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WO2025175166A1 - Combination therapies with btn1a1 binding proteins and chemotherapeutic agents - Google Patents

Combination therapies with btn1a1 binding proteins and chemotherapeutic agents

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Publication number
WO2025175166A1
WO2025175166A1 PCT/US2025/016025 US2025016025W WO2025175166A1 WO 2025175166 A1 WO2025175166 A1 WO 2025175166A1 US 2025016025 W US2025016025 W US 2025016025W WO 2025175166 A1 WO2025175166 A1 WO 2025175166A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
btn1a1
acid sequence
seq
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/016025
Other languages
French (fr)
Inventor
Stephen S. YOO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Stcube & Co Inc
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Stcube & Co Inc
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Filing date
Publication date
Application filed by Stcube & Co Inc filed Critical Stcube & Co Inc
Publication of WO2025175166A1 publication Critical patent/WO2025175166A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • 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.
  • 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.
  • the present disclosure provides methods of treating cancer comprising a combination treatment that includes binding proteins that bind to BTN1A1 and a chemotherapy.
  • binding proteins can bind to a BTN1A1 polypeptide, a BTN1A1 fragment, and/or a BTN1A1 epitope.
  • binding proteins, including antibodies can be antagonist (e.g., inhibiting BTN1A1 mediated signaling).
  • the combination treatment is effective in treating small cell lung cancer.
  • the combination treatment is effective in treating colorectal cancer.
  • 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 1 Attorney 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.
  • GAL-1 Galectin-1
  • GAL-9 Galectin-9
  • NRP-2 NRP-2
  • BTLA B- and T-Lymphocyte Attenuator
  • 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.
  • the subject has been previously treated with a second chemotherapy; optionally wherein the first chemotherapy and the second chemotherapy are the same or different.
  • the subject has been previously treated for cancer with a radiation therapy.
  • the subject has been previously treated for cancer with an anti- PD-1 therapy or anti-PD-L1 therapy.
  • the anti-PD-1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).
  • the cancer is resistant to or relapsed from prior treatment with the second chemotherapy, radiation therapy, anti-PD-1 or anti-PD-L1 therapy.
  • the cancer is small cell lung cancer
  • the first chemotherapy comprises one or more agents selected from carboplatin, cisplatin, etoposide, paclitaxel, Armitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, NAI-1543197688v1 2 Attorney Docket No.: 13532-031-228 methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).
  • the cancer is small cell lung cancer, and wherein the first chemotherapy comprises paclitaxel.
  • 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
  • the cancer is colorectal cancer, wherein the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.
  • 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.
  • the cancer is colorectal cancer, and wherein the first chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).
  • the method further comprises administering to the subject an antibody or antigen binding fragment thereof that specifically binds to VEGF.
  • the antibody that binds to VEGF is bevacizumab.
  • the colorectal cancer is a colon cancer of Stage I, Stage II, Stage III, or Stage IV.
  • 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 3 Attorney 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.
  • Lonsurf Trifluridine and Tipiracil
  • bevacizumab a molecule comprising an antigen
  • 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.
  • 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.
  • BTN1A1 is expressed on at least about 60% of cancer cells in a sample taken from the subject.
  • PD-L1 is expressed on less than about 20% of cancer cells in a sample taken from the subject.
  • the subject has been previously treated with the chemotherapy or the radiation therapy.
  • the cancer is resistant to or relapsed from the chemotherapy or the radiation therapy.
  • the cancer is small cell lung cancer
  • the chemotherapy comprises one or more agents selected from carboplatin, cisplatin, etoposide, paclitaxel, Armitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).
  • the cancer is small cell lung cancer, and wherein the chemotherapy comprises paclitaxel.
  • the cancer is colorectal cancer
  • the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, NAI-1543197688v1 4 Attorney 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), Z
  • the cancer is colorectal cancer, wherein the chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.
  • 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.
  • the cancer is colorectal cancer, and wherein the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).
  • the cancer is colorectal cancer
  • the chemotherapy comprises a combination of Lonsurf (Trifluridine and Tipiracil) and an antibody or antigen binding fragment thereof that specifically binds to VEGF.
  • the antibody that binds to VEGF is bevacizumab.
  • 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.
  • provided herein is a method of eliminating cancer cells from a cell population.
  • 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.
  • 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;
  • the immune effector cells comprise CD8+ cells. NAI-1543197688v1 5 Attorney 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.
  • the cancer cells have been previously treated with radiation.
  • the first chemotherapeutic agent does not induce apoptosis or inhibit proliferation of the cancer cells when contacted with the cancer cells alone.
  • provided herein is a method of sensitizing a response of cancer cells to a chemotherapeutic agent.
  • 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).
  • 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).
  • 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.
  • 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.
