negative control. NAI-1543197688v1 13Attorney Docket No.: 13532-031-228

[0110] FIG.19 shows first panel from the left is an image of Coomassie blue stained SDS- PAGE gel, showing locations of monomer and dimer forms of the BTN1A1 protein in both native and reduced conditions along with a size standard. The second through fifth panels show western blots visualizing the monomer and dimer forms of the BTN1A1 protein in both native and reduced conditions using STC810, STC2602, STC2714 and STC 2781 antibody, respectively.

[0111] FIG.20A shows Sensograms showing real-time binding of soluble BTN1A1-Fc protein (2-64 nm with 2-fold dilution) to STC2714 immobilized on a Protein A-CM5 chip (Biacore). FIG.20B shows Sensograms showing real-time binding of soluble BTN1A1-His protein (2-64 nm with 2-fold dilution) to STC2714 immobilized on a Protein A-CM5 chip (Biacore).

[0112] FIG.21 depicts a bar diagram illustrating BTN1A1 expression across a variety of human cancer types, according to cBioPortal. The frequency of mutations, deletions, amplifications, or multiple aberrations is plotted by cancer type. CAN = copy number aberration.

[0113] FIG.22 depicts the heavy chain and light chain of hSTC810. As shown, hSTC810 is a monoclonal antibody (IgG4) targeting BTN1A1. The amino acid sequence of hSTC810 monomer is composed of a total of 666 amino acids; 452 amino acids from heavy chain (SEQ ID NO:33) and 214 amino acids from light chain (SEQ ID NO:34). hSTC810 contains 12 intra- molecular disulfide bonds and 4 inter-chain disulfide bonds.

[0114] FIG.23 depicts the scheme of a study monitoring anti-tumor effects of an anti- mouse BTN1A1 syngeneic antibody (STC109) used alone or in combination with Lonsurf (TAS- 102) and an anti-mouse VEGF antibody in CT26 xenograft mouse model. As shown, treatment began on Day 0 in four groups of mice (n >= 10 / group) with an established subcutaneous CT26 tumor (mean volume, 65 mm3). All animals were engrafted with 1 x 106cells ten days prior to the start of antibody treatment. All animals were scheduled to receive TAS-102 formulated in 0.5% HPMC that were administered orally (p.o.) five times per week for two weeks and to receive STC109 formulated in PBS that were administered intraperitoneally (i.p.) three times per week for one week. Anti-mouse VEGF antibody was administered intraperitoneally (i.p.) one times per week for two weeks. Group 1 served as the control for the study and was treated with a rat IgG1 isotype control antibody at 200 μg / animal and a rat IgG2a isotype control antibody at NAI-1543197688v1 14Attorney Docket No.: 13532-031-228 100 μg / animal. Group 2 received STC109 at 200 μg / animal. Group 3 received STC109 at 200 μg / animal and TAS-102 at 150 mg / kg. Group 4 received STC109 at 200 μg / animal, TAS-102 at 150 mg / kg and anti-mouse VEGF at 100 μg / animal. Tumors were measured three times weekly until the tumor endpoint. Each mouse was euthanized when its tumor reached the endpoint volume of 2000 mm3. Mice were monitored for complete regression (CR) and partial regression (PR) responses. Treatment tolerability was assessed through body weight measurements and frequent observation for signs of treatment-related side effects.

[0115] FIG.24 depicts the mean tumor volumes for Group 1, Group 2, Group 3, and Group 4 monitored for about 23 days post tumor injection.

[0116] FIG.25 is a scatter plot showing the individual tumor volumes for animals in Group 1, Group 2, Group 3, and Group 4 on day 23 post tumor injection.

[0117] FIG.26 depicts individual tumor growth for animals in Group 1, Group 2, Group 3, and Group 4 as monitored for about 23 days post tumor injection.

[0118] FIG.27 depicts a scheme of a study monitoring anti-tumor effects of a humanized anti-BTN1A1 antibody (hSTC810), anti-VEGF antibody (bevacizumab), and Lonsurf (TAS-102) alone or in various combinations with one another on patient-derived colon cancer organoids in the presence or absence of activated peripheral blood mononuclear cell (PBMCs). PBMCs were activated with anti-CD3 / CD28 (on Day -2) for two days, and then added to organoids (on day 1). The organoids were stimulated with IFNγ (on Day -1) for 1 day when receiving the activated PBMC (on day 1). In parallel study groups, the organoids were similarly treated with IFNγ, but did not receive PBMC. On day 1, the organoids were treated with different therapeutic agents as indicated, and the size of organoids were measured daily for 5 consecutive days for both PBMC- treated and untreated groups.

[0119] FIG.28 depicts relative organoid size for each group treated with the indicated therapeutic agent or combination thereof from day 1 to day 5 in the absence of PBMC.

[0120] FIG.29 depicts relative organoid size for each group of organoids co-cultured with PBMC after treatment with the indicated therapeutic agent or combination thereof from day 1 to Day 5.

[0121] FIG.30 depicts the individual organoid sizes on day 5 and average thereof for each group of organoids after receiving the indicated treatment. Left – organoids without PBMC; right organoids co-cultured with PBMC. NAI-1543197688v1 15Attorney Docket No.: 13532-031-228 4. DETAILED DESCRIPTION

[0122] BTN1A1 expression is generally restricted in normal tissues and immune cells [(Shibui et al., “Cloning, expression analysis, and chromosomal localization of a novel butyrophilin-like receptor,” J. Hum Genet., 44, 249-252 (1999)) and (Ogg et al., “Expression of butyrophilin (Btn1a1) in lactating mammy gland is essential for the regulated secretion of milk- lipid droplets,” Proc Natl Acad Sci USA, (101)27, 10084-10089, (2004))] while its presence is considerably high in tumor tissues, specifically in bladder, colon, head and neck, lung, and ovarian cancers. Analysis of BTN1A1- / -mice has shown that the lack of this butyrophilin family member results in an increased inflammatory response and activation of STAT3 signaling. Jeong et al., “The butyrophilin 1a1 knockout mouse revisited: Ablation of Btn1a1 leads to concurrent cell death and renewal in the mammary epithelium during lactaction,” FASEB BioAdvances, 3, 971-997, (2021).

[0123] It has been demonstrated that BTN1A1 is expressed by a plurality of human cancers and displays mutually exclusive expression pattern with PD-L1 (see, e.g., Example 2 herein and WO 2018 / 222685, the content of which is incorporated herein by reference in its entirety). Particularly, it has been demonstrated that GAL-1, GAL-9, NRP-2 and BTLA can act as BTN1A1 ligands (see e.g., Examples 3 and 4 herein, and WO 2018 / 226671, the content of which is incorporated herein by reference in its entirety). Without being limited by any specific theory, it is believed that inhibition of GAL-1, GAL-9, NRP-2, or BTLA complex formation with BTN1A1, including disruptions of already formed complexes of BTN1A1 with BTN1A1 ligands, such as GAL-1, GAL-9, NRP-2, or BTLA, can modulate a BTLA activity or signaling. It is further believed that this modulation of BTLA activity or signaling can activate T-cells, such as CD8+ T-cells, e.g., by promoting T-cell proliferation, inhibiting T-cell apoptosis, or inducing cytokine secretion (e.g., IFN^ or IL2). T-cell activation can result in an anti-cancer immune response that is useful for treating or preventing cancer.

[0124] In some instances, when anti-cancer therapies place cancer cells into a stressed state, the cancer cells active defensive mechanisms to develop resistance to the treatment and thereby escape cell death. It has been shown that BTN1A1 expression level is significantly upregulated in the tumor microenvironment of tumor that is subjected to radiation (see e.g., Example 1 herein, WO2016 / 191315 and WO2017 / 096051, the content of each of which is incorporated NAI-1543197688v1 16Attorney Docket No.: 13532-031-228 herein by reference in its entirety). It has also been demonstrated that cancer patients who have developed resistance to, or whose cancers have relapsed from prior chemotherapy treatment, surprisingly react to the chemotherapy treatment again shortly after being treated with BTN1A1- inhibiting therapy (see e.g., Examples 6, and 7 herein).

[0125] These data suggest that BTN1A1 is involved in drug resistance in cancer patients, and BTN1A1 inhibition therapy may prevent, reduce or reverse drug resistance and offer therapeutic advantages to cancer patients.

[0126] Accordingly, provided herein is a method for treating cancer in a subject in need thereof with an anti-cancer therapy (e.g., chemotherapy or radiation) in combination with a BTN1A1 antagonist (e.g., a molecule inhibiting binding of BTN1A1 to one or more of its receptors). Also provided herein is a method for preparing a subject suffering from cancer for treatment with an anti-cancer therapy (e.g., chemotherapy or radiation), by first administering to the subject an effective amount of a BTN1A1 antagonist. Also provided herein is a method for eliminating cancer cells from a cell population by contacting the cell population with anti-cancer therapeutic agent in the presence of a BTN1A1 antagonist. In some embodiments, such anti- cancer therapeutic agent can comprise one or more chemotherapeutic agent, a radiation treatment, or a population of immune effector cells, and upon the contacting the percentage of cancer cells in the cell population is reduced. Also provided herein is a method for sensitizing a response of cancer cells to an anti-cancer therapeutic agent by contacting the cancer cells with a BTN1A1 antagonist, wherein upon the contacting, a reaction of the cancer cells to the anti- cancer therapeutic agent is enhanced. BTN1A1 antagonistic molecules and compositions thereof suitable for using in the methods disclosed herein are also provided. 4.1 General Techniques

[0127] Techniques and procedures described or referenced herein include those that are generally well understood and / or commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3d ed.2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed.2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed.2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Dübel eds., 2d ed.2010). NAI-1543197688v1 17Attorney Docket No.: 13532-031-228 4.2 Definitions

[0128] Unless described otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that any description of terms set forth conflicts with any document incorporated herein by reference, the description of term set forth below shall control.

[0129] 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 such as primates (e.g., humans, cynomolgus monkey (cyno)), dogs, and rodents (e.g., mice and rats). Unless otherwise specified, BTN1A1 also includes various BTN1A1 isoforms, related BTN1A1 polypeptides, including SNP variants thereof, as well as different modified forms of BTN1A1, including but not limited to phosphorylated BTN1A1, glycosylated BTN1A1, and ubiquitinated BTN1A1. As used herein, glycosylated BTN1A1 include BTN1A1 with N55, N215, and / or N449 glycosylation.

[0130] An exemplary amino acid sequence of human BTN1A1 (BC096314.1 GI: 64654887), is provided below: MAVFPSSGLPRCLLTLILLQLPKLDSAPFDVIGPPEPILAVVGEDAKLPCRLSPNASAEHL ELRWFRKKVSPAVLVHRDGREQEAEQMPEYRGRATLVQDGIAKGRVALRIRGVRVSD DGEYTCFFREDGSYEEALVHLKVAALGSDPHISMQVQENGEICLECTSVGWYPEPQVQ WRTSKGEKFPSTSESRNPDEEGLFTVAASVIIRDTSAKNVSCYIQNLLLGQEKKVEISIPAS SLPRLTPWIVAVAVILMVLGLLTIGSIFFTWRLYNERPRERRNEFSSKERLLEELKWKKA TLHAVDVTLDPDTAHPHLFLYEDSKSVRLEDSRQKLPEKTERFDSWPCVLGRETFTSGR HYWEVEVGDRTDWAIGVCRENVMKKGFDPMTPENGFWAVELYGNGYWALTPLRTPL PLAGPPRRVGIFLDYESGDISFYNMNDGSDIYTFSNVTFSGPLRPFFCLWSSGKKPLTICPI ADGPERVTVIANAQDLSKEIPLSPMGEDSAPRDADTLHSKLIPTQPSQGAP (SEQ ID NO:1)

[0131] An exemplary encoding nucleic acid sequence of human BTN1A1 (BC096314.1 GI: 64654887), is provided below: NAI-1543197688v1 18Attorney Docket No.: 13532-031-228 ATGGCAGTTTTCCCAAGCTCCGGTCTCCCCAGATGTCTGCTCACCCTCATTCTCCTCC AGCTGCCCAAACTGGATTCAGCTCCCTTTGACGTGATTGGACCCCCGGAGCCCATCC TGGCCGTTGTGGGTGAGGACGCCAAGCTGCCCTGTCGCCTGTCTCCGAACGCGAGCG CCGAGCACTTGGAGCTACGCTGGTTCCGAAAGAAGGTTTCGCCGGCCGTGCTGGTGC ATAGGGACGGGCGCGAGCAGGAAGCCGAGCAGATGCCCGAGTACCGCGGGCGGGC GACGCTGGTCCAGGACGGCATCGCCAAGGGGCGCGTGGCCTTGAGGATCCGTGGCG TCAGAGTCTCTGACGACGGGGAGTACACGTGCTTTTTCAGGGAGGATGGAAGCTAC GAAGAAGCCCTGGTGCATCTGAAGGTGGCTGCTCTGGGCTCTGACCCTCACATCAGT ATGCAAGTTCAAGAGAATGGAGAAATCTGTCTGGAGTGCACCTCAGTGGGATGGTA CCCAGAGCCCCAGGTGCAGTGGAGAACTTCCAAGGGAGAGAAGTTTCCATCTACAT CAGAGTCCAGGAATCCTGATGAAGAAGGTTTGTTCACTGTGGCTGCTTCAGTGATCA TCAGAGACACTTCTGCGAAAAATGTGTCCTGCTACATCCAGAATCTCCTTCTTGGCC AGGAGAAGAAAGTAGAAATATCCATACCAGCTTCCTCCCTCCCAAGGCTGACTCCCT GGATAGTGGCTGTGGCTGTCATCCTGATGGTTCTAGGACTTCTCACCATTGGGTCCA TATTTTTCACTTGGAGACTATACAACGAAAGACCCAGAGAGAGGAGGAATGAATTC AGCTCTAAAGAGAGACTCCTGGAAGAACTCAAATGGAAAAAGGCTACCTTGCATGC AGTTGATGTGACTCTGGACCCAGACACAGCTCATCCCCACCTCTTTCTTTATGAGGA TTCAAAATCTGTTCGACTGGAAGATTCACGTCAGAAACTGCCTGAGAAAACAGAGA GATTTGACTCCTGGCCCTGTGTGTTGGGCCGTGAGACCTTCACCTCAGGAAGGCATT ACTGGGAGGTGGAGGTGGGAGACAGGACTGACTGGGCAATCGGCGTGTGTAGGGA GAATGTGATGAAGAAAGGATTTGACCCCATGACTCCTGAGAATGGGTTCTGGGCTGT AGAGTTGTATGGAAATGGGTACTGGGCCCTCACTCCTCTCCGGACCCCTCTCCCATT GGCAGGGCCCCCACGCCGGGTTGGGATTTTCCTAGACTATGAATCAGGAGACATCTC CTTCTACAACATGAATGATGGATCTGATATCTATACTTTCTCCAATGTCACTTTCTCT GGCCCCCTCCGGCCCTTCTTTTGCCTATGGTCTAGCGGTAAAAAGCCCCTGACCATC TGCCCAATTGCTGATGGGCCTGAGAGGGTCACAGTCATTGCTAATGCCCAGGACCTT TCTAAGGAGATCCCATTGTCCCCCATGGGGGAGGACTCTGCCCCTAGGGATGCAGA CACTCTCCATTCTAAGCTAATCCCTACCCAACCCAGCCAAGGGGCACCTTAA (SEQ ID NO:2).

[0132] An exemplary amino acid sequence of an exemplary dimeric BTN1A1 extracellular domain construct (BTN1A1-ECD-Fc) is provided below: NAI-1543197688v1 19Attorney Docket No.: 13532-031-228 APFDVIGPPEPILAVVGEDAELPCRLSPNASAEHLELRWFRKKVSPAVLVHRDGREQEAE QMPEYRGRATLVQDGIAKGRVALRIRGVRVSDDGEYTCFFREDGSYEEALVHLKVAAL GSDPHISMQVQENGEICLECTSVGWYPEPQVQWRTSKGEKFPSTSESRNPDEEGLFTVA ASVIIRDTSAKNVSCYIQNLLLGQEKKVEISIPASSLPRDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:3).

[0133] An exemplary amino acid sequence of an exemplary monomeric BTN1A1 extracellular domain construct (BTN1A1-His6) is provided below. APFDVIGPPEPILAVVGEDAELPCRLSPNASAEHLELRWFRKKVSPAVLVHRDGREQEAE QMPEYRGRATLVQDGIAKGRVALRIRGVRVSDDGEYTCFFREDGSYEEALVHLKVAAL GSDPHISMQVQENGEICLECTSVGWYPEPQVQWRTSKGEKFPSTSESRNPDEEGLFTVA ASVIIRDTSAKNVSCYIQNLLLGQEKKVEISIPASSLPRHHHHHH (SEQ ID NO:4).

[0134] An exemplary amino acid sequence of mouse BTN1A1 (GenBank: AAH11497.1), is provided below with the potential glycosylation sites bolded and underlined: MAVPTNSCLLVCLLTLTVLQLPTLDSAAPFDVTAPQEPVLALVGSDAELTCGFSPNASSE YMELLWFRQTRSKAVLLYRDGQEQEGQQMTEYRGRATLATAGLLDGRATLLIRDVRV SDQGEYRCLFKDNDDFEEAAVYLKVAAVGSDPQISMTVQENGEMELECTSSGWYPEPQ VQWRTGNREMLPSTSESKKHNEEGLFTVAVSMMIRDSSIKNMSCCIQNILLGQGKEVEIS LPAPFVPRLTPWIVAVAIILLALGFLTIGSIFFTWKLYKERSSLRKKEFGSKERLLEELRCK KTVLHEVDVTLDPDTAHPHLFLYEDSKSVRLEDSRQILPDRPERFDSWPCVLGRETFTSG RHYWEVEVGDRTDWAIGVCRENVVKKGFDPMTPDNGFWAVELYGNGYWALTPLRTS LRLAGPPRRVGVFLDYDAGDISFYNMSNGSLIYTFPSISFSGPLRPFFCLWSCGKKPLTICS TANGPEKVTVIANVQDDIPLSPLGEGCTSGDKDTLHSKLIPFSPSQAAP (SEQ ID NO:5).

[0135] An exemplary encoding nucleic acid sequence of mouse BTN1A1 (GenBank: BC011497.1), is provided below: ATGGCAGTTCCCACCAACTCCTGCCTCCTGGTCTGTCTGCTCACCCTCACTGTCCTAC AGCTGCCCACGCTGGATTCGGCAGCTCCCTTCGATGTGACCGCACCTCAGGAGCCAG NAI-1543197688v1 20Attorney Docket No.: 13532-031-228 TGTTGGCCCTAGTGGGCTCAGATGCCGAGCTGACCTGTGGCTTTTCCCCAAACGCGA GCTCAGAATACATGGAGCTGCTGTGGTTTCGACAGACGAGGTCGAAAGCGGTACTT CTATACCGGGATGGCCAGGAGCAGGAGGGCCAGCAGATGACGGAGTACCGCGGGA GGGCGACGCTGGCGACAGCCGGGCTTCTAGACGGCCGCGCTACTCTGCTGATCCGA GATGTCAGGGTCTCAGACCAGGGGGAGTACCGGTGCCTTTTCAAAGACAACGACGA CTTCGAGGAGGCCGCCGTATACCTCAAAGTGGCTGCTGTGGGTTCAGATCCTCAAAT CAGTATGACGGTTCAAGAGAATGGAGAAATGGAGCTGGAGTGCACCTCCTCTGGAT GGTACCCAGAGCCTCAGGTGCAGTGGAGAACAGGCAACAGAGAGATGCTACCATCC ACGTCAGAGTCCAAGAAGCATAATGAGGAAGGCCTGTTCACTGTGGCAGTTTCAAT GATGATCAGAGACAGCTCCATAAAGAACATGTCCTGCTGCATCCAGAATATCCTCCT TGGCCAGGGGAAGGAAGTAGAGATCTCCTTACCAGCTCCCTTCGTGCCAAGGCTGA CTCCCTGGATAGTAGCTGTGGCTATCATCTTACTGGCCTTAGGATTTCTCACCATTGG GTCCATATTTTTCACTTGGAAACTATACAAGGAAAGATCCAGTCTGCGGAAGAAGG AATTTGGCTCTAAAGAGAGACTTCTGGAAGAACTCAGATGCAAAAAGACTGTACTG CATGAAGTTGACGTGACTCTGGATCCAGACACAGCCCACCCCCACCTCTTCCTGTAT GAAGATTCAAAGTCAGTTCGATTGGAAGATTCACGTCAGATCCTGCCTGATAGACCA GAGAGATTTGACTCCTGGCCCTGTGTGTTGGGCCGTGAGACCTTTACTTCAGGGAGA CATTACTGGGAGGTGGAGGTGGGAGATAGAACTGACTGGGCCATTGGTGTGTGTAG GGAGAATGTGGTGAAGAAAGGGTTTGACCCCATGACTCCTGATAATGGGTTCTGGG CTGTGGAGTTGTATGGAAATGGGTACTGGGCCCTCACCCCACTCAGGACCTCTCTCC GATTAGCAGGGCCCCCTCGCAGAGTTGGGGTTTTTCTGGACTATGACGCAGGAGACA TTTCCTTCTACAACATGAGTAACGGATCTCTTATCTATACTTTCCCTAGCATCTCTTTC TCTGGCCCCCTCCGTCCCTTCTTTTGTCTGTGGTCCTGTGGTAAAAAGCCCCTGACCA TCTGTTCAACTGCCAATGGGCCTGAGAAAGTCACAGTCATTGCTAATGTCCAGGACG ACATTCCCTTGTCCCCGCTGGGGGAAGGCTGTACTTCTGGAGACAAAGACACTCTCC ATTCTAAACTGATCCCGTTCTCACCTAGCCAAGCGGCACCATAA (SEQ ID NO:6).