  • a method of removing slow-reproduction cancer cells in a subject in need thereof is provided herein.
  • 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 6
  • a BTN1A1 ligand NAI-1543197688v1 6 Attorney 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).
  • 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.
  • the slow-reproduction cancer cells are lung cancer cells dividing at a doubling time of longer than about 40 hours.
  • the slow-reproduction cancer cells express BTN1A1.
  • the slow-reproduction cancer cells comprise cancer stem cells.
  • the subject has been previously treated with a chemotherapy or a radiation therapy.
  • the subject has been previously treated for cancer with an anti- PD-1 therapy or anti-PD-L1 therapy.
  • the anti-PD-1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).
  • the cancer is resistant to or relapsed from prior treatment with the second chemotherapy, radiation therapy, anti-PD-1 or anti-PD-L1 therapy.
  • the molecule is administered intravenously.
  • 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.
  • the molecule is administered at a dosage in the range of from about 400 mg to about 800mg.
  • the molecule preferentially binds to dimeric BTN1A1 relative to monomeric BTN1A1.
  • the molecule preferentially binds to glycosylated BTN1A1 relative to non-glycosylated BTN1A1.
  • NAI-1543197688v1 7 Attorney Docket No.: 13532-031-228
  • the antigen binding fragment is a Fab’, a F(ab’)2, a F(ab’)3, a monovalent scFv, or a bivalent scFv.
  • the molecule is an antibody.
  • the antibody is a monoclonal antibody.
  • the antibody is a humanized antibody.
  • 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:31; and (b)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • VH heavy chain variable region
  • CDR VH complementarity- determining region
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • VL light chain variable region
  • the VH comprises the amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31
  • the VL comprises the amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:32.
  • the VH comprises the amino acid sequence of SEQ ID NO:31
  • the VL comprises the amino acid sequence of SEQ ID NO:32.
  • the VH consists of the amino acid sequence of SEQ ID NO:31
  • the VL consists of the amino acid sequence of SEQ ID NO:32.
  • FIGS.1A-1B show BTN1A1 expression levels and doubling time in lung cancer cell lines.
  • FIG.2 show BTN1A1 and PD-L1 expression of SCLC patients’ tumors.
  • FIG.3 shows a confocal single-optical section images showing BTN1A1 (red) and PD-L1 (green) in SCLC patient specimen.
  • 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.
  • 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.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • FIGS.6A to 6D show NCI-H345 SCLC spheroid formation and efficacy of hSTC810 in combination with Paclitaxel.
  • 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 11 Attorney 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.
  • 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.
  • 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.
  • FIGS.9A and 9B show the treatment history of two male colon cancer human patients, respectively.
  • 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.
  • 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.
  • 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.
  • FIGS.13A-13D show sensograms of exemplary SPR assays.
  • FIG.14A shows a schematic illustrating a ⁇ -galactosidase ( ⁇ -gal) complementation assay, in which ⁇ -gal is split into enzyme donor (ED) and the enzyme acceptor (EA).
  • ED enzyme donor
  • EA enzyme acceptor
  • FIG.14B shows a bar diagram illustrating the results of an exemplary ⁇ -galactosidase ( ⁇ -gal) complementation assay.
  • 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).
  • 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 ⁇ M.
  • 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.
  • FIG.17 shows sensograms of BLI experiments in which soluble BTLA was contacted at indicated concentrations with immobilized BTN1A1-Fc.
  • 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 13 Attorney Docket No.: 13532-031-228
  • 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.
  • 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).
  • 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).
  • 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.
  • STC109 anti- mouse BTN1A1 syngeneic antibody
  • TAS- 102 Lonsurf
  • an anti-mouse VEGF antibody in CT26 xenograft mouse model.
  • mice 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 ⁇ g/animal and a rat IgG2a isotype control antibody at NAI-1543197688v1 14 Attorney Docket No.: 13532-031-228 100 ⁇ g/animal.
  • Group 2 received STC109 at 200 ⁇ g/animal.
  • 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.
  • 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.
  • 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.
  • 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 peripheral blood mononuclear cell
  • 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.
  • 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.
  • 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 15 Attorney Docket No.: 13532-031-228 4.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 16 Attorney 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).
  • 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.
  • a method for treating cancer in a subject in need thereof with an anti-cancer therapy e.g., chemotherapy or radiation
  • a BTN1A1 antagonist e.g., a molecule inhibiting binding of BTN1A1 to one or more of its receptors.
  • a method for preparing a subject suffering from cancer for treatment with an anti-cancer therapy e.g., chemotherapy or radiation
  • 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.
  • 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.
  • 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.
  • BTN1A1 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.
  • glycosylated BTN1A1 include BTN1A1 with N55, N215, and/or N449 glycosylation.
  • An exemplary amino acid sequence of human BTN1A1 (BC096314.1 GI: 64654887), is provided below: MAVFPSSGLPRCLLTLILLQLPKLDSAPFDVIGPPEPILAVVGEDAKLPCRLSPNASAEHL ELRWFRKKVSPAVLVHRDGREQEAEQMPEYRGRATLVQDGIAKGRVALRIRGVRVSD DGEYTCFFREDGSYEEALVHLKVAALGSDPHISMQVQENGEICLECTSVGWYPEPQVQ WRTSKGEKFPSTSESRNPDEEGLFTVAASVIIRDTSAKNVSCYIQNLLLGQEKKVEISIPAS SLPRLTPWIVAVAVILMVLGLLTIGSIFFTWRLYNERPRERRNEFSSKERLLEELKWKKA TLHAVDVTLDPDTAHPHLFLYEDSKS
  • BTN1A1 extracellular domain construct (BTN1A1-ECD-Fc) is provided below: NAI-1543197688v1 19 Attorney Docket No.: 13532-031-228 APFDVIGPPEPILAVVGEDAELPCRLSPNASAEHLELRWFRKKVSPAVLVHRDGREQEAE QMPEYRGRATLVQDGIAKGRVALRIRGVRVSDDGEYTCFFREDGSYEEALVHLKVAAL GSDPHISMQVQENGEICLECTSVGWYPEPQVQWRTSKGEKFPSTSESRNPDEEGLFTVA ASVIIRDTSAKNVSCYIQNLLLGQEKKVEISIPASSLPRDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
  • BTN1A1-His6 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).
  • Galectin-1 encompasses 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.
  • the terms NAI-1543197688v1 21 Attorney Docket No.: 13532-031-228 include “related GAL-1 polypeptides,” including SNP variants thereof.
  • 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).
  • mRNA nucleic acid sequence
  • Galectin-9 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.
  • 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 22 Attorney Docket No.: 13532-031-228 [00140]
  • An exemplary amino acid sequence of human GAL-9 (NCBI Reference Sequence NP_001317092), is provided below.
  • 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).
  • mRNA exemplary human NRP-2 nucleic acid sequence
  • An exemplary amino acid sequence of human NRP-2 (NCBI Reference Sequence NP_003863), is provided below.
  • B- and T-lymphocyte attenuator 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).
  • 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.
  • 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).
  • nucleic acid sequence of human BTLA is provided below (NCBI Reference Sequence NM_001085357.1 (coding sequence)): NAI-1543197688v1 26 Attorney Docket No.: 13532-031-228 ATGAAGACATTGCCTGCCATGCTTGGAACTGGGAAATTATTTTGGGTCTTCTTCTTAA TCCCATATCTGGACATCTGGAACATCCATGGGAAAGAATCATGTGATGTACAGCTTT ATATAAAGAGACAATCTGAACACTCCATCTTAGCAGGAGATCCCTTTGAACTAGAAT GCCCTGTGAAATACTGTGCTAACAGGCCTCATGTGACTTGGTGCAAGCTCAATGGAA CAACATGTGTAAAACTTGAAGATAGACAAACAAGTTGGAAGGAAGAAGAACATT TCATTCTACATTTTGAACCAGTGCTTCCTAATGACAATGGGTCATACCGCT GTTCTGCAAATTTTCAGTCTAATCTCATTGAAAGCCACTCAACAACTCTTTATGT
  • 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.
  • the terms include “related PD-1 polypeptides,” including SNP variants thereof.
  • 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.
  • GenBankTM accession number L27440.1 provides an exemplary human PD-1 nucleic acid sequence.
  • anti-PD-1 therapy encompasses any inhibitor of PD-1.
  • 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).
  • the anti-PD-1 therapy includes nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-514, or AMP-224.
  • 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. [00151] 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.
  • 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.
  • the anti-PD-1 therapy includes an anti-PD-1 antibody provided in International Application No. PCT/US2016/64394.
  • 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.
  • 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.
  • the terms include “related PD-L1 polypeptides,” including SNP variants thereof.
  • 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.
  • GenBankTM accession number NM_014143 provides an exemplary human PD-1 nucleic acid sequence.
  • anti-PD-L1 therapy encompasses any inhibitor of PD-L1.
  • an anti-PD-1 therapy can include NAI-1543197688v1 28 Attorney 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).
  • the anti-PD-L1 therapy includes YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX- 1105.
  • 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.
  • cancer stem cells are slow reproduction cells.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 30 Attorney Docket No.: 13532-031-228 [00162]
  • 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.
  • 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.
  • CDR Complementarity Determining Region
  • a nonhuman species e.g., donor antibody
  • one or more FR region residues of the human immunoglobulin are replaced by corresponding nonhuman residues.
  • 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.