[0136] As used herein, and unless otherwise specified, the terms “Galectin-1,” “GAL-1,” “GAL1,” “GBP,” or “LGALS1” encompass a polypeptide (“polypeptide” and “protein” are used interchangeably herein), including any native 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, the terms NAI-1543197688v1 21Attorney Docket No.: 13532-031-228 include “related GAL-1 polypeptides,” including SNP variants thereof. The term “GAL-1” also encompasses “full-length,” unprocessed GAL-1 as well as any form of GAL-1 that results from processing in the cell. NCBI Reference Sequence NP_002296 provides an exemplary human GAL-1 amino acid sequence. NCBI Reference Sequence NM_002305 provides an exemplary human GAL-1 nucleic acid sequence (mRNA).

[0137] An exemplary amino acid sequence of human GAL-1 (NCBI Reference Sequence NP_002296), is provided below. MACGLVASNLNLKPGECLRVRGEVAPDAKSFVLNLGKDSNNLCLHFNPRFNAHGDAN TIVCNSKDGGAWGTEQREAVFPFQPGSVAEVCITFDQANLTVKLPDGYEFKFPNRLNLE AINYMAADGDFKIKCVAFD (SEQ ID NO:7).

[0138] An exemplary nucleic acid sequence of human GAL-1 (NCBI Reference Sequence NM_002305 (coding sequence)), is provided below. ATG GCTTGTGGTC TGGTCGCCAG CAACCTGAAT CTCAAACCTG GAGAGTGCCTTCGAGTGCGAGGCGAGGTGGCTCCTGACGCTAAGAGCTTCGTGCTG AACCTGGGCAAAGACAGCAACAACCTGTGCCTGCACTTCAACCCTCGCTTCAACGCC CACGGCGACGCCAACACCATCGTGTGCAACAGCAAGGACGGCGGGGCCTGGGGGA CCGAGCAGCGGGAGGCTGTCTTTCCCTTCCAGCCTGGAAGTGTTGCAGAGGTGTGCA TCACCTTCGACCAGGCCAACCTGACCGTCAAGCTGCCAGATGGATACGAATTCAAGT TCCCCAACCGCCTCAACCTGGAGGCCATCAACTACATGGCAGCTGACGGTGACTTCA AGATCAAATGT GTGGCCTTTGACTGA (SEQ ID NO:8).

[0139] As used herein, and unless otherwise specified, the terms “Galectin-9,” “HUAT,” “GAL-9,” “GAL9,” “LGALS9,” or “LGALS9A” encompass a polypeptide (“polypeptide” and “protein” are used interchangeably herein), including any native 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, the terms include “related GAL-9 polypeptides,” including SNP variants thereof. The term “GAL-9” also encompasses “full-length,” unprocessed GAL-9 as well as any form of GAL-9 that results from processing in the cell. NCBI Reference Sequence NP_001317092 provides an exemplary human GAL-9 amino acid sequence. NCBI Reference Sequence NM_002308 provides an exemplary human GAL-9 nucleic acid sequence (mRNA). NAI-1543197688v1 22Attorney Docket No.: 13532-031-228

[0140] An exemplary amino acid sequence of human GAL-9 (NCBI Reference Sequence NP_001317092), is provided below. MAFSGSQAPYLSPAVPFSGTIQGGLQDGLQITVNGTVLSSSGTRFAVNFQTGFSGNDIAF HFNPRFEDGGYVVCNTRQNGSWGPEERKTHMPFQKGMPFDLCFLVQSSDFKVMVNGIL FVQYFHRVPFHRVDTISVNGSVQLSYISFQPPGVWPANPAPITQTVIHTVQSAPGQMFSTP AIPPMMYPHPAYPMPFITTILGGLYPSKSILLSGTVLPSAQRCGSCVKLTASRWPWMVST CLNTTIA (SEQ ID NO:9).

[0141] An exemplary nucleic acid sequence of human GAL-9 (NCBI Reference Sequence NM_002308 (coding sequence)), is provided below. ATGGCCTTCAGCGGTTCCCAGGCTCCCTACCTGAGTCCAGCTGTCCCCTTTTCTGGGA CTATTCAAGGAGGTCTCCAGGACGGACTTCAGATCACTGTCAATGGGACCGTTCTCA GCTCCAGTGGAACCAGGTTTGCTGTGAACTTTCAGACTGGCTTCAGTGGAAATGACA TTGCCTTCCACTTCAACCCTCGGTTTGAAGATGGAGGGTACGTGGTGTGCAACACGA GGCAGAACGGAAGCTGGGGGCCCGAGGAGAGGAAGACACACATGCCTTTCCAGAA GGGGATGCCCTTTGACCTCTGCTTCCTGGTGCAGAGCTCAGATTTCAAGGTGATGGT GAACGGGATCCTCTTCGTGCAGTACTTCCACCGCGTGCCCTTCCACCGTGTGGACAC CATCTCCGTCAATGGCTCTGTGCAGCTGTCCTACATCAGCTTCCAGCCTCCCGGCGT GTGGCCTGCCAACCCGGCTCCCATTACCCAGACAGTCATCCACACAGTGCAGAGCG CCCCTGGACAGATGTTCTCTACTCCCGCCATCCCACTATGATGTACCCCCACCCCGC CTATCCGATGCCTTTCATCACCACCATTCTGGGAGGGCTGTACCCATCCAAGTCCAT CCTCCTGTCAGGCACTGTCCTGCCCAGTGCTCAGAGGTTCCACATCAACCTGTGCTC TGGGAACCACATCGCCTTCCACCTGAACCCCCGTTTTGATGAGAATGCTGTGGTCCG CAACACCCAGATCGACAACTCCTGGGGGTCTGAGGAGCGAAGTCTGCCCCGAAAAA TGCCCTTCGTCCGTGGCCAGAGCTTCTCAGTGTGGATCTTGTGTGAAGCTCACTGCCT CAAGGTGGCCGTGGATGGTCAGCACCTGTTTGAATACTACCATCGCCTGAGGAACCT GCCCACCATCAACAGACTGGA AGTGGGGGGCGACATCCAGCTGACCCATGTGCAGACATAG (SEQ ID NO:10)

[0142] As used herein, and unless otherwise specified, the terms “Neuropilin-2,” “NRP- 2,” “NRP2,” “NP2,” “PRO2714,” or “VEGF165R2” encompass a polypeptide (“polypeptide” and “protein” are used interchangeably herein), including any native polypeptide, from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys NAI-1543197688v1 23Attorney Docket No.: 13532-031-228 (cynomolgus)), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. In certain embodiments, the terms include “related NRP-2 polypeptides,” including SNP variants thereof. The term “NRP-2” also encompasses “full-length,” unprocessed NRP-2 as well as any form of NRP-2 that results from processing in the cell. NCBI Reference Sequence NP_003863 provides an exemplary human NRP-2 amino acid sequence. NCBI Reference Sequence NM_003872 provides an exemplary human NRP-2 nucleic acid sequence (mRNA).

[0143] An exemplary amino acid sequence of human NRP-2 (NCBI Reference Sequence NP_003863), is provided below. MDMFPLTWVFLALYFSRHQVRGQPDPPCGGRLNSKDAGYITSPGYPQDYPSHQNCEWI VYAPEPNQKIVLNFNPHFEIEKHDCKYDFIEIRDGDSESADLLGKHCGNIAPPTIISSGSML YIKFTSDYARQGAGFSLRYEIFKTGSEDCSKNFTSPNGTIESPGFPEKYPHNLDCTFTILAK PKMEIILQFLIFDLEHDPLQVGEGDCKYDWLDIWDGIPHVGPLIGKYCGTKTPSELRSSTG ILSLTFHTDMAVAKDGFSARYYLVHQEPLENFQCNVPLGMESGRIANEQISASSTYSDGR WTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFLTMLTAIATQGAISRETQNGYYVKSY KLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLNKLHAPLLTRFVRIRPQTWHSGI ALRLELFGCRVTDAPCSNMLGMLSGLIADSQISASSTQEYLWSPSAARLVSSRSGWFPRI PQAQPGEEWLQVDLGTPKTVKGVIIQGARGGDSITAVEARAFVRKFKVSYSLNGKDWE YIQDPRTQQPKLFEGNMHYDTPDIRRFDPIPAQYVRVYPERWSPAGIGMRLEVLGCDWT DSKPTVETLGPTVKSEETTTPYPTEEEATECGENCSFEDDKDLQLPSGFNCNFDFLEEPCG WMYDHAKWLRTTWASSSSPNDRTFPDDRNFLRLQSDSQREGQYARLISPPVHLPRSPVC MEFQYQATGGRGVALQVVREASQESKLLWVIREDQGGEWKHGRIILPSYDMEYQIVFE GVIGKGRSGEIAIDDIRISTDVPLENCMEPISAFAVDIPEIHEREGYEDEIDDEYEVDWSNS SSATSGSGAPSTDKEKSWLYTLDPILITIIAMSSLGVLLGATCAGLLLYCTCSYSGLSSRSC TTLENYNFELYDGLKHKVKMNHQKCCSEA (SEQ ID NO:11).

[0144] An exemplary nucleic acid sequence of human GAL-1 (NCBI Reference Sequence NM_003872 (coding sequence)), is provided below. ATGTTTCCTCTCACCTGGGTTTTCTTAGCCCTCTACTTTTCAAGACACCAAGTGAGAG GCCAACCAGACCCACCGTGCGGAGGTCGTTTGAATTCCAAAGATGCTGGCTATATCA CCTCTCCCGGTTACCCCCAGGACTACCCCTCCCACCAGAACTGCGAGTGGATTGTTT ACGCCCCCGAACCCAACCAGAAGATTGTCCTCAACTTCAACCCTCACTTTGAAATCG AGAAGCACGACTGCAAGTATGACTTTATCGAGATTCGGGATGGGGACAGTGAATCC NAI-1543197688v1 24Attorney Docket No.: 13532-031-228 GCAGACCTCCTGGGCAAACACTGTGGGAACATCGCCCCGCCCACCATCATCTCCTCG GGCTCCATGCTCTACATCAAGTTCACCTCCGACTACGCCCGGCAGGGGGCAGGCTTC TCTCTGCGCTACGAGATCTTCAAGACAGGCTCTGAAGATTGCTCAAAAAACTTCACA AGCCCCAACGGGACCATCGAATCTCCTGGGTTTCCTGAGAAGTATCCACACAACTTG GACTGCACCTTTACCATCCTGGCCAAACCCAAGATGGAGATCATCCTGCAGTTCCTG ATCTTTGACCTGGAGCATGACCCTTTGCAGGTGGGAGAGGGGGACTGCAAGTACGA TTGGCTGGACATCTGGGATGGCATTCCACATGTTGGCCCCCTGATTGGCAAGTACTG TGGGACCAAAACACCCTCTGAACTTCGTTCATCGACGGGGATCCTCTCCCTGACCTT TCACACGGACATGGCGGTGGCCAAGGATGGCTTCTCTGCGCGTTACTACCTGGTCCA CCAAGAGCCACTAGAGAACTTTCAGTGCAATGTTCCTCTGGGCATGGAGTCTGGCCG GATTGCTAATGAACAGATCAGTGCCTCATCTACCTACTCTGATGGGAGGTGGACCCC TCAACAAAGCCGGCTCCATGGTGATGACAATGGCTGGACCCCCAACTTGGATTCCA ACAAGGAGTATCTCCAGGTGGACCTGCGCTTTTTAACCATGCTCACGGCCATCGCAA CACAGGGAGCGATTTCCAGGGAAACACAGAATGGCTACTATGTCAAATCCTACAAG CTGGAAGTCAGCACTAATGGAGAGGACTGGATGGTGTACCGGCATGGCAAAAACCA CAAGGTATTTCAAGCCAACAACGATGCAACTGAGGTGGTTCTGAACAAGCTCCACG CTCCACTGCTGACAAGGTTTGTTAGAATCCGCCCTCAGACCTGGCACTCAGGTATCG CCCTCCGGCTGGAGCTCTTCGGCTGCCGGGTCACAGATGCTCCCTGCTCCAACATGC TGGGGATGCTCTCAGGCCTCATTGCAGACTCCCAGATCTCCGCCTCTTCCACCCAGG AATACCTCTGGAGCCCCAGTGCAGCCCGCCTGGTCAGCAGCCGCTCGGGCTGGTTCC CTCGAATCCCTCAGGCCCAGCCCGGTGAGGAGTGGCTTCAGGTAGATCTGGGAACA CCCAAGACAGTGAAAGGTGTCATCATCCAGGGAGCCCGCGGAGGAGACAGTATCAC TGCTGTGGAAGCCAGAGCATTTGTGCGCAAGTTCAAAGTCTCCTACAGCCTAAACGG CAAGGACTGGGAATACATTCAGGACCCCAGGACCCAGCAGCCAAAGCTGTTCGAAG GGAACATGCACTATGACACCCCTGACATCCGAAGGTTTGACCCCATTCCGGCACAGT ATGTGCGGGTATACCCGGAGAGGTGGTCGCCGGCGGGGATTGGGATGCGGCTGGAG GTGCTGGGCTGTGACTGGACAGACTCCAAGCCCACGGTAGAGACGCTGGGACCCAC TGTGAAGAGCGAAGAGACAACCACCCCCTACCCCACCGAAGAGGAGGCCACAGAG TGTGGGGAGAACTGCAGCTTTGAGGATGACAAAGATTTGCAGCTCCCTTCGGGATTC AATTGCAACTTCGATTTCCTCGAGGAGCCCTGTGGTTGGATGTATGACCATGCCAAG TGGCTCCGGACCACCTGGGCCAGCAGCTCCAGCCCAAACGACCGGACGTTTCCAGA NAI-1543197688v1 25Attorney Docket No.: 13532-031-228 TGACAGGAATTTCTTGCGGCTGCAGAGTGACAGCCAGAGAGAGGGCCAGTATGCCC GGCTCATCAGCCCCCCTGTCCACCTGCCCCGAAGCCCGGTGTGCATGGAGTTCCAGT ACCAGGCCACGGGCGGCCGCGGGGTGGCGCTGCAGGTGGTGCGGGAAGCCAGCCA GGAGAGCAAGTTGCTGTGGGTCATCCGTGAGGACCAGGGCGGCGAGTGGAAGCACG GGCGGATCATCCTGCCCAGCTACGACATGGAGTACCAGATTGTGTTCGAGGGAGTG ATAGGGAAAGGACGTTCCGGAGAGATTGCCATTGATGACATTCGGATAAGCACTGA TGTCCCACTGGAGAACTGCATGGAACCCATCTCGGCTTTTGCAGTGGACATCCCAGA AATACATGAGAGAGAAGGATATGAAGATGAAATTGATGATGAATACGAGGTGGACT GGAGCAATTCTTCTTCTGCAACCTCAGGGTCTGGCGCCCCCTCGACCGACAAAGAAA AGAGCTGGCTGTACACCCTGGATCCCATCCTCATCACCATCATCGCCATGAGCTCAC TGGGCGTCCTCCTGGGGGCCACCTGTGCAGGCCTCCTGCTCTACTGCACCTGTTCCT ACTCGGGCCTGAGCTCCCGAAGCTGCACCACACTGGAGAACTACAACTTCGAGCTCT ACGATGGCCTTAAGCACAAGGTCAAGATGAACCACCAAAAGTGCTGCTCCGAGGCA TGA (SEQ ID NO:12).

[0145] As used herein, and unless otherwise specified, the term “B- and T-lymphocyte attenuator” or “BTLA” refers to BTLA from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkey (cyno)), dogs, and rodents (e.g., mice and rats). Unless otherwise specified, BTLA also includes various BTLA isoforms, related BTLA polypeptides, including SNP variants thereof, as well as different modified forms of BTLA, including but not limited to phosphorylated BTLA, glycosylated BTLA, and ubiquitinated BTLA.

[0146] An exemplary amino acid sequence of human BTLA is provided below, in which the sites for N-linked glycosylation are bolded underlined (N75, N94, and N110): MKTLPAMLGTGKLFWVFFLIPYLDIWNIHGKESCDVQLYIKRQSEHSILAGDPFELECPV KYCANRPHVTWCKLNGTTCVKLEDRQTSWKEEKNISFFILHFEPVLPNDNGSYRCSANF QSNLIESHSTTLYVTDVKSASERPSKDEMASRPWLLYRLLPLGGLPLLITTCFCLFCCLRR HQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDNDPDLCFRMQEG SEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEAPTEYASICVRS (SEQ ID NO:13).

[0147] An exemplary nucleic acid sequence of human BTLA is provided below (NCBI Reference Sequence NM_001085357.1 (coding sequence)): NAI-1543197688v1 26Attorney Docket No.: 13532-031-228 ATGAAGACATTGCCTGCCATGCTTGGAACTGGGAAATTATTTTGGGTCTTCTTCTTAA TCCCATATCTGGACATCTGGAACATCCATGGGAAAGAATCATGTGATGTACAGCTTT ATATAAAGAGACAATCTGAACACTCCATCTTAGCAGGAGATCCCTTTGAACTAGAAT GCCCTGTGAAATACTGTGCTAACAGGCCTCATGTGACTTGGTGCAAGCTCAATGGAA CAACATGTGTAAAACTTGAAGATAGACAAACAAGTTGGAAGGAAGAGAAGAACATT TCATTTTTCATTCTACATTTTGAACCAGTGCTTCCTAATGACAATGGGTCATACCGCT GTTCTGCAAATTTTCAGTCTAATCTCATTGAAAGCCACTCAACAACTCTTTATGTGAC AGGAAAGCAAAATGAACTCTCTGACACAGCAGGAAGGGAAATTAACCTGGTTGATG CTCACCTTAAGAGTGAGCAAACAGAAGCAAGCACCAGGCAAAATTCCCAAGTACTG CTATCAGAAACTGGAATTTATGATAATGACCCTGACCTTTGTTTCAGGATGCAGGAA GGGTCTGAAGTTTATTCTAATCCATGCCTGGAAGAAAACAAACCAGGCATTGTTTAT GCTTCCCTGAACCATTCTGTCATTGGACCGAACTCAAGACTGGCAAGAAATGTAAAA GAAGCACCAACAGAATATGCATCCATATGTGTGAGGAGTTAAG (SEQ ID NO:14).

[0148] 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 a polypeptide (“polypeptide” and “protein” are used interchangeably herein), including any native 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, the terms include “related PD-1 polypeptides,” including SNP variants thereof. The term “PD-1” also encompasses “full-length,” unprocessed PD-1 as well as any form of PD-1 that results from processing in the cell. NCBI Reference Sequence NP_005009.2 provides and exemplary human PD-L1 amino acid sequence. GenBank™ accession number L27440.1 provides an exemplary human PD-1 nucleic acid sequence.

[0149] As used herein, and unless otherwise specified, the term “anti-PD-1 therapy” encompasses any inhibitor of PD-1. In some embodiments, an 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., a 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. NAI-1543197688v1 27Attorney Docket No.: 13532-031-228

[0150] In some embodiments, the anti-PD-1 therapy includes Nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is also known as MDX- 1106, MDX- 1106-04, 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 / 121168.

[0151] 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, e.g., in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, WO2009 / 114335, and US 8,354,509.

[0152] 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.

[0153] In some embodiments, the anti-PD-1 therapy includes an anti-PD-1 antibody provided in International Application No. PCT / US2016 / 64394.

[0154] Additional anti-PD 1 antibodies that can be useful as anti-PD1 therapies are disclosed in US 8,609,089, US 2010028330, and / or US 20120114649.

[0155] 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 a polypeptide (“polypeptide” and “protein” are used interchangeably herein), including any native 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, the terms include “related PD-L1 polypeptides,” including SNP variants thereof. The term “PD-L1” also encompasses “full-length,” unprocessed PD-L1 as well as any form of PD-L1 that results from processing in the cell. NCBI Reference Sequence NP_054862.1 provides and exemplary human PD-L1 amino acid sequence. GenBank™ accession number NM_014143 provides an exemplary human PD-1 nucleic acid sequence.

[0156] As used herein, and unless otherwise specified, the term “anti-PD-L1 therapy” encompasses any inhibitor of PD-L1. In some embodiments, an anti-PD-1 therapy can include NAI-1543197688v1 28Attorney Docket No.: 13532-031-228 an anti-PD-L1 antibody or antigen binding fragment thereof, an inhibitory nucleic acid, or a soluble PD-L1 ligand (e.g., a 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.

[0157] “Cancer stem cells” or “CSCs” are terms of the art and refer to a population of cells that has the driving force of carcinogenesis. Without being bound by any theory, these cells exhibit distinctive self-renewal, proliferation, and differentiation capabilities that are believed to play a critical role in cancer initiation, maintenance, progression, drug resistance, and cancer recurrence or metastasis. Factors such as increased activation of drug-efflux pumps, enhanced capacity of DNA damage repair, dysregulation of growth and developmental signaling pathways, alterations of cellular metabolism, environmental niche, and impaired apoptotic response are attributed to CSCs in their resistance to the adjuvant chemoradiotherapy to cancer. The development of strategies targeting CSCs via drug transporters, specific surface markers, inhibiting signaling pathways or their components, and destroying their tumor microenvironment have multifocal effects that may improve the clinical outcome of patients with cancer. In some embodiments, cancer stem cells are slow reproduction cells.

[0158] As used herein, the term “slow reproduction cells” refers to a population of cells that divide at a speed slower than that of a reference cell population of comparable cell type under a comparable condition. For example, a population of lung cancer cells, under a given condition, can divide at the speed of a doubling time of about 40 hours (e.g., the number of cells in the population doubles about every 40 hours). A population of slow reproduction lung cancer cells divides at a significantly lower speed, with a doubling time of greater than 40 hours, such as between 40 to 160 hours.

[0159] 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 able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, whereby each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa) and each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids and each carboxy-terminal portion of each chain includes a constant region (See Borrebaeck (ed.) (1995) Antibody Engineering, Second Edition, Oxford University Press.; Kuby (1997) Immunology, Third Edition, W.H. Freeman and Company, New NAI-1543197688v1 29Attorney Docket No.: 13532-031-228 York). Here, the specific molecular antigen includes the targets BTN1A1, GAL-1, GAL-9, NRP-2 and BTLA which can be a BTN1A1 polypeptide, GAL-1 polypeptide, GAL-9 polypeptide, NRP-2 polypeptide or BTLA polypeptide, a BTN1A1 fragment, a GAL-1 fragment, a GAL-9 fragment, a NRP-2 fragment or a BTLA fragment, or BTN1A1 epitope, GAL-1 epitope, GAL-9 epitope, NRP-2 epitope, or BTLA epitope. Antibodies provided herein include, but are not limited to, monoclonal antibodies, synthetic antibodies, recombinantly produced antibodies, bi-specific antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies.

[0160] 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. A monoclonal antibody also is intended to refer to an antibody produced by recombinant methods from heavy and light chain encoding immunoglobulin genes to produce a single molecular immunoglobulin species. Amino acid sequences for antibodies within a monoclonal antibody preparation are substantially homogeneous and the binding activity of antibodies within such a preparation exhibit substantially the same antigen binding activity. In contrast, polyclonal antibodies are obtained from different B cells within a population, which are a combination of immunoglobulin molecules that bind a specific antigen. Each immunoglobulin of the polyclonal antibodies can bind a different epitope of the same antigen. Methods for producing both monoclonal antibodies 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)).

[0161] As used herein, and unless otherwise specified, the term “human antibody” refers to an antibody that has a human variable region and / or a human constant region or a portion thereof corresponding to human germline immunoglobulin sequences. Such human germline immunoglobulin sequences are described by Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242. Here, a human antibody can include an antibody that binds to BTN1A1 and is encoded by a nucleic acid sequence that is a naturally occurring somatic variant of the human germline immunoglobulin nucleic acid sequence. NAI-1543197688v1 30Attorney Docket No.: 13532-031-228

[0162] As used herein, and unless otherwise specified, the term “chimeric antibody” refers to an antibody that a portion of the heavy and / or light chain is identical with 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(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Patent No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

[0163] As used herein, and unless otherwise specified, the term “humanized antibody” refers to chimeric antibodies that include human immunoglobulins (e.g., recipient antibody) in which the native Complementarity Determining Region (“CDR”) residues are replaced by residues from the corresponding CDR of a nonhuman species (e.g., donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, one or more FR region residues of the human immunoglobulin are replaced by corresponding nonhuman residues. Furthermore, humanized antibodies can have residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. A humanized antibody heavy or light chain can have substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a nonhuman immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody can have 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. Acd. 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.

[0164] As used herein, and unless otherwise specified, the term “recombinant antibody” refers to an antibody that is prepared, expressed, created or isolated by recombinant means. Recombinant antibodies can be antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial antibody library, antibodies isolated from an animal (e.g., a mouse or cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see, e.g., Taylor, L. D. et al., Nucl. Acids NAI-1543197688v1 31Attorney Docket No.: 13532-031-228 Res.20:6287-6295(1992)) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of immunoglobulin gene sequences to other DNA sequences. Such recombinant antibodies can have variable and constant regions, including those derived from human germline immunoglobulin sequences (see Kabat, E. A. et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242). The recombinant antibodies can also be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies can be sequences that, while derived from and related to human germline VH and VL sequences, do not naturally exist within the human antibody germline repertoire in vivo.

[0165] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof. In some embodiments, two nucleic acids or polypeptides are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the amino acid sequences that is at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 residues, such as at least about 80-100 residues, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, such as the coding region of a target protein or an antibody. In some embodiments, identity exists over a region of the nucleotide sequences that is at least about 10 NAI-1543197688v1 32Attorney Docket No.: 13532-031-228 bases, at least about 20 bases, at least about 40-60 bases, at least about 60-80 bases in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 bases, such as at least about 80-1000 bases or more, and in some embodiments the sequences are substantially identical over the full-length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest.

[0166] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a side chain with similar chemical characteristics. Families of amino acid residues having similar side chains have been generally defined in the art, including 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), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is a conservative substitution. Generally, conservative substitutions in the sequences of the polypeptides, soluble proteins, and / or antibodies of the disclosure do not abrogate the binding of the polypeptide, soluble protein, or antibody containing the amino acid sequence, to the target binding site. Methods of identifying amino acid conservative substitutions which do not eliminate binding are well-known in the art.

[0167] As used herein, and unless otherwise specified, a “neutralizing molecule” refers to a molecule that blocks the binding the BTN1A1 with its natural ligands, such as GAL-1, GAL-9, NRP-2 or BTLA, and inhibits the signaling pathways mediated by BTN1A1 and / or its other physiological activities. In some embodiments, the neutralizing molecule is a neutralizing antibody. In some embodiments, the neutralizing molecule comprises an antigen binding fragment that immunospecifically binds BTN1A1 or a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2 or BTLA. The IC50 of a neutralizing molecule or neutralizing antibody refers to the concentration of the molecule or antibody that is required to neutralize 50% of BTN1A1 in a neutralization assay. The IC50 of the neutralizing molecule or neutralizing antibody can range between 0.01 - 10 µg / ml in the neutralization assay. In some embodiments a neutralizing molecule or neutralizing antibody can immunospecifically bind to BTN1A1. In some NAI-1543197688v1 33Attorney Docket No.: 13532-031-228 embodiments, a neutralizing molecule or neutralizing antibody can bind to a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2 or BTLA.

[0168] As used herein, and unless otherwise specified, the term “antigen binding fragment” and similar terms refer to a portion of an antibody which includes the amino acid residues that immunospecifically bind to an antigen and 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.

[0169] Molecules having an antigen binding fragment include, for example, an Fd, Fv, Fab, F(ab’), F(ab)2, F(ab’)2, single chain Fv (scFv), diabody, triabody, tetrabody, minibody, or a single domain antibody. A scFv can be monovalent scFv or bivalent 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 in, for example, 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 Publisher, Inc.; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E.D., Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc., 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 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.

[0170] The heavy chain of an antibody refers to a polypeptide chain of about 50-70 kDa, whereby the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids and a carboxy-terminal portion that includes a constant region. The constant region NAI-1543197688v1 34Attorney Docket No.: 13532-031-228 can be one of five distinct types, referred to as alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (µ), based on the amino acid sequence of the heavy chain constant region. The distinct heavy chains differ in size: α, δ and γ contain approximately 450 amino acids, while µ and ε contain approximately 550 amino acids. When combined with a light chain, these distinct types of heavy chains give rise to five well known classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including four subclasses of IgG, namely IgG1, IgG2, IgG3 and IgG4. A heavy chain can be a human heavy chain.

[0171] The light chain of an antibody refers to a polypeptide chain of about 25 kDa, whereby the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids and a carboxy-terminal portion that includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, referred to as kappa (κ) of lambda (λ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. A light chain can be a human light chain.

[0172] The variable domain or variable region of an antibody refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen. The variable domains differ extensively in sequence between different antibodies. The variability in sequence is concentrated in the CDRs while the less variable portions in the variable domain are referred to as framework regions (FR). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with antigen. Numbering of amino acid positions used herein is according to the EU Index, as in Kabat et al. (1991) Sequences of proteins of immunological interest. (U.S. Department of Health and Human Services, Washington, D.C.) 5thed. A variable region can be a human variable region.

[0173] A CDR refers to one of 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 three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL β-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody NAI-1543197688v1 35Attorney Docket No.: 13532-031-228 variable (V) domains (Kabat et al., J. Biol. Chem.252:6609-6616 (1977); Kabat, Adv. Prot. Chem.32:1-75 (1978)). CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved β-sheet framework, and thus are able to adapt different conformations (Chothia and Lesk, J. Mol. Biol.196:901-917 (1987)). Both terminologies are well recognized in the art. The positions of CDRs within a canonical antibody variable domain 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 a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable domain numbering scheme (Al-Lazikani et al., supra (1997)). Such nomenclature is similarly well known to those skilled in the art.

[0174] Recently, a universal numbering system has been developed and widely adopted, ImMunoGeneTics (IMGT) Information System®(Lafranc et al., 2003, Dev. Comp. Immunol. 27(1):55-77). IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Plückthun, 2001, J. Mol. Biol.309: 657-70. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). In some embodiments, the CDRs are as defined by the IMGT numbering system. In other embodiments, the CDRs are as defined by the Kabat numbering system. In certain embodiments, the CDRs are as defined by the AbM numbering system. In other embodiments, the CDRs are as defined by the Chothia system. In yet other embodiments, the CDRs are as defined by the Contact numbering system. NAI-1543197688v1 36Attorney Docket No.: 13532-031-228

[0175] For example, CDRs defined according to standard designations are set forth in the Table 1 below. Table: CDR Definitions Exemplary IMGT Kabat AbM Chothia Contact [ ly or noncova ent y to ma e t an mmunoad es n. n mmunoad es n can ncorporate t e 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 CDRs permit the immunoadhesin to bind to a particular antigen of interest.

[0177] The “framework” or “FR” residues refer to those variable domain residues flanking the CDRs. FR residues are present, e.g., in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues herein defined.

[0178] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in the VH. As used herein, the terms “HVR” and “CDR” are used interchangeably.

[0179] The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The term refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence NAI-1543197688v1 37Attorney Docket No.: 13532-031-228 relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site. The constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0180] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.

[0181] The term “inhibition” or “inhibit,” when used herein, refers to partial (such as, 1%, 2%, 5%, 10%, 20%, 25%, 50%, 75%, 90%, 95%, 99%) or complete (i.e., 100%) inhibition.

[0182] The term “attenuate,” “attenuation,” or “attenuated,” when used herein, refers to partial (such as, 1%, 2%, 5%, 10%, 20%, 25%, 50%, 75%, 90%, 95%, 99%) or complete (i.e., 100%) reduction in a property, activity, effect, or value.

[0183] As used herein, and unless otherwise specified, the term “isolated” as used in reference to an antibody means the antibody is substantially free of cellular material or other contaminating proteins from the cell or tissue source and / or other contaminant components from which the antibody is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language “substantially free of cellular material” includes preparations of an antibody 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 antibody having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”). In certain embodiments, when the antibody is recombinantly produced, it is substantially free of culture medium, e.g., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. In certain embodiments, when the antibody is NAI-1543197688v1 38Attorney Docket No.: 13532-031-228 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 which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. Contaminant components can also include, but are not limited to, materials that would interfere with therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In certain embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method (Lowry et al. J. Bio. Chem.193: 265-275, 1951), such as 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. In a specific embodiment, antibodies provided herein are isolated.

[0184] As used herein, and unless otherwise specified, the term “polynucleotide,” “nucleotide,” nucleic acid” “nucleic acid molecule” and other similar terms are used interchangeable and include DNA, RNA, mRNA and the like.

[0185] As used herein, and unless otherwise specified, the term “isolated” as used in reference to a nucleic acid molecule means the nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. In a specific embodiment, a nucleic acid molecule(s) encoding an antibody provided herein is isolated or purified.

[0186] As used herein and unless otherwise specified, the term “bind” or “binding” refers to an interaction between molecules. Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. The strength of the total non-covalent interactions between an antibody and a single epitope of a target molecule, such as BTN1A1, GAL-1, GAL-9, NRP-2, or BTLA is the affinity NAI-1543197688v1 39Attorney Docket No.: 13532-031-228 of the antibody for that epitope. “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding protein such as an antibody) and its binding partner (e.g., an antigen).

[0187] The affinity of a binding molecule X, such as an antibody, for its binding partner Y, such as the antibody’s cognate antigen can generally be represented by the dissociation constant (KD). Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. The “KD” or “KD value” can be measured by assays known in the art, for example by a binding assay. The KD can be measured in a radiolabeled antigen binding assay (RIA), for example, performed with the Fab version of an antibody of interest and its antigen (Chen, et al., (1999) J. Mol. Biol.293:865-881). The KD or KD value can also be measured by using surface plasmon resonance assays by Biacore, using, for example, a BIAcoreTM-2000 or a BIAcoreTM-3000 BIAcore, Inc., Piscataway, NJ), or by biolayer interferometry using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA).

[0188] As used herein, and unless otherwise specified, a molecule is said to be able to “immunospecifically bind” a second molecule if such binding exhibits the specificity and affinity of an antibody to its cognate antigen. An antibody immunospecifically binds to a target region or conformation (“epitope”) of an antigen if such binding involves the antigen recognition site of the antibody. An antibody that immunospecifically binds to a particular antigen can bind to other antigens with lower affinity if the other antigen has some sequence or conformational similarity that is recognized by the antigen recognition site as determined by, e.g., immunoassays, BIACORE® assays, or other assays known in the art. An antibody in general do not bind to a totally unrelated antigen. Some antibodies (and their antigen binding fragments) does not cross-react with other antigens. Antibodies can also bind to other molecules in a way that is not immunospecific, such as to FcR receptors, by virtue of binding domains in other regions / domains of the antibody that do not involve the antigen recognition site, such as the Fc region.

[0189] An “epitope” is the site on the surface of an antigen molecule to which a single antibody molecule binds, such as a localized region on the surface of an antigen, such as a BTN1A1 polypeptide or a BTN1A1 polypeptide fragment, that is capable of being bound to one NAI-1543197688v1 40Attorney Docket No.: 13532-031-228 or more antigen binding regions of an antibody, and that has antigenic or immunogenic activity in an animal, such as a mammal (e.g., a human), that is capable of eliciting an immune response. An epitope having immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal. An epitope having antigenic activity is a portion of a polypeptide to which an antibody binds as determined by any method well known in the art, including, for example, by an immunoassay. Antigenic epitopes need not necessarily be immunogenic. Epitopes often consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. Antibody epitopes may be linear epitopes or conformational epitopes. Linear epitopes are formed by a continuous sequence of amino acids in a protein. Conformational epitopes are formed of amino acids that are discontinuous in the protein sequence, but which are brought together upon folding of the protein into its three-dimensional structure. Induced epitopes are formed when the three-dimensional structure of the protein is in an altered conformation, such as following activation or binding of another protein or ligand. In certain embodiments, a BTN1A1 epitope is a three-dimensional surface feature of a BTN1A1 polypeptide. In other embodiments, a BTN1A1 epitope is linear feature of a BTN1A1 polypeptide. Generally, an antigen has several or many different epitopes and may react with many different antibodies.

[0190] The terms “antibodies that immunospecifically bind to BTN1A1,” “antibodies that immunospecifically bind to a BTN1A1 epitope,” and analogous terms are also used interchangeably herein and refer to antibodies that specifically bind to a BTN1A1 polypeptide, such as a BTN1A1 antigen, or fragment, or epitope (e.g., human BTN1A1 such as a human BTN1A1 polypeptide, antigen, or epitope). An antibody that specifically binds to BTN1A1 (e.g., human BTN1A1) may bind to the extracellular domain or a peptide derived from the extracellular domain of BTN1A1. An antibody that specifically binds to a BTN1A1 antigen (e.g., human BTN1A1) may be cross-reactive with related antigens (e.g., cynomolgus BTN1A1). In certain embodiments, an antibody that specifically binds to a BTN1A1 antigen does not cross- react with other antigens. An antibody that specifically binds to a BTN1A1 antigen can be identified, for example, by immunoassays, Biacore®, or other techniques known to those of skill in the art. An antibody binds specifically to a BTN1A1 antigen when it binds to a BTN1A1 antigen with higher affinity than to any cross-reactive antigen as determined using experimental NAI-1543197688v1 41Attorney Docket No.: 13532-031-228 techniques, such as radioimmunoassays (RIA) and enzyme linked immunosorbent assays (ELISAs). Typically a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed.1989) for a discussion regarding antibody specificity. An antibody which “binds an antigen of interest” (e.g., a target antigen such as BTN1A1) is one that binds the antigen with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody to a “non-target” protein will be less than about 10% of the binding of the antibody to its particular target protein, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIA. With regard to the binding of an antibody to a target molecule, the term “immunospecific binding,” “immunospecifically binds to,” or “is specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term “anti-BTN1A1 antibody” or “an antibody that binds to BTN1A1” includes an antibody that is capable of binding BTN1A1 with sufficient affinity such that the antibody is useful, for example, as a diagnostic agent in targeting BTN1A1. The term “specific binding,” “specifically binds to,” or “is specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. In certain embodiments, an antibody that binds to BTN1A1 has a dissociation constant (KD) of less than or equal to 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. In certain embodiments, anti-BTN1A1 antibody binds to an epitope of BTN1A1 that is conserved among BTN1A1 from different species (e.g., between human and cynomolgus BTN1A1). NAI-1543197688v1 42Attorney Docket No.: 13532-031-228

[0191] An antibody or antigen binding fragment that immunospecifically binds to an antigen or an epitope of an antigen that includes a glycosylation site can bind to the antigen or the epitope in both glycosylated form or unglycosylated form. In some embodiments, the antibody or antigen binding fragment preferentially binds the glycosylated antigen or epitope over the unglycosylated antigen or epitope. The preferential binding can be determined by binding affinity. For example, an antibody or antigen binding fragment that preferentially binds glycosylated BTN1A1 over unglycosylated BTN1A1 can bind to glycosylated BTN1A1 with a KD less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antibody or antigen binding fragment binds to glycosylated BTN1A1 with a KD less than half of the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antibody or antigen binding fragment binds to glycosylated BTN1A1 with KD at least 10 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antibody or antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of the KD exhibited relative to unglycosylated BTN1A1.

[0192] 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 a BTN1A1 dimer over a BTN1A1 monomers. BTN1A1 binding can occur, e.g., to a cell surface expressed BTN1A1 or to a soluble BTN1A1 domain construct, such as a BTN1A1 extracellular domain (ECD) construct (e.g., flag-tagged BTN1A1-ECD or a 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 binds to BTN1A1 dimer with a KD less than half of the KD exhibited relative to a BTN1A1 monomer. In some embodiments, the antibody or antigen binding fragment binds to aBTN1A1 dimer with a KD at least 10 times less than the KD exhibited relative to a BTN1A1 monomer. In some embodiments, the antibody or antigen binding fragment binds to a BTN1A1 dimer with a KD that is about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of the KD exhibited relative to aBTN1A1 monomer.

[0193] The preferential binding can also be determined by binding assays and be indicated by, for example, mean fluorescence intensity (“MFI”). For example, an antibody or antigen NAI-1543197688v1 43Attorney Docket No.: 13532-031-228 binding fragment that preferentially binds the glycosylated BTN1A1 can bind to glycosylated BTN1A1 with an MFI that is higher than the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antibody or antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least twice as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, antibody or the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least three times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, antibody or the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least five times, at least ten times, at least fifteen times, or at least twenty times as high as the MFI as exhibited relative to unglycosylated BTN1A1.

[0194] As used herein, and unless otherwise specified, a molecule is said to “immunospecifically mask” glycosylation of an antigen or epitope, or a specified glycosylation site thereof, refers to its ability to either (1) block the glycosylation site of an unglycosylated antigen or epitope so that the antigen or epitope cannot be glycosylated, or (2) bind to the glycosylated antigen or epitope or at the specified glycosylation site of the glycosylated antigen or epitope and prevent the physiological effect of the glycosylation, such as the downstream signaling mediated by the glycosylation. For example, an antibody or antigen binding fragment that immunospecifically masks BTN1A1 glycosylation refers to the antibody or antigen binding fragment that (1) either blocks the glycosylation site of an unglycosylated BTN1A1 and prevents its glycosylation or (2) binds to glycosylated BTN1A1 and prevents the physiological effects of the glycosylation, such as the immunosuppressive effect mediated by the glycosylation. For another example, an antibody or antigen binding fragment that immunospecifically masks BTN1A1 glycosylation at N55 and N215 refers to the antibody or antigen binding fragment that either (1) blocks N55 and N215 of an unglycosylated BTN1A1 and prevents the glycosylation of N55 and N215 or (2) binds to BTN1A1 glycosylated at N55 and N215 and prevent the physiological effect of the glycosylation, such as the immunosuppressive effect mediated by the glycosylation.

[0195] As used herein, and unless otherwise specified, the term “vector” refers to a substance that is used to introduce a nucleic acid molecule into a host cell. Vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes and artificial chromosomes, which can include selection sequences or markers operable for stable NAI-1543197688v1 44Attorney Docket No.: 13532-031-228 integration into a host cell’s chromosome. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included, for example, provide resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not in the culture media. Expression control sequences can 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 are to be co-expressed (e.g., both an antibody heavy and light chain), both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors. For single vector expression, the encoding nucleic acids can be operationally linked to one common expression control sequence or linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. The introduction of nucleic acid molecules into a host cell can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA, or immunoblotting for expression of gene products, or other suitable analytical methods to test the expression of an introduced nucleic acid sequence or its corresponding gene product. It is understood by those skilled in the art that the nucleic acid molecule is expressed in a sufficient amount to produce the desired product (e.g., an anti-BTN1A1 antibody provided herein), and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0196] As used herein, and unless otherwise specified, the term “host cell” refers to the particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. 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 succeeding generations or integration of the nucleic acid molecule into the host cell genome.

[0197] As used herein, and unless otherwise specified, the term “cancer” or “cancerous” refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, lung cancer and colorectal cancer.

[0198] As used herein, and unless otherwise specified, the term “treat,” “treating,” “treatment,” when used in reference to a cancer patient, refer to an action that reduces the severity of the cancer, or retards or slows the progression of the cancer, including (a) inhibiting NAI-1543197688v1 45Attorney Docket No.: 13532-031-228 the cancer growth, or arresting development of the cancer, and (b) causing regression of the cancer, or delaying or minimizing one or more symptoms associated with the presence of the cancer.

[0199] As used herein, and unless otherwise specified, the term “resistant” or “refractory” refers to a circumstance where patients, even after intensive treatment, have residual cancer cells (e.g., lung cancer or colorectal cancer cells) in a tissue or an organ (e.g., lung or colon).

[0200] The term “sensitivity” or “sensitive” when made in reference to a cancer treatment is a relative term which refers to the degree of effectiveness of the cancer treatment in lessening or decreasing the progress of a tumor or the cancer being treated. For example, the term “increased sensitivity” or “sensitizing” when used in reference to treatment of a cell or tumor in connection with a compound refers to an increase of, at least about 5%, or more, in the effectiveness of the cancer treatment.