  • Fc immunoglobulin constant region
  • 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 31 Attorney 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.
  • 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.
  • 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.
  • 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.
  • 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 32 Attorney 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.
  • 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.
  • 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).
  • basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic
  • substitution of a phenylalanine for a tyrosine is a conservative substitution.
  • 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.
  • 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.
  • the neutralizing molecule is a neutralizing antibody.
  • 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 ⁇ g/ml in the neutralization assay.
  • a neutralizing molecule or neutralizing antibody can immunospecifically bind to BTN1A1.
  • a neutralizing molecule or neutralizing antibody can bind to a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2 or BTLA.
  • an antigen binding fragment refers 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.
  • 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.
  • 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.
  • 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 residue
  • 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 34 Attorney Docket No.: 13532-031-228 can be one of five distinct types, referred to as alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) and mu ( ⁇ ), based on the amino acid sequence of the heavy chain constant region.
  • the distinct heavy chains differ in size: ⁇ , ⁇ and ⁇ contain approximately 450 amino acids, while ⁇ and ⁇ contain approximately 550 amino acids.
  • 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.
  • 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.
  • variable region can be a human variable region.
  • 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 ⁇ -sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL ⁇ -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 35 Attorney Docket No.: 13532-031-228 variable (V) domains (Kabat et al., J. Biol.
  • CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved ⁇ -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)).
  • IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates.
  • CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain.
  • 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.
  • AHon additional numbering system
  • 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).
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • 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 36 Attorney Docket No.: 13532-031-228 [00175] 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 n oncova 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.
  • 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.
  • 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.
  • HVR and “CDR” are used interchangeably.
  • 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 37 Attorney 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.
  • 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.
  • 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.
  • inhibitor refers to partial (such as, 1%, 2%, 5%, 10%, 20%, 25%, 50%, 75%, 90%, 95%, 99%) or complete (i.e., 100%) inhibition.
  • attenuate 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.
  • 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.
  • 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”).
  • the antibody 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.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the antibody when the antibody is NAI-1543197688v1 38 Attorney 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.
  • 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. [00184] 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.
  • nucleic acid molecule 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.
  • bind 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 39 Attorney 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).
  • a binding molecule X such as an antibody
  • Y such as the antibody
  • cognate antigen can generally be represented by the dissociation constant (KD).
  • KD dissociation constant
  • KD KD value
  • RIA radiolabeled antigen binding assay
  • 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).
  • 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.
  • 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 40 Attorney 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.
  • a mammal e.g., a human
  • 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.
  • a BTN1A1 epitope is a three-dimensional surface feature of a BTN1A1 polypeptide.
  • a BTN1A1 epitope is linear feature of a BTN1A1 polypeptide.
  • an antigen has several or many different epitopes and may react with many different antibodies.
  • antibodies that immunospecifically bind to BTN1A1 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 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 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 41 Attorney Docket No.: 13532-031-228 techniques, such as radioimmunoassays (RIA) and enzyme linked immunosorbent assays (ELISAs).
  • RIA radioimmunoassays
  • ELISAs enzyme linked immunosorbent assays
  • 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” 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • specific binding 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.
  • 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.
  • KD dissociation constant
  • anti-BTN1A1 antibody binds to an epitope of BTN1A1 that is conserved among BTN1A1 from different species (e.g., between human and cynomolgus BTN1A1).
  • 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.
  • 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.
  • 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.
  • the antibody or antigen binding fragment binds to glycosylated BTN1A1 with a KD less than half of the KD exhibited relative to unglycosylated BTN1A1.
  • 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.
  • 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.
  • An antibody or antigen binding fragment that immunospecifically binds to BTN1A1 can bind to a BTN1A1 monomer or a BTN1A1 dimer.
  • 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).
  • ECD extracellular domain
  • the BTN1A1 monomer or dimer is glycosylated at one or more positions.
  • 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.
  • 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. [00193] The preferential binding can also be determined by binding assays and be indicated by, for example, mean fluorescence intensity (“MFI”).
  • MFI mean fluorescence intensity
  • an antibody or antigen NAI-1543197688v1 43 Attorney 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 44 Attorney 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.
  • both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors.
  • 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.
  • 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.
  • PCR polymerase chain reaction
  • suitable analytical methods to test the expression of an introduced nucleic acid sequence or its corresponding gene product.
  • 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.
  • 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.
  • 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.
  • 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 45 Attorney 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.
  • 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).
  • residual cancer cells e.g., lung cancer or colorectal cancer cells
  • sensitivity 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • treatment contemplates both a complete and a partial response.
  • 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.
  • the term “predict” generally means to determine or tell in advance.
  • 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.
  • the term “monitor,” as used herein, generally refers to the overseeing, supervision, regulation, watching, tracking, or surveillance of an activity.
  • 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.