[0201] The term “responsiveness” or “responsive” when used in reference to a treatment refers to the degree of effectiveness of the treatment in lessening or decreasing the symptoms of a disease, e.g., lung cancer or colorectal cancer, being treated. For example, the term “increased responsiveness” when used in reference to a treatment of a cell or a subject refers to an increase in the effectiveness in lessening or decreasing 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) when measured using any methods known in the art. In certain embodiments, the increase in the 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%.

[0202] As used herein, the terms “effective subject response,” “effective patient response,” and “effective patient tumor response” refer to any increase in the therapeutic benefit to the patient. An “effective patient tumor response” can be, for example, about 5%, about 10%, about 25%, about 50%, or about 100% decrease in the rate of progress of the tumor. An “effective patient tumor response” can be, for example, about 5%, about 10%, about 25%, about 50%, or about 100% decrease in the physical symptoms of a cancer. An “effective patient tumor response” can also be, for example, about 5%, about 10%, about 25%, about 50%, about 100%, about 200%, or more increase in the response of the patient, as measured by any suitable means, such as gene expression, cell counts, assay results, tumor size, etc. NAI-1543197688v1 46Attorney Docket No.: 13532-031-228

[0203] An improvement in the cancer or cancer-related disease can be characterized as a complete or partial response. “Complete response” refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. “Partial response” refers to at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions. The term “treatment” contemplates both a complete and a partial response.

[0204] The term “likelihood” generally refers to an increase in the probability of an event. The term “likelihood” when used in reference to the effectiveness of a patient tumor response generally contemplates an increased probability that the rate of tumor progress or tumor cell growth will decrease. The term “likelihood” when used in reference to the effectiveness of a patient tumor response can also generally mean the increase of indicators, such as mRNA or protein expression, that may evidence an increase in the progress in treating the tumor.

[0205] The term “predict” generally means to determine or tell in advance. When used to “predict” the effectiveness of a cancer treatment, for example, the term “predict” can mean that the likelihood of the outcome of the cancer treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially.

[0206] The term “monitor,” as used herein, generally refers to the overseeing, supervision, regulation, watching, tracking, or surveillance of an activity. For example, the term “monitoring the effectiveness of a compound” refers to tracking the effectiveness in treating cancer in a patient or in a tumor cell culture. Similarly, the term “monitoring,” when used in connection with patient compliance, either individually, or in a clinical trial, refers to the tracking or confirming that the patient is actually taking a drug being tested as prescribed. The monitoring can be performed, for example, by following the expression of mRNA or protein biomarkers.

[0207] “Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. “Neoplastic,” as used herein, refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having dysregulated or unregulated cell growth. NAI-1543197688v1 47Attorney Docket No.: 13532-031-228

[0208] As used herein, and unless otherwise specified, the term “therapeutically effective amount” refers to the amount of an agent (e.g., an antibody described herein or any other agent described herein) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto. A therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary for (i) reduction or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the 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 and / or chemotherapy) can vary according to factors such as the disease state, age, sex, and weight of the individual, and 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.

[0209] As used herein, and unless otherwise specified, the term “administer” or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery and / or any other method of physical delivery described herein or known in the art. When a disease, disorder or condition, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of disease, disorder or condition or symptoms thereof. When a disease, disorder or condition, or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease, disorder or condition or symptoms thereof.

[0210] 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 indicating the presence of cancer.

[0211] In some embodiments, a “biomarker” indicates a change in the level of mRNA expression that may correlate with the risk or progression of a disease, or with the susceptibility NAI-1543197688v1 48Attorney Docket No.: 13532-031-228 of the disease to a given treatment. In some embodiments, the biomarker is a nucleic acid, such as mRNA or cDNA (e.g., BTN1A1 mRNA or cDNA).

[0212] In additional 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 patient’s susceptibility to treatment. In some embodiments, the biomarker can be a polypeptide or protein, or a fragment thereof (e.g., BTN1A1 protein). The relative level of specific proteins can be determined by methods known in the art. For example, antibody-based methods, such as an immunoblot, enzyme-linked immunosorbent assay (ELISA), or other methods can be used.

[0213] The term “expressed” or “expression” as used herein refers to the transcription from a gene to give an RNA nucleic acid molecule at least complementary in part to a region of one of the two nucleic acid strands of the gene. The term “expressed” or “expression” as used herein also refers to the translation from the RNA molecule to give a protein, a polypeptide, or a portion thereof.

[0214] The term “level” refers to the amount, accumulation, or rate of a biomarker molecule (e.g., BTN1A1). A level can be represented, for example, by the amount or the rate of synthesis of a messenger RNA (mRNA) encoded by a gene, the amount or the rate of synthesis of a polypeptide or protein encoded by a gene, or the amount or the rate of synthesis of a biological molecule accumulated in a cell or biological fluid. The term "level" refers to an absolute amount of a molecule in a sample or a relative amount of the molecule, determined under steady-state or non-steady-state conditions.

[0215] The terms “determining,” “measuring,” “evaluating,” “assessing,” and “assaying” as used herein generally refer to any form of measurement and include determining whether an element is present or not. These terms include quantitative and / or qualitative determinations. Assessing may 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.

[0216] The term “sample” as used herein relates to a material or mixture of materials, typically, although not necessarily, in fluid form, containing one or more components of interest.

[0217] “Biological sample” as used herein refers to a sample obtained from a biological subject, including a sample of biological tissue or fluid origin, obtained, reached, or collected in vivo or in situ. A biological sample also includes samples from a region of a biological subject containing precancerous or cancer cells or tissues. Such samples can be, but are not limited to, NAI-1543197688v1 49Attorney Docket No.: 13532-031-228 organs, tissues, and cells isolated from a mammal. Exemplary biological samples include but are not limited to cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, a skin sample, and the like. Preferred biological samples include, but are not limited to, whole blood, partially purified blood, PBMC, tissue biopsies, and the like.

[0218] “Polyclonal antibodies” as used herein refer to an antibody population generated in an immunogenic response to a protein having many epitopes and thus includes a variety of different antibodies directed to the same or different epitopes within the protein. Methods for producing polyclonal antibodies are known in the art (See, e.g., Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed.2002)).

[0219] In the context of a peptide or polypeptide, the term “fragment” as used herein refers to a peptide or polypeptide that comprises less than the full-length amino acid sequence. Such a fragment may arise, for example, from a truncation at the amino terminus, a truncation at the carboxy terminus, and / or an internal deletion of a residue(s) from the amino acid sequence. Fragments may, for example, result from alternative RNA splicing or from in vivo protease activity. In certain embodiments, BTN1A1 fragments or anti-BTN1A1 antibody fragments include polypeptides comprising 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 30 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least contiguous 100 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, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, or at least 950 contiguous amino acid residues of the amino acid sequence of a BTN1A1 polypeptide or an anti-BTN1A1 antibody. In a specific embodiment, a fragment of a BTN1A1 polypeptide or an anti-BTN1A1 antibody retains at least 1, at least 2, at least 3, or more functions of the polypeptide or antibody. NAI-1543197688v1 50Attorney Docket No.: 13532-031-228

[0220] An “antigen” is a predetermined antigen to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide.

[0221] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., the CDRs).

[0222] The term “detectable probe” refers to a composition that provides a detectable signal. The term includes, without limitation, any fluorophore, chromophore, radiolabel, enzyme, antibody or antibody fragment, and the like, that provide a detectable signal via its activity.

[0223] The term “detectable agent” refers to a substance that can be used to ascertain the existence or presence of a desired molecule, such as an anti-BTN1A1 antibody as described herein, in a sample or subject. A detectable agent can be a substance that is capable of being visualized or a substance that is otherwise able to be determined and / or measured (e.g., by quantitation).

[0224] The term “diagnostic agent” refers to a substance administered to a subject that aids in the diagnosis of a disease, disorder, or condition. Such substances can be used to reveal, pinpoint, and / or define the localization of a disease-causing process. In certain embodiments, a diagnostic agent includes a substance that is conjugated to an anti-BTN1A1 antibody as described herein, that when administered to a subject or contacted with a sample from a subject aids in the diagnosis of a BTN1A1-mediated disease.

[0225] The term “composition” is intended to encompass a product containing the specified ingredients (e.g., an antibody provided herein) in, optionally, the specified amounts.

[0226] “Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, NAI-1543197688v1 51Attorney Docket No.: 13532-031-228 disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. The term “carrier” can also refer to a diluent, adjuvant (e.g., Freund’s adjuvant (complete or incomplete)), excipient, or vehicle. Such carriers, including pharmaceutical carriers, can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary carrier when a composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable excipients (e.g., pharmaceutical excipients) include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral compositions, including formulations, can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington and Gennaro, Remington’s Pharmaceutical Sciences (18th ed.1990). Compositions, including pharmaceutical compounds, may contain an anti-BTN1A1 antibody, for example, in isolated or purified form, together with a suitable amount of carriers.

[0227] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the Federal or a state government, or listed in United States Pharmacopeia, European Pharmacopeia, or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0228] The term “excipient” refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, NAI-1543197688v1 52Attorney Docket No.: 13532-031-228 maltose, trehalose, etc.), and polyols (e.g., mannitol, sorbitol, etc.). See, also, Remington and Gennaro, Remington’s Pharmaceutical Sciences (18th ed.1990), which is hereby incorporated by reference in its entirety.

[0229] The term “effective amount” as used herein refers to the amount of an antibody or chemotherapy provided herein which is sufficient to result in the desired outcome.

[0230] “Substantially all” refers to at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.

[0231] The phrase “substantially similar” or “substantially the same” denotes a sufficiently high degree of similarity between two numeric values (e.g., one associated with an antibody of the present disclosure and the other associated with a reference antibody) such that one of skill in the art would consider the difference between the two values to be of little or no biological and / or statistical significance within the context of the biological characteristic measured by the values (e.g., KD values). For example, the difference between the two values may be less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, or less than about 5%, as a function of the value for the reference antibody.

[0232] The phrase “substantially increased,” “substantially reduced,” or “substantially different,” as used herein, denotes a sufficiently high degree of difference between two numeric values (e.g., one associated with an antibody of the present disclosure and the other associated with a reference antibody) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by the values. For example, the difference between said two values can be greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or greater than about 50%, as a function of the value for the reference antibody.

[0233] As used herein, the term “source” when used in reference to a reference sample refers to the origin of a sample. For example, a sample that is taken from blood would have a reference sample that is also taken from blood. Similarly, a sample that is taken from bone marrow would have a reference sample that is also taken from the bone marrow.

[0234] The terms “polypeptide” and “protein,” as used interchangeably herein, refer to a polymer of three or more amino acids in a serial array, linked through peptide bonds. The term “polypeptide” includes proteins, protein fragments, protein analogues, oligopeptides, and the NAI-1543197688v1 53Attorney Docket No.: 13532-031-228 like. The term “polypeptide” as used herein can also refer to a peptide. The amino acids making up the polypeptide may be naturally derived or may be synthetic. The polypeptide can be purified from a biological sample. The polypeptide, protein, or peptide also encompasses modified polypeptides, proteins, and peptides, e.g., glycopolypeptides, glycoproteins, or glycopeptides; or lipopolypeptides, lipoproteins, or lipopeptides.

[0235] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0236] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification can mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0237] As used herein, unless otherwise specified or indicated from context, the term “pre- treatment” as used in accordance with the methods described herein refers to prior to administration of a treatment.

[0238] As used herein, the terms “patient” and “subject” refer to an animal, such as a mammal. In certain embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a non-human animal, such as a dog, cat, farm animal (e.g., horse, pig, or donkey), chimpanzee, or monkey. In specific embodiments, the patient or subject is a human with lung cancer (e.g., small cell lung cancer) in need of treatment. 4.3 Antagonistic BTN1A1 Binding Molecules

[0239] In one aspect, provided herein are antagonist BTN1A1 binding molecules. In some embodiments, the BTN1A1 binding molecule includes an antigen binding fragment that immunospecifically binds to BTN1A1. In some embodiments, the molecules having an antigen binding fragment that immunospecifically bind to BTN1A1 can inhibit the binding of the BTN1A1 ligand to BTN1A1. In some embodiments, the molecule can inhibit formation of a BTN1A1 – BTN1A1 ligand complex (e.g., a complex including GAL-1, GAL-9, NRP-2, or BTLA, and BTN1A1). In some embodiments, the molecule can disrupt a formed BTN1A1- BTN1A1 ligand complex (e.g., a complex including GAL-1, GAL-9, NRP-2, or BTLA, and NAI-1543197688v1 54Attorney Docket No.: 13532-031-228 BTN1A1). In some embodiments, the molecule is an anti-BTN1A1 antibody. In some embodiments, the antigen binding fragment that immunospecifically binds BTN1A1 binds to a fragment, or an epitope of BTN1A1. In some embodiments, the antigen binding fragment immunospecifically binds to a BTN1A1 dimer. In some embodiments, the BTN1A1 epitope is found in a BTN1A1 dimer and not found in a BTN1A1 monomer. In some embodiments, the molecules provided herein have an antigen binding fragment that immunospecifically binds to BTN1A1.

[0240] In some embodiments, provided herein is a BTN1A1 binding molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1, whereby the molecule can inhibit binding of a BTN1A1 ligand, such as Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), or B- and T-Lymphocyte Attenuator (BTLA), to BTN1A1. In some embodiments, the molecule can inhibit binding of BTN1A1 to GAL-1. In some embodiments, the molecule can inhibit binding of BTN1A1 to GAL-9. In some embodiments, the molecule can inhibit binding of BTN11A1 to NRP-2. In some embodiments, the molecule can inhibit binding of BTN1A1 to BTLA. In some embodiments, the molecule can inhibit binding of a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2, or BTLA to BTN1A1 completely. In some embodiments, the molecule can inhibit binding of a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2, or BTLA, to BTN1A1 at least partially. In some embodiments, the molecule can inhibit at least 1%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of binding of a BTN1A1 ligand, such as GAL-1, GAL-9, NPR-2, or BTLA to BTN1A1. In some embodiments, binding of BTN1A1 to a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2, or BTLA, or inhibition thereof, is determined using surface plasmon resonance, biolayer interferometry, or co-immunoprecipitation. In some embodiments, the molecule can inhibit binding of a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2, or BTLA, to BTN1A1 with an IC50 value of less than 1 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 9 nM, less than 8 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. In some embodiments, the neutralization assay is a surface NAI-1543197688v1 55Attorney Docket No.: 13532-031-228 plasmon resonance, biolayer interferometry, co-immunoprecipitation, FRET, or TR-FRET assay, or an ELISA.

[0241] In some embodiments, the BTN1A1 binding molecule includes an antigen binding fragment that immunospecifically binds to BTN1A1, whereby the molecule can inhibit binding of two or more BN1A1 ligands, such as GAL-1, GAL-9, NRP-2, or BTLA, to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1 and GAL-9 to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1 and NRP-2 to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1 and BTLA to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-9 and NRP-2 to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-9 and BTLA to BTN1A1. In some embodiments, the molecule can inhibit binding of NRP-2 and BTLA to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1, GAL-9, and NRP-2 to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1, GAL-9, and BTLA to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1, NRP-2, and BTLA to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-9, NRP-2 and BTLA to BTN1A1. In some embodiments, the molecule can inhibit binding of GAL-1, GAL-9, NRP-2, and BTLA to BTN1A1.

[0242] In some embodiments, the BTN1A1 binding molecule includes an antigen-binding domain that binds to the extracellular domain (ECD) of BTN1A1.

[0243] In some embodiments, the BTN1A1 binding molecule can modulate an activity or signaling of BTN1A1 or an activity or signaling of a complex of BTN1A1 and a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2, or BTLA.

[0244] In some embodiments, the BTN1A1 binding molecule can modulate T-cell activity. In some embodiment, the T-cell is a CD8+ cell. In some embodiments, the BTN1A1 binding molecule can increase T-cell activation or T-cell proliferation. In some embodiments, the BTN1A1 binding molecule can inhibit T-cell apoptosis.

[0245] N-glycosylation is a posttranslational 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 first catalyzed by a membrane- associated oligosaccharyl transferase (OST) complex that transfers a preformed glycan composed of oligosaccharides to an asparagine (Asn) side-chain acceptor located within the NAI-1543197688v1 56Attorney Docket No.: 13532-031-228 NXT motif (-Asn-X-Ser / Thr-) (Cheung and Reithmeier, Methods, 41:451-4592007); Helenius and Aebi, Science, 291 (5512):2364-9 (2001). The addition or removal of saccharides from the preformed glycan is mediated by a group of glycotransferases and glycosidases, respectively, which tightly regulate the N-glycosylation cascade in a cell- and location-dependent manner.

[0246] In some embodiments, the BTN1A1 binding molecules have 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 the adjacent peptide. In some embodiments, the antigen binding fragment immunospecifically binds to a peptide sequence that is located near one or more of the glycosylation motifs in three dimensions. In some embodiments, the antigen binding fragment selectively binds one or more glycosylation motifs of a BTN1A1 dimer over the one or more glycosylation’s motifs of a BTN1A1 monomer.

[0247] In some embodiments, the BTN1A1 binding molecules have an antigen binding fragment that binds to glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) with KD less than at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the KD exhibited relative to unglycosylated BTN1A1. In certain embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDless than 50% of the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDthat is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD at least 10 times less than the KD exhibited relative to unglycosylated BTN1A1.

[0248] In some embodiments, the specific glycosylation sites of a particular BTN1A1 isoform or variant can vary from amino acids at position 55, 215, or 449 of that particular BTN1A1 isoform or variant. In those circumstances, a person of ordinary skill in the art would be able to determine the glycosylation sites of any particular BTN1A1 isoform or variant that correspond to N55, N215, and N449 of the human BTN1A1 exemplified above based on sequence alignment and other common knowledge in the art. As such, provided herein are also molecules having an antigen binding fragment that immunospecifically binds to a glycosylated form of a BTN1A1 isoform or variant relative to the unglycosylated BTN1A1 isoform or variant. NAI-1543197688v1 57Attorney Docket No.: 13532-031-228 The glycosylated sites of a BTN1A1 isoform or variant can be the corresponding sites of N55, N215, and N449 of human BTN1A1 sequence as provided above.

[0249] In some embodiments, the BTN1A1 binding molecules have 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 glycosylated at positions N55, N215, and / or N449. In some embodiments, the antigen binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55. In some embodiments, the antigen binding fragment immunospecifically binds to BTN1A1 glycosylated at position N215. In some embodiments, the antigen binding fragment immunospecifically binds to BTN1A1 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 glycosylated at positions N55 and N215. In some embodiments, the antigen binding fragments immunospecifically binds to BTN1A1 glycosylated at positions N215 and N449. In some embodiments, the antigen binding fragments immunospecifically binds to BTN1A1 glycosylated at positions N55 and N449. In some embodiments, the antigen binding fragments immunospecifically binds to BTN1A1 glycosylated at positions N55, N215 and N449.

[0250] In some embodiments, the BTN1A1 binding molecules have an antigen binding fragment that immunospecifically binds to glycosylated BTN1A1, whereby the antigen binding fragment preferentially binds glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to BTN1A1 glycosylated at positions N55, N215, and / or N449 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to BTN1A1 glycosylated at position N55 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to BTN1A1 glycosylated at position N215 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to BTN1A1 glycosylated at position N449 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to one or more glycosylation motifs. In some embodiments, the antigen binding fragments preferentially binds BTN1A1 glycosylated at positions N55 and N215 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to BTN1A1 glycosylated at positions N215 and NAI-1543197688v1 58Attorney Docket No.: 13532-031-228 N449 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially bind to BTN1A1 glycosylated at positions N55 and N449 over non-glycosylated BTN1A1. In some embodiments, the antigen binding fragments preferentially binds BTN1A1 glycosylated at positions N55, N215 and N449 over non-glycosylated BTN1A1.

[0251] In some embodiments, the preferential binding can be determined by binding affinity. For example, a BTN1A1 binding molecule comprising an antigen binding fragment that preferentially binds to the glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) can bind to glycosylated BTN1A1 with a KD less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDless than half of the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD at least 2 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDat least 5 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD at least 10 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDat least 15 times less than the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDat least 20 times less than the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD at least 25 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDat least 30 times less than the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD at least 40 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD at least 50 times less than the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDthat is about 75% of the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 50% of the KD exhibited relative to unglycosylated BTN1A1. In some NAI-1543197688v1 59Attorney Docket No.: 13532-031-228 embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 25% of the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDthat is about 10% of the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 5% of the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KDthat is about 2.5% of the KDexhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 1% of the KDexhibited relative to unglycosylated BTN1A1.

[0252] In some embodiments, the preferential binding can also be determined by in a binding assay as indicated by, for example, fluorescence intensity (“MFI”). For example, an BTN1A1 binding molecule containing an antigen binding fragment that preferentially binds to the glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer) can bind to glycosylated BTN1A1 with an MFI that is higher than the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least twice as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least two times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least three times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least five times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least ten times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least fifteen times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least twenty times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least twenty-five times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 NAI-1543197688v1 60Attorney Docket No.: 13532-031-228 with an MFI that is at least thirty times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least forty times as high as the MFI as exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with an MFI that is at least fifty times as high as the MFI as exhibited relative to unglycosylated BTN1A1.

[0253] In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation (e.g., in a glycosylated BTN1A1 dimer) at positions N55, N215, and / or N449. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at position N55. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at position N215. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at position N449. In some embodiments, the antigen binding fragments immunospecifically mask one or more glycosylation motifs of BTN1A1. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at positions N55 and N215. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at positions N215 and N449. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at positions N55 and N449. In some embodiments, the antigen binding fragments immunospecifically mask BTN1A1 glycosylation at positions N55, N215 and N449.

[0254] In some embodiments, the BTN1A1 binding molecules have an antigen binding fragment that selectively binds to a BTN1A1 dimer over a BTN1A1 monomer. In some embodiments, the BTN1A1 dimer is expressed at the surface of a cell. In some embodiments, the BTN1A1 dimer is a soluble protein fragment of BTN1A1, e.g., an extracellular domain construct of BTN1A1, such as an Fc-fusion protein construct (e.g., BTN1A1-ECD-Fc). In some embodiments, the BTN1A1 monomer is an extracellular domain construct of BTN1A1, such as a Flag-tagged or a His6-tagged BTN1A1-ECD construct. In some embodiments, the molecules selectively binding to a BTN1A1 dimer are molecules provided herein that selectively bind to glycosylated BTN1A1. In some embodiments, preferential binding to a BTN1A1 dimer over a BTN1A1 monomer is determined by determining preferential binding to a BTN1A1-ECD-Fc NAI-1543197688v1 61Attorney Docket No.: 13532-031-228 construct over a BTN1A1-ECD-His6 or a BTN1A1-ECD-Flag construct, e.g., using a surface plasmon resonance assay (e.g., BIAcore).

[0255] In some embodiments, the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with KD less than at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the KD exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In certain embodiments, the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with KDless than 50% of the KDexhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with KDthat is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of the KDexhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). In some embodiments, the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with KDat least 10 times less than the KDexhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer)

[0256] In some embodiments, the BTN1A1 binding molecule provided herein is a molecule, including an antibody or antigen binding fragment thereof, as described in International Patent Application No. PCT / US2016 / 064436 (published as WO2017 / 096051 on June 8, 2017), in International Patent Application No.: PCT / US2018 / 035090 (published as WO2018 / 222689 on December 6, 2018) or in International Patent Application No.: PCT / US2018 / 035082 (published as WO2018 / 222685 on December 6, 2018), the content of each which is incorporated herein by reference in its entireties. In specific embodiments, the BTN1A1 binding molecule provided herein comprises an antigen binding fragment (e.g., a VH, VL, and / or CDR sequences) of the anti-BTN1A1 antibodies STC703, STC810, STC820, STC1011, STC1012, or STC1029, or a humanized variant thereof, as described in WO2017 / 096051, WO2018 / 222689, or WO2018 / 222685. In specific embodiments, the BTN1A1 binding molecule provided herein comprises an antigen-binding fragment (e.g., a VH, VL, and / or CDR sequences) of the anti- BTN1A1 antibody STC810 as described in WO2017 / 096051.

[0257] In some embodiments, the BTN1A1 binding molecule comprises an antigen binding fragment that binds to BTN1A1. In some embodiments, the antigen binding fragment, described herein comprise a VH region, VL region, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of the BTN1A1 binding region, such as an amino acid sequence of a NAI-1543197688v1 62Attorney Docket No.: 13532-031-228 VH region, VL region, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 depicted in the Sequence Tables 1A to 1C and 2A to 2C. Accordingly, in some embodiments, an antigen binding fragment described herein comprises any one, any two, and / or all three heavy chain CDRs and / or any one, any two, and / or all three light chain CDRs from the BTN1A1 binding molecules as shown in the Sequence Tables 1A to 1C and 2A to 2C. In some embodiments, an antigen binding fragment described herein comprises any one, any two, and / or all three heavy chain CDRs and any one, any two, and / or all three light chain CDRs from BTN1A1 binding molecules as shown in the Sequence Tables 1A to 1C and 2A to 2C. In some embodiments, the antigen binding fragment provided herein inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

[0258] In some embodiments, an antigen binding fragment comprises a VH region, which comprises a VH CDR1, a VH CDR2, and / or a VH CDR3, and / or a VL region, which comprises a VL CDR1, a VL CDR2, and / or a VL CDR3, of any one of the binding molecules described herein (see, e.g., the Sequence Tables 1A to 1C and 2A to 2C). Accordingly, in some embodiments, an antigen binding fragment described herein comprises any one, any two, and / or all three heavy chain CDRs and / or any one, any two, and / or all three light chain CDRs from the Sequence Table 1A or 2A.

[0259] In some embodiments, the antigen binding fragment provided herein comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:31 and / or (ii) a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the antigen binding fragment comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:35 and / or (ii) a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:36. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to Chothia numbering. In some embodiments, the CDRs are according to AbM numbering. In some embodiments, the CDRs are according to Kabat numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDR sequences are determined according to a combination of any two or more of the above-mentioned numbering systems, for example, a NAI-1543197688v1 63Attorney Docket No.: 13532-031-228 combination of Kabat and Chothia. Various exemplary CDR numbering systems are described and illustrated above in Section 4.2 (Definitions).

[0260] In some embodiments, the antigen binding fragment provided herein comprises (a) a VH region comprising: (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 21, 23, and 25; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:16, 22, 24, and 26; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs:17 and 27; and / or (b) a VL region comprising: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs:18 and 28; (2) VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs:19 and 29; and (3) a VL CDR3 having an amino acid sequences selected from the group consisting of SEQ ID NO:20, and 30.

[0261] In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:16, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:17. In some embodiments, the antigen binding fragment provided herein comprises a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:17; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:20.

[0262] In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:22, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:17. In some embodiments, the antigen binding fragment comprises a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, the antigen NAI-1543197688v1 64Attorney Docket No.: 13532-031-228 binding fragment comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:22, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:27; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:20.

[0263] In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:24, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:17. In some embodiments, the antigen binding fragment comprises a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:20. In some embodiments, the antigen binding fragment comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:24, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:17; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:20

[0264] In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:27. In some embodiments, the antigen binding fragment comprises a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:30. In some embodiments, antigen binding fragment comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:26, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:27; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:28, a VL CDR2 comprising the NAI-1543197688v1 65Attorney Docket No.: 13532-031-228 amino acid sequence of SEQ ID NO:29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:30.

[0265] In some embodiments, the antigen binding fragment provided herein comprises (i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:59 and / or (ii) a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:60. CDR sequences can be determined according to well-known numbering systems or a combination thereof. In some embodiments, the CDRs are according to Kabat numbering described in Section 4.2 (Definitions).

[0266] In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:37, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:38, and a VH CDR3 comprising the amino acid sequence of SEQ ID NO:39. In some embodiments, the antigen binding fragment comprises a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:40, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:41, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, antigen binding fragment comprises a VH region comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:37, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:38, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:39; and a VL region comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:40, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:41, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:42.

[0267] In some embodiments, the antigen binding fragment provided herein further comprises one or more framework regions of SEQ ID NOs:31, 32, 35, 36, 43, 44, 59, and 60. In some embodiments, the antigen binding fragment further comprises a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence as set forth in any one of SEQ ID NOs: 31, 32, 35, 36, 43, 44, 59 and 60. In some embodiments, the antigen binding fragment provided herein is derived from a humanized antibody. Framework regions described herein are determined based upon the boundaries of the CDR numbering system as described in Section 4.2 (Definitions) above. NAI-1543197688v1 66Attorney Docket No.: 13532-031-228

[0268] In some embodiments, the antigen binding fragment provided herein comprises a VH region comprising: (1) a VH FR1 having the amino acid sequence of SEQ ID NO:48; (2) a VH FR2 having the amino acid sequence of SEQ ID NO:49; (3) a VH FR3 having the amino acid sequence of SEQ ID NO:50; and (4) a VH FR4 having the amino acid sequence of SEQ ID NO:51. In some embodiments, the antigen binding fragment provided herein comprises a VL region comprising: (1) a VL FR1 having the amino acid sequence of SEQ ID NO:54, (2) a VL FR2 having the amino acid sequence of SEQ ID NO:55, (3) a VL FR3 having the amino acid sequence of SEQ ID NO:56, and (4) a VL FR4 having the amino acid sequence of SEQ ID NO:57.

[0269] In some embodiments, the antigen binding fragment provided herein comprises (a) a VH region comprising: (1) a VH FR1 having the amino acid sequence of SEQ ID NO:48; (2) a VH FR2 having the amino acid sequence of SEQ ID NO:49; (3) a VH FR3 having the amino acid sequence of SEQ ID NO:50; and (4) a VH FR4 having the amino acid sequence of SEQ ID NO:51, and (b) a VL region comprising: (1) a VL FR1 having the amino acid sequence of SEQ ID NO:54, (2) a VL FR2 having the amino acid sequence of SEQ ID NO:55, (3) a VL FR3 having the amino acid sequence of SEQ ID NO:56, and (4) a VL FR4 having the amino acid sequence of SEQ ID NO:57.

[0270] In some embodiments, the antigen binding fragment provided herein comprises a VH region or VH domain. In some embodiments, the antigen binding fragment provided herein comprises a VL region or VL domain. In some embodiments, the antigen binding fragment provided herein has a combination of (i) a VH domain or VH region; and (ii) a VL domain or VL region.

[0271] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:31. In some embodiments, the antigen binding fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:31 and a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the antigen binding fragment provided herein comprises a VH consisting of the amino acid sequence of SEQ ID NO:31 and a VL consisting of the amino acid sequence of SEQ ID NO:32. NAI-1543197688v1 67Attorney Docket No.: 13532-031-228

[0272] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35. In some embodiments, the antigen binding fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35 and a VL comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the antigen binding fragment provided herein comprises a VH consisting of the amino acid sequence of SEQ ID NO:35 and a VL consisting of the amino acid sequence of SEQ ID NO:36.

[0273] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:31. In some embodiments, the antigen binding fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:31 and a VL comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the antigen binding fragment provided herein comprises a VH consisting of the amino acid sequence of SEQ ID NO:31 and a VL consisting of the amino acid sequence of SEQ ID NO:36.

[0274] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35. In some embodiments, the antigen binding fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35 and a VL comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the antigen binding fragment provided herein comprises a VH consisting of the amino acid sequence of SEQ ID NO:35 and a VL consisting of the amino acid sequence of SEQ ID NO:32.

[0275] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:59. In some embodiments, the antigen binding fragment provided herein comprises a VL comprising the amino acid sequence of SEQ ID NO:60. In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:59 and a VL comprising the amino acid sequence of SEQ ID NO:60. In some embodiments, the antigen binding fragment provided NAI-1543197688v1 68Attorney Docket No.: 13532-031-228 herein comprises a VH consisting of the amino acid sequence of SEQ ID NO:59 and a VL consisting of the amino acid sequence of SEQ ID NO:60.

[0276] In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain constant region. In some embodiments, the BTN1A1 binding molecule provided herein comprises a light chain constant region. In some embodiments, the BTN1A1 binding molecule has a combination of (i) a heavy chain constant region and (ii) a light chain constant region.

[0277] In some embodiments, the BTN1A1 binding molecule comprises a heavy chain. In some embodiments, the BTN1A1 binding molecule comprises a light chain. In some embodiments, the BTN1A1 binding molecule has a combination of (i) a heavy chain, and (ii) a light chain. In some embodiments, the BTN1A1 binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:33. In some embodiments, the BTN1A1 binding molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, the BTN1A1 binding molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:33, and a light chain comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, the BTN1A1 binding molecule comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:33, and a light chain consisting of the amino acid sequence of SEQ ID NO:34.

[0278] In some embodiments, the antigen binding fragment provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:43. In some embodiments, the antigen binding fragment provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:44. In some embodiments, the antigen binding fragment provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:43 and a light chain comprising the amino acid sequence of SEQ ID NO:44. In some embodiments, the antigen binding fragment provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:43 and a light chain consisting of the amino acid sequence of SEQ ID NO:44.

[0279] In some embodiments, the antigen binding fragment provided herein comprises amino acid sequences with certain percent identity (such as at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or as at NAI-1543197688v1 69Attorney Docket No.: 13532-031-228 least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or higher) relative to any antibody or fragment thereof provided herein, for example, a CDR, VH ,VL, or a full-length antibody heavy or light chain in the Sequence Tables 1A to 1C and 2A to 2C. In some embodiments, the antigen binding fragment provided herein comprises CDRs of any antibody or fragment thereof provided herein, for example in the Sequence Tables 1A and 2A. In further embodiments, the antigen binding fragment provided herein comprises amino acid sequences with certain percent identity (such as at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or as at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or higher) relative to any antibody or fragment thereof provided herein, for example, a VH, VL, or a full-length antibody heavy or light chain in the Tables 1A to 1C and 2A to 2C. The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using methods known in the art.

[0280] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, Proc. Natl. Acad. Sci. U.S.A.87:22642268 (1990), modified as in Karlin and Altschul, Proc. Natl. Acad. Sci. U.S.A.90:58735877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., J. Mol. Biol.215:403 (1990). BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, word length=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, word length=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res.25:33893402 (1997). In some embodiments, the percent identity between two sequences is calculated by dividing the number of residue(s) varied NAI-1543197688v1 70Attorney Docket No.: 13532-031-228 (excluding or including conservative amino acid substitution(s) or degenerate nucleotide substitution(s)) between the two sequences in the alignment with the residue number of any one of the following: (i) full length of the shorter sequence, (ii) full length of the longer sequence, (iii) mean length of the two sequences, (iv) total length of the non-gap portion of the alignment, (v) length of the alignment excluding overhangs, or (vi) length of the alignment including overhangs. Overhangs as used herein with respect to a sequence alignment refer to either or both ends of the alignment where residues of one sequence are considered as aligning to no residues (e.g., gap) in the other sequence. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS 4:11-17 (1998). Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0281] In some embodiments, the antigen binding fragment provided herein contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the molecule comprising that sequence retains the ability to bind to BTN1A1. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in a reference amino acid sequence. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (e.g., in the FRs, constant regions, and / or Fc regions).

[0282] In some embodiments, the position of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) region of a BTN1A1 binding domain described herein may vary by one, two, three, four, five, or six amino acid positions so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). For example, in some embodiments, the position defining a CDR of the Sequence Tables 1A NAI-1543197688v1 71Attorney Docket No.: 13532-031-228 and 2A may vary by shifting the N-terminal and / or C-terminal boundary of the CDR by one, two, three, four, five, or six amino acids, relative to the current CDR position, so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Additionally or alternatively, in some embodiments, the length of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) region of a BTN1A1 binding domain described herein may vary (e.g., be shorter or longer) by one, two, three, four, five, or more amino acids, so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). For example, in some embodiments, a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be one, two, three, four, five or more amino acids shorter than one or more of the CDRs described by SEQ ID NOS:15 to 30 or SEQ ID NOS:37 to 42, so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In other embodiments, a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be one, two, three, four, five or more amino acids longer than one or more of the CDRs described by SEQ ID NOS:15 to 30 or SEQ ID NOS:37 to 42, so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In some embodiments, the amino terminus of a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be extended or shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS:15 to 30 or SEQ ID NOS:37 to 42, so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Additionally or alternatively, in some embodiments, the carboxy terminus of a VH and / or VL CDR1, CDR2, and / or CDR3 described herein may be extended or shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS:15 to 30 or SEQ ID NOS:37 to 42, so long as binding to BTN1A1 (e.g., human BTN1A1) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Any method known in the art can be used to ascertain NAI-1543197688v1 72Attorney Docket No.: 13532-031-228 whether binding to BTN1A1 (e.g., human BTN1A1) is maintained, for example, the binding assays and conditions described in the “Examples” section described herein.

[0283] In other embodiments, the BTN1A1 binding molecule provided herein further comprise conservative sequence modifications in the antigen binding fragment. Conservative sequence modifications are described in more detail in Section 4.2 (Definition) above. In some embodiments, the conservative sequence modifications described herein modify the amino acid sequences of the BTN1A1 binding molecule by 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 98%, or 99%. In some embodiments, the amino acid sequence modifications refer to at most 1, 2, 3, 4, 5, or 6 amino acid substitutions to the CDRs, such as those described in the Sequence Tables 1A and 2A. Thus, for example, each such CDR may contain up to 5 conservative amino acid substitutions, for example up to (not more than) 4 conservative amino acid substitutions, for example up to (not more than) 3 conservative amino acid substitutions, for example up to (not more than) 2 conservative amino acid substitutions, or no more than 1 conservative amino acid substitution. In some embodiments, the BTN1A1 binding molecule contains one or more, including six, CDRs having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the CDRs of the BTN1A1 binding molecule designated as STC810 (see, e.g., Sequence Table 1A). In some embodiments, the BTN1A1 binding molecule contains one or more, including six, CDRs having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the CDRs of the BTN1A1 binding molecule designated as STC109 (see, e.g., Sequence Table 2A).

[0284] In some embodiments, a BTN1A1 binding molecule contains a VH and a VL comprising CDRs identical to those of the BTN1A1 binding molecule designated as hSTC810 (see, e.g., Sequence Tables 1A and 1B). In some embodiments, the amino acid sequence modifications do not include any modification within an CDR. In some embodiments, the amino acid sequence modifications do not include any modification within a CDR (such as CDR1, CDR2, CDR3, or any combination thereof). In further embodiments, the amino acid sequence modifications are in the framework, constant region, and / or Fc region.

[0285] In some embodiments, the antigen binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:31, and / or a VL domain having at NAI-1543197688v1 73Attorney Docket No.: 13532-031-228 least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:32, and the binding of the binding agent to BTN1A1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0286] In one embodiment, the BTN1A1 binding molecule provided herein comprises a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:31. In some embodiments, the BTN1A1 binding molecule provided herein comprises a VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:32. In one embodiment, the BTN1A1 binding molecule provided herein comprises (i) a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:31; and (ii) VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:32.

[0287] In some embodiments, the antigen binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:35, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:36, and the binding of the binding agent to BTN1A1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0288] In one embodiment, the BTN1A1 binding molecule provided herein comprises a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:35. In some embodiments, the BTN1A1 binding molecule provided herein comprises a VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:36. In one embodiment, the BTN1A1 binding molecule provided herein comprises (i) a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:35; and (ii) VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:36. NAI-1543197688v1 74Attorney Docket No.: 13532-031-228

[0289] In one embodiment, the BTN1A1 binding molecule provided herein comprises (i) a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:31; and (ii) VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:36. In one embodiment, the BTN1A1 binding molecule provided herein comprises (i) a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:35; and (ii) VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:32.

[0290] In some embodiments, the antigen binding fragment provided herein comprises a heavy chain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:33, and / or a light chain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:34, and the binding of the binding agent to BTN1A1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0291] In one embodiment, the BTN1A1 binding molecule provided herein comprises a heavy chain having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:33. In some embodiments, the BTN1A1 binding molecule provided herein comprises a light chain having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:34. In one embodiment, the BTN1A1 binding molecule provided herein comprises (i) a heavy chain having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:33; and (ii) a light chain having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:34.

[0292] In some embodiments, the BTN1A1 binding molecule is hSTC810 having the full heavy chain and light chain sequences as shown in the Sequence Table 1B. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:33. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:33. In some embodiments, the BTN1A1 binding molecule provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:34. In some NAI-1543197688v1 75Attorney Docket No.: 13532-031-228 embodiments, the BTN1A1 binding molecule provided herein comprises a light chain consisting of the amino acid sequence of SEQ ID NO:34. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:33, and a light chain comprising the amino acid sequence of SEQ ID NO:34. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:33, and a light chain consisting of the amino acid sequence of SEQ ID NO:34.

[0293] In some embodiments, a BTN1A1 binding molecule contains a VH and a VL comprising CDRs identical to those of the BTN1A1 binding molecule designated as STC109 (see, e.g., Sequence Tables 2A to 2C). In some embodiments, the amino acid sequence modifications do not include any modification within an CDR. In some embodiments, the amino acid sequence modifications do not include any modification within a CDR (such as CDR1, CDR2, CDR3, or any combination thereof). In further embodiments, the amino acid sequence modifications are in the framework, constant region, and / or Fc region.

[0294] In some embodiments, , the BTN1A1 binding molecule provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:59, and / or a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:60, and the binding of the binding agent to BTN1A1 is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).

[0295] In some embodiments, the BTN1A1 binding molecule provided herein comprises a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:59. In some embodiments, the BTN1A1 binding molecule provided herein comprises a VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:60. In some embodiments, the BTN1A1 binding molecule provided herein comprises (i) a VH having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:59, and (ii) a VL having an amino acid sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:60. NAI-1543197688v1 76Attorney Docket No.: 13532-031-228

[0296] In some embodiments, the BTN1A1 binding molecule is STC109 having a heavy chain and a light chain comprising the heavy chain and light chains sequences, respectively, as shown in Sequence Table 2C. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:43. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:43. In some embodiments, the BTN1A1 binding molecule provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:44. In some embodiments, the BTN1A1 binding molecule provided herein comprises a light chain consisting of the amino acid sequence of SEQ ID NO:44. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:43, and a light chain comprising the amino acid sequence of SEQ ID NO:44. In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:43, and a light chain consisting of the amino acid sequence of SEQ ID NO:44.

[0297] In some embodiments, the molecules provided herein having an antigen binding fragment that immunospecifically binds to BTN1A1 can be anti-BTN1A1 antibodies. Antibodies provided herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bi-specific antibodies), human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments of any of the above. Non-limiting examples of functional fragments include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab’) fragments, F(ab)2fragments, F(ab’)2fragments, disulfide-linked Fvs (sdFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody and minibody.

[0298] In particular, molecules provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, e.g., molecules that contain an antigen binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1. The immunoglobulin molecules provided herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. NAI-1543197688v1 77Attorney Docket No.: 13532-031-228

[0299] The molecules provided herein can be monospecific, bispecific, trispecific antibodies or antibodies of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a BTN1A1 as described here or can be specific for both a BTN1A1 polypeptide as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. In specific embodiments, the antibodies provided herein are monospecific for a given epitope of a BTN1A1 polypeptide and do not bind to other epitopes. NAI-1543197688v1 78Attorney Docket No.: 13532-031-228 Sequence Tables Table 1A: BTN1A1 Antibody (STC810 / hSTC810) CDR Sequences Chothia AbM Kabat Contact H v Ch in ) T ) Y ) ) ) )NAI-1543197688v1 79Attorney Docket No.: 13532-031-228 Table 1B: Humanized anti-BTN1A1 Antibody (hSTC810) VH, VL, Heavy Chain, and Light Chain Sequences VH (SEQ ID NO:31) G F P G F A G P P P SNAI-1543197688v1 80Attorney Docket No.: 13532-031-228 Table 1C: Mouse anti-human BTN1A1 Antibody (STC810) VH and VL Sequences VH (SEQ ID NO:35) EVQLQQSGPELVKPGASVKISCKASGYTFTHYNMDWVKQSHGKSLEWIGYIYPSNGG D PNAI-1543197688v1 81Attorney Docket No.: 13532-031-228 Table 2A: BTN1A1 Antibody (STC109) CDR Sequences Kabat Heavy Chain DFAMANAI-1543197688v1 82Attorney Docket No.: 13532-031-228 Table 2B: Mouse anti-BTN1A1 Antibody (STC109) VH and VL Amino Acid Sequences VH (SEQ ID NO:59) N PNAI-1543197688v1 83Attorney Docket No.: 13532-031-228 Table 2C: Mouse anti-BTN1A1 Antibody (STC109) Heavy Chain and Light Chain Amino Acid Sequences Heavy Chain (SEQ ID NO:43) TF L TNAI-1543197688v1 84Attorney Docket No.: 13532-031-228 Table 2D: STC109 VH Leader, Framework, and Tail Sequences Sequence Region Sequence Fragment Residues Length IDNAI-1543197688v1 85Attorney Docket No.: 13532-031-228 Table 2E: STC109 VL Leader, Framework, and Tail Sequences Sequence Region Sequence Fragment Residues Length IDNAI-1543197688v1 86Attorney Docket No.: 13532-031-228 4.4 Methods for Sensitizing Responsiveness of Cancer Cells

[0300] In one aspect, provided herein are methods for sensitizing responsiveness of cancer cells to an anti-cancer treatment. In some embodiments, provided herein is a method for sensitizing a response of cancer cells to an anti-cancer treatment, wherein the method comprises contacting the cancer cells with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein. In some embodiments, the contacting is performed by administering the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein to the cancer cells. In other embodiments, the contacting is performed by administering the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein to a subject having the cancer.