  • 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.
  • Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • Neoplastic refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth.
  • neoplastic cells include malignant and benign cells having dysregulated or unregulated cell growth.
  • 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.
  • an agent e.g., an antibody described herein or any other agent described herein
  • a therapeutically effective amount of an 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).
  • 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 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.
  • administer 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.
  • administration of the substance typically occurs after the onset of disease, disorder or condition or symptoms thereof.
  • administration of the substance typically occurs before the onset of the disease, disorder or condition or symptoms thereof.
  • 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. [00211] 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 48 Attorney Docket No.: 13532-031-228 of the disease to a given treatment.
  • the biomarker is a nucleic acid, such as mRNA or cDNA (e.g., BTN1A1 mRNA or cDNA).
  • 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.
  • 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.
  • 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.
  • 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.
  • mRNA messenger RNA
  • 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.
  • 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.
  • 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.
  • “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 49 Attorney 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.
  • Polyclonal antibodies 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)).
  • fragment 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.
  • 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
  • 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 50 Attorney Docket No.: 13532-031-228 [00220]
  • 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.
  • antigen-binding fragment refers 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • composition is intended to encompass a product containing the specified ingredients (e.g., an antibody provided herein) in, optionally, the specified amounts.
  • 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.
  • 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 51 Attorney 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 TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, cit
  • carrier can also refer to a diluent, adjuvant (e.g., Freund’s adjuvant (complete or incomplete)), excipient, or vehicle.
  • 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 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.
  • compositions 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.
  • pharmaceutically acceptable 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.
  • 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 52 Attorney Docket No.: 13532-031-228 maltose, trehalose, etc.), and polyols (e.g., mannitol, sorbitol, etc.).
  • proteins e.g., serum albumin, etc.
  • amino acids e.
  • 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.
  • “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%.
  • 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).
  • 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.
  • 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.
  • the term “source” when used in reference to a reference sample refers to the origin of a sample.
  • polypeptide and protein refer to a polymer of three or more amino acids in a serial array, linked through peptide bonds.
  • polypeptide includes proteins, protein fragments, protein analogues, oligopeptides, and the NAI-1543197688v1 53 Attorney Docket No.: 13532-031-228 like.
  • 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.
  • modified polypeptides, proteins, and peptides e.g., glycopolypeptides, glycoproteins, or glycopeptides; or lipopolypeptides, lipoproteins, or lipopeptides.
  • 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.
  • the terms “patient” and “subject” refer to an animal, such as a mammal.
  • the patient or subject is a human.
  • 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.
  • 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 [00239] In one aspect, provided herein are antagonist BTN1A1 binding molecules.
  • the BTN1A1 binding molecule includes an antigen binding fragment that immunospecifically binds to BTN1A1.
  • the molecules having an antigen binding fragment that immunospecifically bind to BTN1A1 can inhibit the binding of the BTN1A1 ligand to BTN1A1.
  • 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).
  • 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 54 Attorney Docket No.: 13532-031-228 BTN1A1).
  • the molecule is an anti-BTN1A1 antibody.
  • the antigen binding fragment that immunospecifically binds BTN1A1 binds to a fragment, or an epitope of BTN1A1.
  • the antigen binding fragment immunospecifically binds to a BTN1A1 dimer.
  • the BTN1A1 epitope is found in a BTN1A1 dimer and not found in a BTN1A1 monomer.
  • the molecules provided herein have an antigen binding fragment that immunospecifically binds to BTN1A1.
  • 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.
  • a BTN1A1 ligand such as Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), or B- and T-Lymphocyte Attenuator (BTLA)
  • 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.
  • 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.
  • a BTN1A1 ligand such as GAL-1, GAL-9, NPR-2, or BTLA to BTN1A1.
  • 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.
  • 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
  • the neutralization assay is a surface NAI-1543197688v1 55 Attorney Docket No.: 13532-031-228 plasmon resonance, biolayer interferometry, co-immunoprecipitation, FRET, or TR-FRET assay, or an ELISA.
  • 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.
  • 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.
  • 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. [00242] In some embodiments, the BTN1A1 binding molecule includes an antigen-binding domain that binds to the extracellular domain (ECD) of BTN1A1.
  • ECD extracellular domain
  • 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.
  • the BTN1A1 binding molecule can modulate T-cell activity.
  • the T-cell is a CD8+ cell.
  • the BTN1A1 binding molecule can increase T-cell activation or T-cell proliferation.
  • the BTN1A1 binding molecule can inhibit T-cell apoptosis.
  • 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 56
  • OST membrane-associated oligosaccharyl transferase
  • the BTN1A1 binding molecules have an antigen binding fragment that selectively binds to one or more glycosylation motifs of BTN1A1.