[0301] In some embodiments, provided herein is a method for preparing a subject suffering from cancer for an anti-cancer treatment, wherein the method comprises administering a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein. In some embodiments, the anti- cancer therapy is selected from a chemotherapy and a radiation therapy. In some embodiments, the molecule is a BTN1A1 antagonist. In some embodiments, the molecule inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

[0302] In some embodiments, provided herein is a method of removing slow-reproduction cancer cells in a subject, wherein the method comprises administering to the subject a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein. In some embodiments, the anti-cancer therapy is selected from a chemotherapy and a radiation therapy. In some embodiments, the molecule is a BTN1A1 antagonist. In some embodiments, the molecule inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

[0303] In some embodiments, the cancer has been previously subjected to an anti-cancer treatment. In some embodiments, the cancer has developed resistance to such treatment. In some embodiments, the cancer’s responsiveness to the treatment has decreased or ceased. In some NAI-1543197688v1 87Attorney Docket No.: 13532-031-228 embodiments, the cancer is relapsed following a previous cycle of the anti-cancer treatment. In some embodiments, after the cancer is treated with a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein, the cancer regains or increases responsiveness to the anti-cancer treatment. In some embodiments, the previous anti- cancer treatment is a chemotherapy. In some embodiments, the previous anti-cancer treatment is a radiation therapy.

[0304] In some embodiments, the cancer to be treated with the present method expresses BTN1A1. In some embodiments, the cancer to be treated with the present method expresses one or more BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

[0305] In some embodiments, the method for sensitizing responsiveness of cancer cells to an anti-cancer treatment is performed by contacting the cancer cells with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein in the presence of a population of immune effector cells. In some embodiments, the immune effector cells are T lymphocytes. In some embodiments, the T lymphocytes are CD8+ cells. In some embodiments, the CD8+ cells are T cells. In some embodiments, the CD8+ cells are cytotoxic T cells. In some embodiments, T lymphocytes are infiltrating lymphocytes in a tumor environment. In some embodiments, the T lymphocytes are CD4+ cells. In some embodiments, the CD4+ cells are T cells. In some embodiments, the CD4+ cells are helper T cells. In some embodiments, the cancer cells lack expression of BTN1A1 and the immune effector cells express BTN1A1. In some embodiments, expression of BTN1A1 in the cancer cells is below a BTN1A1 reference level, and expression of BTN1A1 in the immune effector cells are equal to or above a BTN1A1 reference level. In some embodiments, the immune effector cells lack expression of PD-L1. In some embodiments, expression of PD-L1 in the immune effector cells are below a PD-L1 reference level. In some embodiments, the immune effector cells express BTN1A1 and lack expression of PD-L1. In some embodiments, expression of BTN1A1 in the immune effector cells are above a BTN1A1 reference level, and expression of PD-L1 in the immune effector cells are below a PD-L1 reference level. In some embodiments, expression of BTN1A1 in the cancer is equal to or above a BTN1A1 reference level. In some embodiments, the BTN1A1 reference level is the average or medium expression level of BTN1A1 in a population of healthy individuals. In some embodiments, the PD-L1 NAI-1543197688v1 88Attorney Docket No.: 13532-031-228 reference level is the average or medium expression level of PD-L1 in the population of healthy individuals.

[0306] In some embodiments, in a cancer sample (e.g., a cancer sample taken from a cancer patient), BTN1A1 is expressed on at least about 5% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 10% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 15% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 20% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 25% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 30% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 35% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 40% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 45% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 50% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 55% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 60% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 65% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 70% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 75% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 80% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 85% of the cancer cells. In some embodiments, BTN1A1 is expressed on at least about 90% of the cancer cells. In some embodiments, BTN1A1 is expressed on about 100% of the cancer cells.

[0307] In some embodiments, BTN1A1 is expressed on at least about 60% of cancer cells in a cancer sample taken from the subject. In some embodiments, the cancer sample is a tumor sample.

[0308] In some embodiments, in a cancer sample (e.g., a cancer sample taken from a cancer patient), a percentage of cancer cells are Ki-67 negative (Ki-67-.). In some embodiments, at least about 5% of the cancer cells are Ki-67 negative. In some embodiments, at least about 10% of the cancer cells are Ki-67 negative. In some embodiments, at least about 15% of the cancer cells are Ki-67 negative. In some embodiments, at least about 20% of the cancer cells are Ki-67 negative. In some embodiments, at least about 25% of the cancer cells are Ki-67 negative. In some embodiments, at least about 30% of the cancer cells are Ki-67 negative. In some embodiments, at NAI-1543197688v1 89Attorney Docket No.: 13532-031-228 least about 35% of the cancer cells are Ki-67 negative. In some embodiments, at least about 40% of the cancer cells are Ki-67 negative. In some embodiments, at least about 45% of the cancer cells are Ki-67 negative. In some embodiments, at least about 50% of the cancer cells are Ki-67 negative. In some embodiments, at least about 55% of the cancer cells are Ki-67 negative. In some embodiments, at least about 60% of the cancer cells are Ki-67 negative. In some embodiments, at least about 65% of the cancer cells are Ki-67 negative. In some embodiments, at least about 70% of the cancer cells are Ki-67 negative. In some embodiments, at least about 75% of the cancer cells are Ki-67 negative. In some embodiments, at least about 80% of the cancer cells are Ki-67 negative. In some embodiments, at least about 85% of the cancer cells are Ki-67 negative. In some embodiments, at least about 90% of the cancer cells are Ki-67 negative. In some embodiments, at least about 95% of the cancer cells are Ki-67 negative. In some embodiments, about 100% of the cancer cells are Ki-67 negative.

[0309] In some embodiments, at least about 50% of the cancer cells in the cancer sample are Ki-67 negative. In specific embodiments, the cancer sample is a tumor sample.

[0310] In some embodiments, in a cancer sample (e.g., a cancer sample taken from a cancer patient), a percentage of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 5% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 10% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 15% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 20% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 25% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 30% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 35% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 40% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 45% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 50% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 55% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 60% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 65% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 70% of the cancer cells express BTN1A1 and are Ki-67 NAI-1543197688v1 90Attorney Docket No.: 13532-031-228 negative. In some embodiments, at least about 75% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 80% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 85% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 90% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, at least about 95% of the cancer cells express BTN1A1 and are Ki-67 negative. In some embodiments, about 100% of the cancer cells express BTN1A1 and are Ki-67 negative.

[0311] In some embodiments, at least about 70% of cancer cells in the cancer sample taken from a subject express BTN1A1 and are Ki-67-. In some embodiments, the cancer sample is a tumor sample.

[0312] In some embodiments, in a cancer sample (e.g., a cancer sample taken from a cancer patient), PD-L1 is not expressed on the cancer cells. In some embodiments, PD-L1 is expressed on less than about 5% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 10% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 15% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 20% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 25% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 30% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 40% of the cancer cells. In some embodiments, PD-L1 is expressed on less than about 50% of the cancer cells.

[0313] In specific embodiments, PD-L1 is expressed on less than about 20% of the cancer cells in a cancer sample taken from the subject. In specific embodiments, the cancer sample is a tumor sample.

[0314] In some embodiments, in a cancer sample (e.g., a cancer sample taken from a cancer patient), a percentage of cancer cells in a sample taken from a patient or subject are slow reproduction cells. In some embodiments, doubling time of the cancer cells is longer than about 30 hours. In some embodiments, doubling time of the cancer cells is longer than about 31 hours. In some embodiments, doubling time of the cancer cells is longer than about 32 hours. In some embodiments, doubling time of the cancer cells is longer than about 33 hours. In some embodiments, doubling time of the cancer cells is longer than about 34 hours. In some embodiments, doubling time of the cancer cells is longer than about 35 hours. In some embodiments, doubling time of the cancer cells is longer than about 36 hours. In some NAI-1543197688v1 91Attorney Docket No.: 13532-031-228 embodiments, doubling time of the cancer cells is longer than about 37 hours. In some embodiments, doubling time of the cancer cells is longer than about 38 hours. In some embodiments, doubling time of the cancer cells is longer than about 39 hours. In some embodiments, doubling time of the cancer cells is longer than about 40 hours. In some embodiments, doubling time of the cancer cells is longer than about 41 hours. In some embodiments, doubling time of the cancer cells is longer than about 42 hours. In some embodiments, doubling time of the cancer cells is longer than about 43 hours. In some embodiments, doubling time of the cancer cells is longer than about 44 hours. In some embodiments, doubling time of the cancer cells is longer than about 45 hours. In some embodiments, doubling time of the cancer cells is longer than about 46 hours. In some embodiments, doubling time of the cancer cells is longer than about 47 hours. In some embodiments, doubling time of the cancer cells is longer than about 48 hours. In some embodiments, doubling time of the cancer cells is longer than about 49 hours. In some embodiments, doubling time of the cancer cells is longer than about 50 hours. In some embodiments, doubling time of the cancer cells is longer than about 55 hours. In some embodiments, doubling time of the cancer cells is longer than about 60 hours. In some embodiments, doubling time of the cancer cells is longer than about 65 hours. In some embodiments, doubling time of the cancer cells is longer than about 70 hours. In some embodiments, doubling time of the cancer cells is longer than about 80 hours. In some embodiments, doubling time of the cancer cells is longer than about 90 hours. In some embodiments, doubling time of the cancer cells is longer than about 100 hours. In some embodiments, doubling time of the cancer cells is longer than about 110 hours. In some embodiments, doubling time of the cancer cells is longer than about 120 hours. In some embodiments, doubling time of the cancer cells is longer than about 130 hours. In some embodiments, doubling time of the cancer cells is longer than about 140 hours. In some embodiments, doubling time of the cancer cells is longer than about 150 hours. In some embodiments, doubling time of the cancer cells is longer than about 160 hours.

[0315] In some embodiments, at least about 5% of the cancer cells are slow reproduction cells. In some embodiments, at least about 10% of the cancer cells are slow reproduction cells. In some embodiments, at least about 15% of the cancer cells are slow reproduction cells. In some embodiments, at least about 20% of the cancer cells are slow reproduction cells. In some NAI-1543197688v1 92Attorney Docket No.: 13532-031-228 embodiments, at least about 25% of the cancer cells are slow reproduction cells. In some embodiments, at least about 30% of the cancer cells are slow reproduction cells. In some embodiments, at least about 35% of the cancer cells are slow reproduction cells. In some embodiments, at least about 40% of the cancer cells are slow reproduction cells. In some embodiments, at least about 45% of the cancer cells are slow reproduction cells. In some embodiments, at least about 50% of the cancer cells are slow reproduction cells. In some embodiments, at least about 55% of the cancer cells are slow reproduction cells. In some embodiments, at least about 60% of the cancer cells are slow reproduction cells. In some embodiments, at least about 65% of the cancer cells are slow reproduction cells. In some embodiments, at least about 70% of the cancer cells are slow reproduction cells. In some embodiments, at least about 75% of the cancer cells are slow reproduction cells. In some embodiments, at least about 80% of the cancer cells are slow reproduction cells. In some embodiments, at least about 85% of the cancer cells are slow reproduction cells. In some embodiments, at least about 90% of the cancer cells are slow reproduction cells. In some embodiments, at least about 95% of the cancer cells are slow reproduction cells. In some embodiments, about 100% of the cancer cells are slow reproduction cells.

[0316] In some embodiments, at least about 50% of cancer cells in a sample from a patient or subject are slow reproduction cells. In specific embodiments, the cancer sample is a tumor sample.

[0317] In some embodiments, the cancer is colorectal cancer. In some embodiments, the colorectal cancer is Stage I colon cancer. In some embodiments, the colorectal cancer is Stage II colon cancer. In some embodiments, the colorectal cancer is Stage III colon cancer. In some embodiments, the colorectal cancer is Stage IV colon cancer.

[0318] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer.

[0319] In some embodiments, the cancer has been previously treated with a chemotherapy, and has developed resistance to or relapsed from such treatment. In some embodiments, the chemotherapy comprises one or more chemotherapeutic agents selected from alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines NAI-1543197688v1 93Attorney Docket No.: 13532-031-228 and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammalI and calicheamicin omegaI1); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as denopterin, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals, such as mitotane and trilostane; folic acid replenisher, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; NAI-1543197688v1 94Attorney Docket No.: 13532-031-228 losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKpolysaccharide complex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; taxoids, e.g., paclitaxel and docetaxel gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; carboplatin, procarbazine,plicomycin, gemcitabien, navelbine, farnesyl-protein transferase inhibitors, transplatinum, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0320] In some embodiments, the cancer is a small cell lung cancer that has been previously treated with a chemotherapeutic agent and developed resistance or relapsed from such treatment. In some embodiments, the chemotherapeutic agent for the small cell lung cancer is selected from carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

[0321] In specific embodiments, the cancer is a small cell lung cancer that has been previously treated with paclitaxel and developed resistance or relapse from such treatment.

[0322] In some embodiments, the cancer is a colorectal cancer that has been previously treated with a chemotherapeutic agent and developed resistance or relapsed from such treatment. In some embodiments, the chemotherapeutic agent for the colorectal cancer is selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv- Aflibercept), and Ziv-Aflibercept. NAI-1543197688v1 95Attorney Docket No.: 13532-031-228

[0323] In specific embodiments, the cancer is a colorectal cancer that has been previously treated with a chemotherapy comprising one or more chemotherapeutic agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine, and developed resistance or relapsed from such treatment.

[0324] In specific embodiments, the cancer is a colorectal cancer that has been previously treated with a chemotherapy comprising a combination of folinic acid, fluorouracil and oxaliplatin (FOLFOX), and developed resistance or relapsed from such treatment.

[0325] In specific embodiments, the cancer is a colorectal cancer that has been previously treated with a chemotherapy comprising a combination of folinic acid, fluorouracil and irinotecan (FOLFIRI), and developed resistance or relapsed from such treatment.

[0326] In specific embodiments, the cancer is a colorectal cancer that has been previously treated with a chemotherapy comprising capecitabine and developed resistance or relapsed from such treatment.

[0327] In some embodiments, the subject in need thereof has been administered one or more cycles of a chemotherapy and developed resistance or relapsed from such treatment. In specific embodiments, the subject has been administered 1 cycle of a chemotherapy and developed resistance or relapsed from such treatment. In specific embodiments, the subject has been administered 2 cycles of a chemotherapy and developed resistance or relapsed from such treatment. In specific embodiments, the subject has been administered 3 cycles of a chemotherapy and developed resistance or relapsed from such treatment. In specific embodiments, the subject has been administered 4 cycles of a chemotherapy and developed resistance or relapsed from such treatment. In specific embodiments, the subject has been administered 5 or more cycles of a chemotherapy and developed resistance or relapsed from such treatment.

[0328] In some embodiments, the cancer has been previously treated with a radiation therapy and has developed resistance to or relapsed from such treatment. In some embodiments, the radiation therapy includes using γ-rays, X-rays, and / or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated, such as microwaves, proton beam irradiation (U.S. Patent Nos.5,760,395 and 4,870,287; all of which are hereby incorporated by references in their entireties), and UV-irradiation. It is most likely that all of NAI-1543197688v1 96Attorney Docket No.: 13532-031-228 these factors affect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes.

[0329] Irradiation can also be X-ray radiation, gamma ray radiation, or charged particle radiation (proton beam, carbon beam, helium beam) (or “radiation” in general). Dosage ranges for radiation range from daily doses of 50 to 600 roentgens for some interval periods of time (2 or more days to several weeks), to single doses of 800 to 6000 roentgens. Radiation can be administered once daily, twice daily, three times daily, or four times daily. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.

[0330] Irradiation can also be X-ray radiation, gamma ray radiation, or charged particle radiation (proton beam, carbon beam, helium beam) (or “radiation” in general). Dosage ranges for radiation range from daily doses of 50 to 600 roentgens for some interval periods of time (2 or more days to several weeks), to single doses of 800 to 6000 roentgens. Radiation can be administered once daily, twice daily, three times daily, or four times daily. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.

[0331] In some embodiments, the present method sensitizes responsiveness of a cancer to a chemotherapeutic agent or radiation by contacting the cancer cells with a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein or administering a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 to a subject having cancer.

[0332] In some embodiments, an effective amount of the molecule is administered to the cancer cells. In some embodiments, a therapeutic effective amount of the molecule is administered to the subject having cancer. In some embodiments, the dose administered will depend on the route of administration, seriousness of the condition, and should be decided according to the judgment of the practitioner and each patients’ circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. In some embodiments, the dose range of the administered molecule is about 0.1 mg / kg body weight to about 30 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to NAI-1543197688v1 97Attorney Docket No.: 13532-031-228 about 14.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 14 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 13.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 13 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 12.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 12 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 11.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 11 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 12.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 12 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 11.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 11 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 10.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 10 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 9.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 9 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 8.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 8 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 7.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 7 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 6.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 6 mg / kg body NAI-1543197688v1 98Attorney Docket No.: 13532-031-228 weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 5.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 4.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 4 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 3.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 3 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 2.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 2 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 1.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 1 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.3 mg / kg body weight to about 0.5 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 0.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 1 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 1.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 2 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 2.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 3 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 3.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 4 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 4.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 5.5 mg / kg body weight to about 15 mg / kg body weight. In some NAI-1543197688v1 99Attorney Docket No.: 13532-031-228 embodiments, the dose range of the administered molecule is about 6 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 6.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 7 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 7.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 8 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 8.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 9 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 9.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 10 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 10.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 11 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 11.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 12 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 12.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 13 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 13.5 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 14 mg / kg body weight to about 15 mg / kg body weight. In some embodiments, the dose range of the administered molecule is about 14.5 mg / kg body weight to about 15 mg / kg body weight.

[0333] In some embodiments, the dose of the administered molecule is between about 0.1 mg / kg to about 1.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 1.0 mg / kg to about 2.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 2.0 mg / kg to about 3.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the NAI-1543197688v1 100Attorney Docket No.: 13532-031-228 administered molecule is between about 3.0 mg / kg to about 4.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 4.0 mg / kg to about 5.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 5.0 mg / kg to about 6.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 6.0 mg / kg to about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 7.0 mg / kg to about 8.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 8.0 mg / kg to about 9.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 9.0 mg / kg to about 10.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 10.0 mg / kg to about 11.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 11.0 mg / kg to about 12.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 12.0 mg / kg to about 13.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 13.0 mg / kg to about 14.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is between about 14.0 mg / kg to about 15.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is greater than about 15 mg / kg of the subject’s body weight.

[0334] In some embodiments, the dose of the administered molecule is about 0.01 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.02 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.03 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.04 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.05 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.06 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.07 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.08 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.09 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.1 mg / kg of the subject’s body NAI-1543197688v1 101Attorney Docket No.: 13532-031-228 weight. In some embodiments, the dose of the administered molecule is about 0.15 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.20 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.25 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.3 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.35 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.40 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.45 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.50 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.55 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.60 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.65 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.70 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.75 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.80 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.85 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.90 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 0.95 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 1.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 1.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 2.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 2.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 3.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 3.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 4.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 5.0 mg / kg of the subject’s body weight. In some NAI-1543197688v1 102Attorney Docket No.: 13532-031-228 embodiments, the dose of the administered molecule is about 6.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 8.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 9.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 10.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 11.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 12.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 13.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 14.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 15.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 16.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 17.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 18.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 19.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 20.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 21.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 22.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 23.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 24.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 25.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 26.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 27.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 28.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 29.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the administered molecule is about 30.0 mg / kg of the subject’s body weight. NAI-1543197688v1 103Attorney Docket No.: 13532-031-228

[0335] In some embodiments, the dose range of the administered molecule is from about 200mg to about 1000mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 450mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 500mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 550mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 600mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 650mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 700mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 750mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 750mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 700mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 650mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 600mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 550mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 500mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 450mg.

[0336] In some embodiments, the dose range of the administered molecule is from about 200mg to about 300mg. In some embodiments, the dose range of the administered molecule is from about 300mg to about 400mg. In some embodiments, the dose range of the administered molecule is from about 400mg to about 500mg. In some embodiments, the dose range of the administered molecule is from about 500mg to about 600mg. In some embodiments, the dose range of the administered molecule is from about 600mg to about 700mg. In some embodiments, the dose range of the administered molecule is from about 700mg to about 800mg. In some embodiments, the dose range of the administered molecule is from about 800mg to about 900mg. In some embodiments, the dose range of the administered molecule is from about 900mg to about 1000mg.