  • the antigen binding fragment immunospecifically binds to a glycopeptide having a glycosylation motif and the adjacent peptide.
  • the antigen binding fragment immunospecifically binds to a peptide sequence that is located near one or more of the glycosylation motifs in three dimensions.
  • 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.
  • 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 with K D less than 50% of the K D exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with K D that is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of the K D 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.
  • 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.
  • 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.
  • glycosylated forms of a BTN1A1 isoform or variant 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 57 Attorney 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.
  • the BTN1A1 binding molecules have an antigen binding fragment that immunospecifically binds to glycosylated BTN1A1 (e.g., a glycosylated BTN1A1 dimer).
  • the antigen binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55, N215, and/or N449.
  • the antigen binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55.
  • the antigen binding fragment immunospecifically binds to BTN1A1 glycosylated at position N215.
  • 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.
  • the antigen binding fragments immunospecifically binds to BTN1A1 glycosylated at positions N55, N215 and N449.
  • 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.
  • 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.
  • 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 58 Attorney Docket No.: 13532-031-228 N449 over non-glycosylated BTN1A1.
  • 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. [00251] In some embodiments, the preferential binding can be determined by binding affinity.
  • 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 with K D less than half of the K D exhibited relative to unglycosylated BTN1A1.
  • 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 K D at 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 with K D at least 15 times less than the K D exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with K D at least 20 times less than the K D exhibited 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 with K D at least 30 times less than the K D exhibited 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 with K D that is about 75% of the K D exhibited 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 59 Attorney 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 with K D that is about 10% of the K D exhibited 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 K D that is about 2.5% of the K D exhibited relative to unglycosylated BTN1A1.
  • the antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 1% of the K D exhibited relative to unglycosylated BTN1A1.
  • the preferential binding can also be determined by in a binding assay as indicated by, for example, fluorescence intensity (“MFI”).
  • MFI fluorescence intensity
  • an BTN1A1 binding molecule containing an antigen binding fragment that preferentially binds to the glycosylated BTN1A1 e.g., a glycosylated BTN1A1 dimer
  • 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.
  • 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.
  • 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.
  • the antigen binding fragment binds to glycosylated BTN1A1 NAI-1543197688v1 60 Attorney 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.
  • 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.
  • 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. [00254] In some embodiments, the BTN1A1 binding molecules have an antigen binding fragment that selectively binds to a BTN1A1 dimer over a BTN1A1 monomer.
  • the BTN1A1 dimer is expressed at the surface of a cell.
  • 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).
  • the BTN1A1 monomer is an extracellular domain construct of BTN1A1, such as a Flag-tagged or a His6-tagged BTN1A1-ECD construct.
  • the molecules selectively binding to a BTN1A1 dimer are molecules provided herein that selectively bind to glycosylated BTN1A1.
  • preferential binding to a BTN1A1 dimer over a BTN1A1 monomer is determined by determining preferential binding to a BTN1A1-ECD-Fc NAI-1543197688v1 61 Attorney 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).
  • a surface plasmon resonance assay e.g., BIAcore
  • 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).
  • a BTN1A1 dimer e.g., a glycosylated BTN1A1 dimer
  • KD e.g., a glycosylated BTN1A1 dimer
  • the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with K D less than 50% of the K D exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer).
  • a BTN1A1 dimer e.g., a glycosylated BTN1A1 dimer
  • K D less than 50% of the K D exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer).
  • the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with K D that is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of the K D exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer).
  • a BTN1A1 dimer e.g., a glycosylated BTN1A1 dimer
  • the antigen binding fragment binds to a BTN1A1 dimer (e.g., a glycosylated BTN1A1 dimer) with K D at least 10 times less than the K D exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer)
  • a BTN1A1 dimer e.g., a glycosylated BTN1A1 dimer
  • K D at least 10 times less than the K D exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer)
  • 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
  • PCT/US2018/035090 published as WO2018/222689 on December 6, 2018
  • PCT/US2018/035082 published as WO2018/222685 on December 6, 2018
  • 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.
  • 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.
  • the BTN1A1 binding molecule comprises an antigen binding fragment that binds to BTN1A1.
  • 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 62 Attorney 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • the CDRs are according to Chothia numbering.
  • the CDRs are according to AbM numbering.
  • the CDRs are according to Kabat numbering.
  • the CDRs are according to Contact numbering.
  • 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 63 Attorney 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the antigen NAI-1543197688v1 64 Attorney 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.
  • 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.
  • 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.
  • 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 [00264]
  • 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.
  • 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.
  • 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 65 Attorney 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. [00271] 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.
  • 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 67 Attorney Docket No.: 13532-031-228 [00272] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35.
  • 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. [00273] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:31.
  • 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. [00274] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:35.
  • 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. [00275] In some embodiments, the antigen binding fragment provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO:59.