[0337] In some embodiments, the dose of the administered molecule is about 200mg. In some embodiments, the dose of the administered molecule is about 250mg. In some NAI-1543197688v1 104Attorney Docket No.: 13532-031-228 embodiments, the dose of the administered molecule is about 300mg. In some embodiments, the dose of the administered molecule is about 350mg. In some embodiments, the dose of the administered molecule is about 400mg. In some embodiments, the dose of the administered molecule is about 450mg. In some embodiments, the dose of the administered molecule is about 500mg. In some embodiments, the dose of the administered molecule is about 550mg. In some embodiments, the dose of the administered molecule is about 600mg. In some embodiments, the dose of the administered molecule is about 650mg. In some embodiments, the dose of the administered molecule is about 700mg. In some embodiments, the dose of the administered molecule is about 750mg. In some embodiments, the dose of the administered molecule is about 800mg. In some embodiments, the dose of the administered molecule is about 850mg. In some embodiments, the dose of the administered molecule is about 900mg. In some embodiments, the dose of the administered molecule is about 750mg. In some embodiments, the dose of the administered molecule is about 1000mg.

[0338] In some embodiments, cancer cells sensitized (e.g., contacted in vitro or administered in vivo) with the molecule as provided herein exhibit increased apoptosis in response to subsequent treatment with the chemotherapeutic agent or the radiation therapy as compared to cancer cells that are not sensitized. In some embodiments, apoptosis of the cancer cells sensitized with the present molecule is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, about 100% as compared to cancer cells that are not sensitized. In some embodiments, the apoptosis rate of unsensitized cancer cells does not increase in response to treatment by the chemotherapeutic agent or radiation therapy.

[0339] In some embodiments, cancer cells sensitized (e.g., contacted in vitro or administered in vivo) with the molecule as provided herein exhibit reduced proliferation in response to subsequent treatment with the chemotherapeutic agent or the radiation therapy as compared to cancer cells that are not sensitized. In some embodiments, proliferation of the cancer cells sensitized with the present molecule is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, NAI-1543197688v1 105Attorney Docket No.: 13532-031-228 at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, about 100% as compared to cancer cells that are not sensitized. In some embodiments, the proliferation rate of unsensitized cancer cells does not reduce in response to treatment by the chemotherapeutic agent or radiation therapy.

[0340] In some embodiments, the cancer is a solid tumor. In some embodiments, a tumor sensitized (e.g., contacted in vitro or administered in vivo) with the molecule as provided herein exhibit reduced tumor volume in response to subsequent treatment with the chemotherapeutic agent or the radiation therapy as compared to a tumor that is not sensitized. In some embodiments, the tumor volume of the tumor sensitized with the present molecule is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, about 100% as compared to the tumor volume of a tumor that is not sensitized. In some embodiments, the tumor volume of a unsensitized tumor does not reduce in response to treatment by the chemotherapeutic agent or radiation therapy.

[0341] In some embodiments, the cancer is in a subject (e.g., a human cancer patient). In some embodiments, the present method prepares the subject for therapeutic treatment with a chemotherapy or a radiation therapy by administering a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein to the subject prior to the therapeutic treatment.

[0342] In some embodiments, a subject prepared (e.g., administered) with the molecule as provided herein exhibited enhanced effective subject response to subsequent treatment with the chemotherapy or the radiation therapy as compared to a subject that is not prepared. In some embodiments, the effective subject response is measured in the decrease of a physical symptom of a cancer by any suitable means, such as gene expression, cell counts, assay results, tumor size, tumor free survival period. In some embodiments, the effective subject response in a subject having cancer is enhanced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about NAI-1543197688v1 106Attorney Docket No.: 13532-031-228 90%, at least about 95%, about 100% as compared to the effective subject response in a subject that is not prepared. In some embodiments, the subject has previously been treated with the chemotherapy and / or the radiation therapy and has developed resistance to such treatment. In some embodiments, the subject has previously been treated with the chemotherapy and / or the radiation therapy and a cancer has relapsed from such treatment. In some embodiments, the subject does not exhibit any effective subject response to the chemotherapy or radiation without being prepared by the molecule as described herein.

[0343] In specific embodiments, provided herein is a method for preparing a lung cancer patient for a chemotherapy, wherein the chemotherapy comprises administering one or more chemotherapeutic agent selected from carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin). In specific embodiments, the lung cancer patient exhibits enhanced effective subject response to the chemotherapy after being prepared by the method. In specific embodiments, the effective subject response is shrinkage of tumor volume in the lung cancer patient. In specific embodiments, the lung cancer patient does not exhibit any effective subject response to the chemotherapy without being prepared by the method. In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the chemotherapy comprises paclitaxel.

[0344] In specific embodiments, the method of preparing a subject suffering from a lung cancer for a chemotherapy or radiation therapy comprising administering to the subject a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) prior to treating the subject with paclitaxel. In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer.

[0345] In specific embodiments, provided herein is a method for preparing a colorectal cancer patient for a chemotherapy, wherein the chemotherapy comprises administering one or more chemotherapeutic agent selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil NAI-1543197688v1 107Attorney Docket No.: 13532-031-228 Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv-Aflibercept. In specific embodiments, the colorectal cancer patient exhibits enhanced effective subject response to the chemotherapy after being prepared by the method. In specific embodiments, the effective subject response is shrinkage of tumor volume in the colorectal cancer patient. In specific embodiments, the colorectal cancer patient does not exhibit any effective subject response to the chemotherapy without being prepared by the method. In some embodiments, the colorectal cancer is Stage I, Stage II, Stage III, or Stage IV colon cancer. In some embodiments, the chemotherapy comprises one or more chemotherapeutic agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine paclitaxel. In some embodiments, the chemotherapy comprises folinic acid, fluorouracil and oxaliplatin (FOLFOX). In some embodiments, the chemotherapy comprises folinic acid, fluorouracil and irinotecan (FOLFIRI). In some embodiments, the chemotherapy comprises capecitabine.

[0346] In some embodiments, the method of preparing a subject suffering from colorectal cancer for a chemotherapy or radiation therapy comprising administering to the subject a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) prior to treating the subject with a chemotherapy comprising one or more chemotherapeutic agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, or capecitabine. In some embodiments, the chemotherapy is selected from FOLFOX, FOLIRI, and capecitabine. In some embodiments, the colorectal cancer is a stage I colon cancer. In some embodiments, the colorectal cancer is a stage II colon cancer. In some embodiments, the colorectal cancer is a stage III colon cancer. In some embodiments, the colorectal cancer is a stage IV colon cancer.

[0347] In some embodiments, the method of sensitizing responsiveness of a cancer to a chemotherapy or radiation therapy as described in this Section 4.4 (Methods for Sensitizing Responsiveness of Cancer Cells) further comprises treating the cancer cells with a chemotherapy or a radiation therapy. NAI-1543197688v1 108Attorney Docket No.: 13532-031-228 4.5 Combination Therapy for Treating Cancer

[0348] In one aspect, provided herein is a method for eliminating cancer cells from a cell population by contacting the cell population with both an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein and an effective amount of one or more chemotherapeutic agent. In a related aspect, provided herein is a method for eliminating cancer cells from a cell population by contacting the cell population with both an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein and subjecting the cell population to an effective amount of radiation. In some embodiments, the cancer cells have been previously treated with the chemotherapy or radiation therapy and developed resistance to the treatment.

[0349] In some embodiments, the method for eliminating cancer cells from a cell population is performed by contacting the cancer cells with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein in the presence of a population of immune effector cells. In some embodiments, the immune effector cells are T lymphocytes. In some embodiments, the T lymphocytes are CD8+ cells. In some embodiments, the CD8+ cells are T cells. In some embodiments, the CD8+ cells are cytotoxic T cells. In some embodiments, T lymphocytes are infiltrating lymphocytes in a tumor environment. In some embodiments, the T lymphocytes are CD4+ cells. In some embodiments, the CD4+ cells are T cells. In some embodiments, the CD4+ cells are helper T cells. In some embodiments, the cancer cell expresses BTN1A1. In some embodiments, the cancer cells lack expression of BTN1A1 and the immune effector cells express BTN1A1. In some embodiments, expression of BTN1A1 in the cancer cells is below a BTN1A1 reference level, and expression of BTN1A1 in the immune effector cells are equal to or above a BTN1A1 reference level. In some embodiments, the immune effector cells lack expression of PD-L1. In some embodiments, expression of PD-L1 in the immune effector cells are below a PD-L1 reference level. In some embodiments, the immune effector cells express BTN1A1 and lack expression of PD-L1. In some embodiments, expression of BTN1A1 in the immune effector cells are above a BTN1A1 reference level, and expression of PD-L1 in the immune effector cells are below a PD-L1 reference level. In some embodiments, expression of BTN1A1 in the cancer is equal to or above NAI-1543197688v1 109Attorney Docket No.: 13532-031-228 a BTN1A1 reference level. In some embodiments, the BTN1A1 reference level is the average or medium expression level of BTN1A1 in a population of healthy individuals. In some embodiments, the PD-L1 reference level is the average or medium expression level of PD-L1 in the population of healthy individuals.

[0350] In a related aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to subject both an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein and an effective amount of one or more chemotherapeutic agent. In a related aspect, provided herein is a method for treating cancer in a subject in need thereof, comprising administering a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein and administering an effective amount of radiation to the subject. In some embodiments, the subject has been previously treated with the chemotherapy or radiation therapy and developed resistance to the treatment. In specific embodiments, the subject has been previously treated with the chemotherapy or radiation therapy, and the cancer has relapsed from such treatment.

[0351] In some embodiments, the cancer cells are treated (e.g., contacted in vitro or administered in vivo) with the chemotherapy or radiation therapy concurrently with the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein. In some embodiments, to achieve the concurrent treatment, the one or more chemotherapeutic agent and the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 are administered to the subject in the same composition. In alternative embodiments, to achieve concurrent treatment, the one or more chemotherapeutic agent and the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 are administered to the subject simultaneously as separate compositions.

[0352] In some embodiments, the cancer cells are treated (e.g., contacted in vitro or administered in vivo) with the chemotherapy or radiation therapy subsequently to being treated with a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein. In some embodiments, the cancer cells are treated with the chemotherapy or radiation therapy no longer than about 1 hour, no longer than about 2 hours, no longer than about 5 hours, no longer than about 12 hours, no longer than about 24 hours, no longer than about 2 days, no longer than about 3 days, no longer than about 7 days, no longer NAI-1543197688v1 110Attorney Docket No.: 13532-031-228 than about 10 days, no longer than about 2 weeks, no longer than about 4 weeks, no longer than about 6 weeks, or no longer than about 12 weeks after being treated with the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein.

[0353] In some embodiments, the cancer cells are treated (e.g., contacted in vitro or administered in vivo) with a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein subsequently to being treated with the chemotherapy or radiation therapy. In some embodiments, the cancer cells are treated with the chemotherapy or radiation therapy no longer than about 1 hour, no longer than about 2 hours, no longer than about 5 hours, no longer than about 12 hours, no longer than about 24 hours, no longer than about 2 days, no longer than about 3 days, no longer than about 7 days, no longer than about 10 days, no longer than about 2 weeks, no longer than about 4 weeks, no longer than about 6 weeks, or no longer than about 12 weeks before being treated with the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein.

[0354] In some embodiments, the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 is an BTN1A1 antagonist. In some embodiments, the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin- 1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA). In some embodiments, the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 is a molecule described in Section 4.3 (Antagonistic BTN1A1 Binding Molecules). In some embodiments, the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 is hSTC810. In some embodiments, the molecule comprising an antigen binding fragment that immunospecifically binds to bTN1A1 is STC109.

[0355] In some embodiments, a first chemotherapy is administered to a subject having the cancer in combination with the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein. In some embodiments, the subject has been previously treated with a second chemotherapy. In some embodiments, the subject has been previously treated with a second chemotherapy and developed resistance to such treatment. NAI-1543197688v1 111Attorney Docket No.: 13532-031-228 In some embodiments, the subject has been previously treated with a second chemotherapy and cancer has relapsed from such treatment. In some embodiments, the first chemotherapy and the second chemotherapy are the same or different.

[0356] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, carcinoma, colorectal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, multiple myeloma, melanoma, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, and uterine cancer. In some embodiments, the cancer is a colorectal cancer. In some embodiments, the colorectal cancer is Stage I colon cancer. In some embodiments, the colorectal cancer is Stage II colon cancer. In some embodiments, the colorectal cancer is Stage III colon cancer. In some embodiments, the colorectal cancer is Stage IV colon cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is small cell lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer.

[0357] In some embodiments, the first and second chemotherapy for treating cancer are independently selected from the group consisting of alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammalI and calicheamicin omegaI1); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, NAI-1543197688v1 112Attorney Docket No.: 13532-031-228 authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as denopterin, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals, such as mitotane and trilostane; folic acid replenisher, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKpolysaccharide complex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; taxoids, e.g., paclitaxel and docetaxel gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; carboplatin, procarbazine,plicomycin, gemcitabien, navelbine, farnesyl-protein transferase inhibitors, transplatinum, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0358] In some embodiments, the cancer is small cell lung cancer. In some embodiments, the first chemotherapy and second chemotherapy for treating the small cell lung cancer are NAI-1543197688v1 113Attorney Docket No.: 13532-031-228 independently selected from the group consisting of carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

[0359] In some embodiments, the cancer is colorectal cancer. In some embodiments, the first chemotherapy and second therapy for treating the colorectal cancer are independently selected from the group consisting of folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv-Aflibercept.

[0360] In some embodiments, a subject with small cell lung cancer is administered a combination treatment. In some embodiments, the combination treatment comprises the molecule described herein and a first chemotherapy. In some embodiments, the combination treatment comprises hSTC810 and a first chemotherapy wherein the first chemotherapy is selected from the group consisting of: carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

[0361] In some embodiments, a subject with small cell lung cancer is administered a combination treatment. In some embodiments, the combination treatment comprises the molecule described herein and the first chemotherapy is paclitaxel. In some embodiments, the combination treatment comprises hSTC810 and the first chemotherapy is paclitaxel.

[0362] In some embodiments, a subject with colorectal cancer is administered a combination treatment. In some embodiments, the combination treatment comprises the molecule described herein and a first chemotherapy. In some embodiments, the combination treatment comprises hSTC810 and a first chemotherapy where the first chemotherapy is selected from the group consisting of: folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine NAI-1543197688v1 114Attorney Docket No.: 13532-031-228 and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv- Aflibercept), and Ziv-Aflibercept.

[0363] In some embodiments, a subject with colorectal cancer is administered a combination treatment. In some embodiments, the combination treatment comprises the molecule described herein and the first chemotherapy is one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine. In some embodiments, the combination treatment comprises hSTC810 and the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.

[0364] In some embodiments, a subject with colorectal cancer is administered a combination treatment. In some embodiments, the combination treatment comprises the molecule described herein and the first chemotherapy is (a) folinic acid, fluorouracil and oxaliplatin (FOLFOX); (b) folinic acid, fluorouracil and irinotecan (FOLFIRI); or (c) capecitabine. In some embodiments, the combination treatment comprises hSTC810 and the first chemotherapy is (a) folinic acid, fluorouracil and oxaliplatin (FOLFOX); (b) folinic acid, fluorouracil and irinotecan (FOLFIRI); or (c) capecitabine.

[0365] In some embodiments, a subject with colorectal cancer is administered a combination treatment. In some embodiments, the combination treatment comprises (a) a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA), (b) a chemotherapy and (c) an antibody or antigen-binding fragment thereof that immunospecifically binds to VEGF. According to the present disclosure, the components of the combination therapy for colorectal cancer described herein can be formulated together or separately with each other for concurrent, separate or sequential administration. In specific embodiments, at least two components of the combination therapy selected from the molecule binding to BTN1A1, the antibody or antigen binding fragment thereof that binds to VEGF and the chemotherapy are administered concurrently with one another. In alternative embodiments, at least two of the components of the combination therapy selected from the molecule binding to BTN1A1, the antibody or antigen binding fragment thereof that binds to VEGF and the chemotherapy are administered sequentially with one another. In specific embodiments, at least NAI-1543197688v1 115Attorney Docket No.: 13532-031-228 two components of the combination therapy selected from the molecule binding to BTN1A1, the antibody or antigen binding fragment thereof that binds to VEGF and the chemotherapy are formulated in a same composition with one another. In alternative embodiments, at least two components of the combination therapy selected from the molecule binding to BTN1A1, the antibody or antigen binding fragment thereof that binds to VEGF and the chemotherapy are formulated in separate compositions from one another.

[0366] In specific embodiments of the combination therapy, the molecule that immunospecifically binds to BTN1A1 comprises any anti-BTN1A1 antibody or antigen binding fragment thereof described herein. In specific embodiments of the combination therapy, the molecule that immunospecifically binds to BTN1A1 comprises hSTC810. In specific embodiments of the combination therapy, the molecule that immunospecifically binds to BTN1A1 comprises STC109. In specific embodiments of the combination therapy, the chemotherapy is selected from the group consisting of: folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv-Aflibercept. In specific embodiments of the combination therapy, the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil). In specific embodiments of the combination therapy, the antibody or antigen-binding fragment thereof that immunospecifically binds to VEGF comprises Bevacizumab (Avastin). In some embodiments, the antibody or antigen binding fragment thereof that specifically binds to VEGF is Ranibizumab (Lucentis). In specific embodiments, the colorectal cancer is colon cancer. In specific embodiments, the colorectal cancer is Stage I colon cancer. In specific embodiments, the colorectal cancer is Stage II colon cancer. In specific embodiments, the colorectal cancer is Stage III colon cancer. In specific embodiments, the colorectal cancer is Stage IV colon cancer. In specific embodiments, the colorectal cancer has been previously treated with anti-PD-1 or anti-PD-L1 therapy. In specific embodiments, the colorectal cancer is resistant to, or relapsed from, prior treatment with anti-PD-1 or anti-PD-L1 therapy. NAI-1543197688v1 116Attorney Docket No.: 13532-031-228

[0367] In some embodiments, provided herein is a method of treating colon cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination therapy, wherein the combination therapy comprises (a) a therapeutically effective amount of Lonsurf (Trifluridine and Tipiracil), (b) a therapeutically effective amount of bevacizumab, and (c) a therapeutically effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA); wherein the cancer is a Stage IV colon cancer that is resistant to or relapsed from prior treatment with anti-PD-1 or anti-PD-L1 therapy. In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises hSTC810. In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises STC109.

[0368] In specific embodiments, provided herein is a method of treating colon cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination therapy, wherein the combination therapy comprises (a) a therapeutically effective amount of Lonsurf (Trifluridine and Tipiracil), (b) a therapeutically effective amount of bevacizumab, and (c) a therapeutically effective amount of hSTC810.

[0369] In yet specific embodiments, provided herein is a method for treating stage IV colon cancer that is resistant to, or relapsed from, prior treatment with anti-PD1 or anti-PD-L1 therapy in a subject in need thereof, wherein the method comprises administering to the subject a combination therapy comprising (a) an therapeutically effective amount of Lonsurf (Trifluridine and Tipiracil), (b) a therapeutically effective amount of bevacizumab, and (c) a therapeutically effective amount of hSTC810.

[0370] In some embodiments, the radiation therapy to be applied to the cancer in combination with the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein comprises using γ-rays, X-rays, and / or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated, such as microwaves, proton beam irradiation (U.S. Patent Nos.5,760,395 and 4,870,287; all of which are hereby incorporated by references in their entireties), and UV- irradiation. It is most likely that all of these factors affect a broad range of damage on DNA, on NAI-1543197688v1 117Attorney Docket No.: 13532-031-228 the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes.

[0371] Irradiation can also be X-ray radiation, gamma ray radiation, or charged particle radiation (proton beam, carbon beam, helium beam) (or “radiation” in general). Dosage ranges for radiation range from daily doses of 50 to 600 roentgens for some interval periods of time (2 or more days to several weeks), to single doses of 800 to 6000 roentgens. Radiation can be administered once daily, twice daily, three times daily, or four times daily. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.

[0372] Irradiation can also be X-ray radiation, gamma ray radiation, or charged particle radiation (proton beam, carbon beam, helium beam) (or “radiation” in general). Dosage ranges for radiation range from daily doses of 50 to 600 roentgens for some interval periods of time (2 or more days to several weeks), to single doses of 800 to 6000 roentgens. Radiation can be administered once daily, twice daily, three times daily, or four times daily. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.

[0373] In some embodiments, the patient or subject with cancer has been previously treated for cancer with a radiation therapy. In some embodiments, the radiation therapy includes using γ-rays, X-rays, and / or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated, such as microwaves, proton beam irradiation (U.S. Patent Nos.5,760,395 and 4,870,287; all of which are hereby incorporated by references in their entireties), and UV-irradiation. It is most likely that all of these factors affect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes.

[0374] In some embodiments, the patient or subject with cancer has been previously treated for cancer with an anti-PD-1 therapy or anti-PD-L1 therapy. In some embodiments, the anti-PD- 1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).

[0375] In some embodiments, the cancer is resistant to or relapsed from prior treatment with the second chemotherapy. In some embodiments, the cancer is resistant to or relapsed from prior treatment with the radiation therapy. In some embodiments, the cancer is resistant to or relapsed NAI-1543197688v1 118Attorney Docket No.: 13532-031-228 from prior treatment with the anti-PD-1 therapy. In some embodiments, the cancer is resistant to or relapsed from prior treatment with the anti-PD-L1 therapy.

[0376] In some embodiments, the method comprises treating lung cancer by administering a combination therapy comprising a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) and a therapeutic effective amount of paclitaxel.

[0377] In some embodiments, the method comprises treating small lung cancer by administering a combination therapy comprising a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) and a therapeutic effective amount of paclitaxel.

[0378] In some embodiments, the method comprises treating colorectal cancer by administering a combination therapy comprising a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) and a therapeutic effective amount of folinic acid, fluorouracil, oxaliplatin, irinotecan, or capecitabine. In some embodiments, the colorectal cancer is selected from Stage I, Stage II, Stage III, and Stage IV colon cancer.

[0379] In some embodiments, the method comprises treating colorectal cancer by administering a combination therapy comprising a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) and a therapeutic effective amount of FOLFOX, FOLIRI, or capecitabine. In some embodiments, the colorectal cancer is selected from Stage I, Stage II, Stage III, and Stage IV colon cancer.