  • 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 68 Attorney 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. [00276] In some embodiments, the BTN1A1 binding molecule provided herein comprises a heavy chain constant region.
  • 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. [00277] 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.
  • 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. [00278] In some embodiments, the antigen binding fragment provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:43.
  • 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.
  • 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 69
  • 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.
  • 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.
  • 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 2
  • the determination of percent identity between two sequences can be accomplished using methods known in the art.
  • the determination of percent identity between two 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).
  • Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res.25:33893402 (1997).
  • the percent identity between two sequences is calculated by dividing the number of residue(s) varied NAI-1543197688v1 70 Attorney 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.
  • PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.).
  • the default parameters of the respective programs e.g., of XBLAST and NBLAST
  • NCBI National Center for Biotechnology Information
  • 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.
  • 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.
  • 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.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in a reference amino acid sequence.
  • substitutions, insertions, or deletions occur in regions outside the CDRs (e.g., in the FRs, constant regions, and/or Fc regions).
  • 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%).
  • the position defining a CDR of the Sequence Tables 1A NAI-1543197688v1 71 Attorney 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%).
  • BTN1A1 e.g., human BTN1A1
  • substantially maintained for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • 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%).
  • 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%).
  • BTN1A1 e.g., human BTN1A1
  • 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%).
  • BTN1A1 e.g., human BTN1A1
  • 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%).
  • BTN1A1 e.g., human BTN1A1
  • 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%).
  • BTN1A1 e.g., human BTN1A1
  • BTN1A1 e.g., human BTN1A1
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
  • the amino acid sequence modifications do not include any modification within an CDR.
  • 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.
  • 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 73 Attorney 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
  • 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.
  • 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%).
  • 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.
  • 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.
  • 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.
  • 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%).
  • 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.
  • the BTN1A1 binding molecule is hSTC810 having the full heavy chain and light chain sequences as shown in the Sequence Table 1B.
  • the BTN1A1 binding molecule provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:33.
  • the BTN1A1 binding molecule provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:33.
  • the BTN1A1 binding molecule provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:34.
  • the BTN1A1 binding molecule provided herein comprises a light chain consisting of the amino acid sequence of SEQ ID NO:34.
  • 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.
  • 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.
  • 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).
  • the amino acid sequence modifications do not include any modification within an CDR.
  • the amino acid sequence modifications do not include any modification within a CDR (such as CDR1, CDR2, CDR3, or any combination thereof).
  • the amino acid sequence modifications are in the framework, constant region, and/or Fc region.
  • 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%).
  • 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.
  • 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.
  • the BTN1A1 binding molecule provided herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:43.
  • the BTN1A1 binding molecule provided herein comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:43.
  • the BTN1A1 binding molecule provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:44.
  • 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.
  • 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) 2 fragments, F(ab’) 2 fragments, disulfide-linked Fvs (sdFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody and minibody.
  • 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.
  • IgG, IgE, IgM, IgD, IgA and IgY class
  • IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 subclass of immunoglobulin molecule.
  • NAI-1543197688v1 77 Attorney Docket No.: 13532-031-228 [00299]
  • 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.
  • the antibodies provided herein are monospecific for a given epitope of a BTN1A1 polypeptide and do not bind to other epitopes.
  • NAI-1543197688v1 78 Attorney 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 79 Attorney 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 S NAI-1543197688v1 80 Attorney Docket No.: 13532-031-228 Table 1C: Mouse anti-human BTN1A1 Antibody (STC810) VH and VL Sequences VH (SEQ ID NO:35) EVQLQQSGPELVKPGASVKISCKASGYTFTHYNMDWVKQSHGKSLEW
  • a method for sensitizing a response of cancer cells to an anti-cancer treatment comprising contacting the cancer cells with an effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 as described herein.
  • 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.
  • 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.
  • 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.
  • the anti- cancer therapy is selected from a chemotherapy and a radiation therapy.
  • the molecule is a BTN1A1 antagonist.
  • 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).
  • 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).
  • GAL-1 Galectin-1
  • Galectin-9 Galectin-9
  • NRP-2 Nrp-2
  • BTLA B- and T-Lymphocyte Attenuator
  • 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).
  • GAL-1 Galectin-1
  • GAL-9 Galectin-9
  • NRP-2 NRP-2
  • BTLA B- and T-Lymphocyte Attenuator
  • 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.
  • the cancer is relapsed following a previous cycle of the anti-cancer treatment.
  • the cancer 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.
  • the previous anti- cancer treatment is a chemotherapy.
  • the previous anti-cancer treatment is a radiation therapy.
  • the cancer to be treated with the present method expresses BTN1A1.
  • 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).
  • 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.
  • the immune effector cells are T lymphocytes.
  • 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.