[0380] In some embodiments, the method comprises treating colorectal cancer by administering a combination therapy comprising a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a NAI-1543197688v1 119Attorney Docket No.: 13532-031-228 BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) and an antibody or antigen binding fragment thereof that immunospecifically binds to VEGF. In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises hSTC810. In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises STC109. In specific embodiments, the antibody that immunospecifically binds to VEGF comprises Bevacizumab (Avastin).

[0381] In some embodiments, the method comprises treating colorectal cancer by administering a combination therapy comprising a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 and inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA) and Lonsurf (Trifluridine and Tipiracil). In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises hSTC810. In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises STC109.

[0382] In some embodiments, the method comprises treating colorectal cancer by administering a combination therapy comprising an antibody or antigen binding fragment thereof that immunospecifically binds to VEGF and a chemotherapy. In some embodiments, the antibody that immunospecifically binds to VEGF comprises Bevacizumab (Avastin). In some embodiments, the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).

[0383] Treatment of a subject with a therapeutically effective amount of antibodies or antigen binding fragments, other molecules or pharmaceutical composition provided herein can include a single treatment or a series of treatments. It is contemplated that the antibodies, antigen binding fragments, molecules, or pharmaceutical compositions provided herein can be administered systemically or locally to treat disease, such as to inhibit tumor cell growth or to kill cancer cells in cancer patients with locally advanced or metastatic cancers. They can be administered intravenously, intrathecally, and / or intraperitoneally. They can be administered alone or in combination with anti-proliferative drugs. In one embodiment, they are administered to reduce the cancer load in the patient prior to surgery or other procedures. Alternatively, they can be administered after surgery to ensure that any remaining cancer (e.g., cancer that the surgery failed to eliminate) does not survive. In some embodiments, they can be administered NAI-1543197688v1 120Attorney Docket No.: 13532-031-228 after the regression of primary cancer to prevent metastasis. 4.6 Compositions and Kit

[0384] The composition can be a pharmaceutical composition having a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 being the active ingredient as well as a pharmaceutically acceptable carrier. In some embodiments, the composition can further comprise one or more chemotherapeutic agents as described herein. The pharmaceutical composition can further include one or more additional active ingredient. A pharmaceutically acceptable carrier can be a carrier approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0385] The preparation of a pharmaceutical composition having the antibodies or other molecules as described herein as active ingredient are known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed., 1990, incorporated herein by reference. Moreover, for animal (including human) administration, it is understood that preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by FDA Office of Biological Standards.

[0386] The amount of active ingredient in each therapeutically useful composition can be prepared in such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors, such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations, can be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.

[0387] A unit dose or dosage refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the pharmaceutical composition calculated to produce the desired responses discussed above in association with its administration, i.e., the appropriate route and treatment regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the effect desired. The actual dosage amount of a composition of the present embodiments administered to a patient or subject can be determined by physical and physiological factors, such as body weight, the age, health, and sex of the subject, the type of disease being treated, the extent of disease penetration, previous or NAI-1543197688v1 121Attorney Docket No.: 13532-031-228 concurrent therapeutic interventions, idiopathy of the patient, the route of administration, and the potency, stability, and toxicity of the particular therapeutic substance. In other non-limiting examples, a dose can have from about 1 microgram / kg / body weight, about 5 microgram / kg / body weight, about 10 microgram / kg / body weight, about 50 microgram / kg / body weight, about 100 microgram / kg / body weight, about 200 microgram / kg / body weight, about 350 microgram / kg / body weight, about 500 microgram / kg / body weight, about 1 milligram / kg / body weight, about 5 milligram / kg / body weight, about 10 milligram / kg / body weight, about 50 milligram / kg / body weight, about 100 milligram / kg / body weight, about 200 milligram / kg / body weight, about 350 milligram / kg / body weight, about 500 milligram / kg / body weight, to about 1000 milligram / kg / body weight or more per administration, and any range derivable therein. In non-limiting examples of a derivable range from the numbers listed herein, a range of about 5 milligram / kg / body weight to about 100 milligram / kg / body weight, about 5 microgram / kg / body weight to about 500 milligram / kg / body weight, etc., can be administered, based on the numbers described above. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

[0388] As a person of ordinary skill in the art would understand, the compositions described herein are not limited by the particular nature of the therapeutic preparation. For example, such compositions can be provided in formulations together with physiologically tolerable liquid, gel, or solid carriers, diluents, and excipients. These therapeutic preparations can be administered to mammals for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents. In general, the dosage required for therapeutic efficacy varies according to the type of use and mode of administration, as well as the particularized requirements of individual subjects. The actual dosage amount of a composition administered to an animal patient, including a human patient, can be determined by physical and physiological factors, such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient, and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and / or an effective amount can vary according to the response of the subject. The practitioner responsible for administration will, in any event, NAI-1543197688v1 122Attorney Docket No.: 13532-031-228 determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

[0389] The present disclosure further provides kits for enclosing one or more compositions comprising the anti-BTN1A1 molecule and the one or more chemotherapeutic agents as described herein. The present disclosure also provides kits for treating cancer (e.g., lung cancer or colorectal cancer) in a subject in need thereof.

[0390] In certain embodiment, the kit comprises the presently disclosed therapeutic agents, e.g., in a container. Such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.

[0391] In certain embodiments, the kit further comprises instructions for administering to a subject having cancer. The instructions generally include information about the use of the composition for the treatment and / or prevention of cancer. In certain embodiments, the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treatment or prevention of cancer or symptoms thereof; precautions; warnings; indications; counter-indications; over-dosage information; adverse reactions; animal pharmacology; clinical studies; and / or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container. 5. EXAMPLES

[0392] The examples in this section (i.e., Section 5) are offered by way of illustration, and not by way of limitation. 5.1 Example 1: Identification of BTN1A1 as a Target for Cancer Therapy

[0393] Radiation can place tumor cells under a stressed condition such that the tumor cells can activate mechanisms to survive the stress, and the molecules activated under such conditions can serve as a target for either independent therapy or combination therapy with radiation. NAI-1543197688v1 123Attorney Docket No.: 13532-031-228 BTN1A1 was identified as a target that overexpresses under such conditions. Naïve T cells were isolated from a non-tumor bearing mouse and placed into a 96 well plate. The naïve T cells were engineered to contain a knocked-down particular gene of interest by infecting T cells using lentivirus vectors that contain a shRNA of interest. The knock-down of a particular candidate gene was done one well at a time.

[0394] After acquiring a stable phenotype, the shRNA treated T cells were incubated with the suppressor cells in the presence of antigen or anti-CD3 + anti-CD28, using two sets of suppressor cells: (1) suppressor cells isolated from an irradiated animal; and (2) suppressor cells isolated from a unirradiated animal. Then T-cell proliferation was assessed in individual wells by monitoring 3[H]-thymidine incorporation using the procedures substantially similar to those described in Dolcetti et al., Current Protocols in Immunlogy, 14.17.1-14.17.25 (2010), which is hereby incorporated by reference in its entirety.

[0395] The responses of T cells isolated from irradiated vs. unirradiated animals were compared in the...

Claims

AMENDED CLAIMS received by the International Bureau on 05 August 2025 (05.08.2025)WHAT IS CLAIMED:

1. A method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a combination therapy, wherein the combination therapy comprises a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1, and a therapeutic effective amount of a first chemotherapy suitable for treating said cancer.

2. The method of claim 1, wherein BTN1 Al is expressed on at least about 60% of cancer cells in a sample taken from the subject.

3. The method of claim 2, wherein at least about 70% of cancer cells in the sample express BTN1 Al and are Ki-67 negative.

4. The method of any one of claims 1 to 3, wherein PD-L1 is expressed on less than about 20% of cancer cells in a sample taken from the subject.

5. The method of claim 1 or claim 2, wherein at least about 50% of cancer cells in a sample taken from the subject are Ki-67 negative.

6. The method of claim 1 or claim 2, wherein at least about 50% of cancer cells in a sample taken from the subject are slow reproduction cells; optionally, a doubling time the cancer cells is longer than about 40 hours.

7. The method of any one of claims 1 to 6, wherein the subject has been previously treated with a second chemotherapy; optionally wherein the first chemotherapy and the second chemotherapy are the same or different.

8. The method of any one of claims 1 to 7, wherein the subject has been previously treated for cancer with a radiation therapy.

9. The method of any one of claims 1 to 8, wherein the subject has been previously treated for cancer with an anti-PD-1 therapy or anti-PD-Ll therapy.

10. The method of claim 9, wherein the anti-PD-1 therapy or anti-PD-Ll therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).

11. The method of any one of claims 7 to 10, wherein the cancer is resistant to or relapsed from prior treatment with the second chemotherapy, radiation therapy, anti-PD-1 or anti-PD-Ll therapy.

12. The method of any one of claims 1 to 11 , wherein the cancer is small cell lung cancer, and the first chemotherapy comprises one or more agents selected from carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

13. The method of claim 12, wherein the cancer is small cell lung cancer, and wherein the first chemotherapy comprises paclitaxel.

14. The method of any one of claims 1 to 11 , wherein the cancer is colorectal cancer, and wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Rego raf enib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv- Aflibercept.

15. The method of claim 14, wherein the cancer is colorectal cancer, wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.

16. The method of claim 14, wherein the cancer is colorectal cancer, and wherein the first chemotherapy comprises:(a) folinic acid, fluorouracil and oxaliplatin (FOLFOX);(b) folinic acid, fluorouracil and irinotecan (FOLFIRI); or(c) capecitabine.

17. The method of claim 14, wherein the cancer is colorectal cancer, and wherein the first chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).

18. The method of claim 14, further comprising administering to the subject an antibody or antigen binding fragment thereof that specifically binds to VEGF.

19. The method of claim 18, wherein the antibody that binds to VEGF is bevacizumab.

20. The method of any one of claims 14 to 19, wherein the colorectal cancer is a colon cancer of Stage I, II, III, or IV.

21. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutic effective amount of a combination therapy, wherein the combination therapy comprises Lonsurf (Trifluridine and Tipiracil), bevacizumab, and a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1 Al ; wherein the cancer is a Stage IV colon cancer, and wherein the cancer is resistant to or relapsed from prior treatment with anti-PD-1 or anti-PD-Ll therapy.

22. The method of any one of claims 1 to 21, wherein the molecule is administered intravenously.

23. The method of any one of claims 1 to 22, wherein the molecule is administered at a dosage in the range of from about 0.1 mg / kg body weight to about 30 mg / kg body weight.

24. The method of any one of claims 1 to 22, wherein the molecule is administered at a dosage in the range of from about 400 mg to about 800mg.

25. A method of preparing a subject suffering from cancer for a chemotherapy or a radiation therapy, wherein the method comprises administering to the subject a therapeutic effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1 Al prior to treating the subject with the chemotherapy or the radiation therapy.

26. The method of claim 25, wherein BTN1 Al is expressed on at least about 60% of cancer cells in a sample taken from the subject.

27. The method of claim 25 or 26, wherein PD-L1 is expressed on less than about 20% of cancer cells in a sample taken from the subject.

28. The method of any one of claims 25 to 27, wherein the subject has been previously treated with the chemotherapy or the radiation therapy.

29. The method of any one of claims 25 to 28, wherein the cancer is resistant to or relapsed from the chemotherapy or the radiation therapy.

30. The method of any one of claims 25 to 29, wherein the cancer is small cell lung cancer, and the chemotherapy comprises one or more agents selected from carboplatin, cisplatin, etoposide, paclitaxel, afinitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).

31. The method of claim 30, wherein the cancer is small cell lung cancer, and wherein the chemotherapy comprises paclitaxel.

32. The method of any one of claims 25 to 29, wherein the cancer is colorectal cancer, and wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil Injection), Fruquintinib Fruzaqla (Fruquintinib), Irinotecan Hydrochloride, Leucovorin Calcium, Lonsurf (Trifluridine and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Rego raf enib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecitabine), Zaltrap (Ziv-Aflibercept), and Ziv- Aflibercept.

33. The method of claim 32, wherein the cancer is colorectal cancer, wherein the chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.

34. The method of claim 32, wherein the cancer is colorectal cancer, and wherein the chemotherapy comprises:(a) folinic acid, fluorouracil and oxaliplatin (FOLFOX);(b) folinic acid, fluorouracil and irinotecan (FOLFIRI); or(c) capecitabine.

35. The method of claim 32, wherein the cancer is colorectal cancer, and wherein the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).

36. The method of claim 32, wherein the cancer is colorectal cancer, and wherein the chemotherapy comprises a combination of Lonsurf (Trifluridine and Tipiracil) and an antibody or antigen binding fragment thereof that specifically binds to VEGF.

37. The method of claim 36, wherein the antibody that binds to VEGF is bevacizumab.

38. The method of any one of claims 25 to 37, wherein the administering to the subject the therapeutic effective amount of the molecule is no more than 2 month, no more than 1 month, no more than 2 weeks, or no more than 1 week prior to treating the subject with the chemotherapy or the radiation therapy.

39. A method of eliminating cancer cells from a cell population, comprising contacting the cell population with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 in the presence of immune effector cells and a first chemotherapeutic agent; wherein one or both of the cancer cells and the immune effector cells express BTN1 Al ; and wherein upon the contacting, a percentage of the cancer cells in the cell population is reduced.

40. The method of claim 39, wherein the immune effector cells comprise CD8+ cells.

41. The method of claim 39 or 40, wherein the immune effector cells are infiltrating lymphocytes in a tumor microenvironment.

42. The method of any one of claims 39 to 41, wherein the immune effector cells comprise CD8+ T cells.

43. The method of any one of claims 39 to 42, wherein (a) the cancer cells lack expression of PD-L1; and / or (b) the immune effector cells lack expression of PD-1.

44. The method of any one of claims 39 to 43, wherein the cancer cells have been previously treated with a second chemotherapeutic agent; optionally wherein the first therapeutic agent and the second therapeutic agent are the same or different.

45. The method of any one of claims 39 to 44, wherein the cancer cells have been previously treated with radiation.

46. The method of any one of claims 39 to 45, wherein the first chemotherapeutic agent does not induce apoptosis or inhibit proliferation of the cancer cells when contacted with the cancer cells alone.

47. A method of sensitizing a response of cancer cells to a chemotherapeutic agent, comprising contacting the cancer cells with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1 Al .

48. The method of claim 47, wherein the response is apoptosis of the cancer cells; optionally wherein apoptosis of the cancer cells is increased for at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% comparing to cancer cells contacted with the chemotherapeutic agent in the absence of the molecule.

49. The method of claim 47 or 48, wherein the response is proliferation of the cancer cells; optionally wherein proliferation of the cancer cells is reduced for at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% comparing to cancer cells contacted with the chemotherapeutic agent in the absence of the molecule.

50. A method of removing slow-reproduction cancer cells in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1 Al .

51. The method of claim 50, wherein the slow-reproduction cancer cells divide at a doubling time of longer than about 40 hours, longer than about 45 hours, longer than about 50 hours, longer than about 55 hours, longer than about 60 hours, longer than about 70 hours, longer than about 80 hours, longer than about 90 hours, longer than about 100 hours, longer than about 110 hours, longer than about 120 hours, longer than about 130 hours, longer than about 140 hours, longer than about 150 hours, or longer than about 160 hours.

52. The method of claim 51 , wherein the slow-reproduction cancer cells are lung cancer cells dividing at a doubling time of longer than about 40 hours.

53. The method of any one of claims 50 to 52, wherein the slow-reproduction cancer cells express BTN1A1.

54. The method of any one of claims 50 to 53, wherein the slow-reproduction cancer cells comprise cancer stem cells.

55. The method of any one of claims 50 to 54, wherein the subject has been previously treated with a chemotherapy or a radiation therapy.

56. The method of any one of claims 50 to 54, wherein the subject has been previously treated for cancer with an anti-PD-1 therapy or anti-PD-Ll therapy.

57. The method of claim 56, wherein the anti-PD-1 therapy or anti-PD-Ll therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).

58. The method of any one of claims 55 to 57, wherein the cancer is resistant to or relapsed from prior treatment with the second chemotherapy, radiation therapy, anti-PD-1 or anti-PD-Ll therapy.

59. The method of any one of claims 50 to 58, wherein the molecule is administered intravenously.

60. The method of any one of claims 50 to 59, wherein the molecule is administered at a dose in the range of from about 0.1 mg / kg body weight to about 30 mg / kg body weight.

61. The method of any one of claims 50 to 60, wherein the molecule is administered at a dosage in the range of from about 400 mg to about 800mg.

62. The method of any one of claims 1 to 61, wherein the molecule preferentially binds to dimeric B TNI Al relative to monomeric B TNI Al.

63. The method of any one of claims 1 to 62, wherein the molecule preferentially binds to glycosylated BTN1A1 relative to non-glycosylated BTN1A1.

64. The method of any one of claims 1 to 63, wherein the antigen binding fragment is a Fab’, a F(ab’)2, a F(ab’)3, a monovalent scFv, or a bivalent scFv.

65. The method of any one of claims 1 to 63, wherein the molecule is an antibody.

66. The method of claim 65, wherein the antibody is a monoclonal antibody.

67. The method of claim 65 or 66, wherein the antibody is a humanized antibody.

68. The method of any one of claims 65 to 67, wherein the antibody is an IgG, IgM, or IgA.

69. The method of claim 65, wherein the antibody is STC810 or hSTCSIO.

70. The method of any one of claims 1 to 69, wherein the antigen-binding fragment comprises:(i) (a) a heavy chain variable region (VH) comprising a VH complementaritydetermining region (CDR) 1 , a VH CDR2, and a VH CDR3 having an amino acid sequence of a VH CDR1 , a VH CDR2, and a VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO: 31 ; and(b) a light chain variable region (VL) comprising a VL CDR1 , a VL CDR2, and a VL CDR3 having an amino acid sequence of a VL CDR1 , a VL CDR2, and a VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:32; or(ii) (a) a VH comprising:(1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 15;(2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 16; and(3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 17; and(b) a VL comprising:(1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 18;(2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 19; and(3) a VL CDR3 having the amino acid sequence of SEQ ID NO:20; or(in) (a) a VH comprising:(1) a VH CDR1 having the amino acid sequence of SEQ ID NO:21 ;(2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 22; and(3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 17; and(b) a VL comprising:(1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 18;(2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 19; and(3) a VL CDR3 having the amino acid sequence of SEQ ID NO:20; or(iv) (a) a VH comprising:(1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 23;(2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 24; and(3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 17; and(b) a VL comprising:(1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 18;(2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 19; and(3) a VL CDR3 having the amino acid sequence of SEQ ID NO:20; or(v) (a) a VH comprising:(1) a VH CDR1 having the amino acid sequence of SEQ ID NO:25;(2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 26; and(3) a VH CDR3 having the amino acid sequence of SEQ ID NO:27; and(b) a VL 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.

71. The method of claim 70, wherein the antigen-binding fragment comprises a VH comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31.

72. The method of claim 70, wherein the antigen-binding fragment comprises a VH comprising the amino acid sequence of SEQ ID NO:31.

73. The method of claim 70, wherein the antigen-binding fragment comprises a VL comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO 32.

74. The method of claim 70, wherein the antigen-binding fragment comprises a VL comprising the amino acid sequence of SEQ ID NO:32.

75. The method of claim 70, wherein the antigen-binding fragment comprises a VH comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 31 ; and a VL comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.

76. The method of claim 70, wherein the antigen-binding fragment comprises a VH comprising the amino acid sequence of SEQ ID NO:31 ; and a VL comprising the amino acid sequence of SEQ ID NO:32.

77. The method of claim 70, wherein the antigen-binding fragment comprises a VH consisting of the amino acid sequence of SEQ ID NO: 31 ; and a VL consisting of the amino acid sequence of SEQ ID NO:32.

78. The method of claim 70, wherein the antigen-binding fragment comprises a heavy chain comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:33.

79. The method of claim 70, wherein the antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of the amino acid sequence of SEQ ID NO:33.

80. The method of claim 70, wherein the antigen-binding fragment comprises a light chain comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:34.

81. The method of claim 70, wherein the antigen-binding fragment comprises a light chain comprising the amino acid sequence of the amino acid sequence of SEQ ID NO:34.

82. The method of claim 70, wherein the antigen-binding fragment comprises a heavy chain comprisingthe amino acid sequenceof SEQ ID NO:33; and a light chain comprising the amino acid sequence of SEQ ID NO:34.

83. The method of claim 70, wherein the antigen-binding fragment comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:33; and a light chain consisting of the amino acid sequence of SEQ ID NO:34.

84. An antibody or antigen binding fragment thereof that binds to human BTN1A1, wherein the antibody or the antigen binding fragment thereof comprises:(a) a heavy chain variable region (VH) comprising a VH complementarity-determining region (CDR) 1 , a VH CDR2, and a VH CDR3 having an amino acid sequence of a VH CDR1 , a VH CDR2, and a VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO:31; and(b) a light chain variable region (VL) comprising an amino acid sequence having at least95% identity to the amino acid sequence of SEQ ID NO:32.

85. An antibody or antigen binding fragment thereof that binds to human BTN1A1, wherein the antibody or the antigen binding fragment thereof comprises:(a) a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31 ; and(b) a light chain variable region (VL) comprising a VL CDR1 , a VL CDR2, and a VL CDR3 having an amino acid sequence of a VL CDR1 , a VL CDR2, and a VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:32.

86. The antibody or antigen binding fragment thereof of claim 84 or 85, wherein the VH comprises the amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31 , and the VL comprises the amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.

87. The antibody or antigen binding fragment thereof of claim 86, whereinthe VH comprises the amino acid sequence of SEQ ID NO:31, and the VL comprises the amino acid sequence of SEQ ID NO 32.

88. The antibody or antigen binding fragment thereof of claim 86, wherein the VH consists of the amino acid sequence of SEQ ID NO:31 , and the VL consists of the amino acid sequence of SEQ ID NO 32.

89. An antibody that binds to human BTN1 Al comprising a heavy chain having the amino acid sequence of SEQ ID NO:33, and a light chain having the amino acid sequence of SEQ ID NO:34.

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