  • 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.
  • the immune effector cells lack expression of PD-L1.
  • expression of PD-L1 in the immune effector cells are below a PD-L1 reference level.
  • the immune effector cells express BTN1A1 and lack expression of PD-L1.
  • 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.
  • expression of BTN1A1 in the cancer is equal to or above a BTN1A1 reference level.
  • the BTN1A1 reference level is the average or medium expression level of BTN1A1 in a population of healthy individuals.
  • the PD-L1 NAI-1543197688v1 88 Attorney Docket No.: 13532-031-228 reference level is the average or medium expression level of PD-L1 in the population of healthy individuals.
  • BTN1A1 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.
  • 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.
  • 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.
  • 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. [00307] 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. [00308] 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.
  • 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 89 Attorney 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.
  • 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.
  • the cancer sample is a tumor sample.
  • a percentage of the cancer cells express BTN1A1 and are Ki-67 negative.
  • at least about 5% of the cancer cells express BTN1A1 and are Ki-67 negative.
  • at least about 10% of the cancer cells express BTN1A1 and are Ki-67 negative.
  • at least about 15% of the cancer cells express BTN1A1 and are Ki-67 negative.
  • 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.
  • 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 90 Attorney 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.
  • 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. [00311] 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.
  • PD-L1 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.
  • 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. [00313] 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. [00314] 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.
  • 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 91 Attorney 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.
  • 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.
  • 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.
  • 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. [00315] 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.
  • 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.
  • 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. [00316] 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. [00317] In some embodiments, the cancer is colorectal cancer.
  • 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. [00318] 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. [00319] In some embodiments, the cancer has been previously treated with a chemotherapy, and has developed resistance to or relapsed from such treatment.
  • 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 93 Attorney 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
  • 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.
  • the chemotherapeutic agent for the small cell lung cancer is selected from carboplatin, cisplatin, etoposide, paclitaxel, Armitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).
  • the cancer is a small cell lung cancer that has been previously treated with paclitaxel and developed resistance or relapse from such treatment.
  • the cancer is a colorectal cancer that has been previously treated with a chemotherapeutic agent and developed resistance or relapsed from such treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • a chemotherapy comprising a combination of folinic acid, fluorouracil and irinotecan (FOLFIRI), and developed resistance or relapsed from such treatment.
  • the cancer is a colorectal cancer that has been previously treated with a chemotherapy comprising capecitabine and developed resistance or relapsed from such treatment.
  • the subject in need thereof has been administered one or more cycles of a chemotherapy and developed resistance or relapsed from such treatment.
  • the subject has been administered 1 cycle of a chemotherapy and developed resistance or relapsed from such treatment.
  • 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.
  • the cancer has been previously treated with a radiation therapy and has developed resistance to or relapsed from such treatment.
  • the radiation therapy includes using ⁇ -rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells.
  • 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 96 Attorney 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.
  • 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.
  • 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.
  • 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.
  • an effective amount of the molecule is administered to the cancer cells.
  • a therapeutic effective amount of the molecule is administered to the subject having cancer.
  • 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.
  • 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 97 Attorney 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 99 Attorney 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.
  • 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.
  • 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. [00333] 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.
  • the dose of the NAI-1543197688v1 100 Attorney 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.
  • 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. [00334] 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.
  • the dose of the administered molecule is about 0.1 mg/kg of the subject’s body NAI-1543197688v1 101 Attorney 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 103 Attorney Docket No.: 13532-031-228 [00335] In some embodiments, the dose range of the administered molecule is from about 200mg to about 1000mg.
  • 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.
  • 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.
  • the dose range of the administered molecule is from about 400mg to about 450mg. [00336] 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.
  • 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. [00337] 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 104 Attorney 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.
  • 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.
  • the dose of the administered molecule is about 1000mg.
  • cancer cells sensitized e.g., contacted in vitro or administered in vivo
  • 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.
  • 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.
  • the apoptosis rate of unsensitized cancer cells does not increase in response to treatment by the chemotherapeutic agent or radiation therapy.
  • cancer cells sensitized e.g., contacted in vitro or administered in vivo
  • 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.
  • 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 105 Attorney 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.
  • the proliferation rate of unsensitized cancer cells does not reduce in response to treatment by the chemotherapeutic agent or radiation therapy.
  • the cancer is a solid tumor.
  • 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.
  • 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.
  • the tumor volume of a unsensitized tumor does not reduce in response to treatment by the chemotherapeutic agent or radiation therapy.
  • the cancer is in a subject (e.g., a human cancer patient).
  • 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.
  • 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.
  • 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.
  • 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 106 Attorney 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.
  • 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.
  • a method for preparing a lung cancer patient for a chemotherapy comprising administering one or more chemotherapeutic agent selected from carboplatin, cisplatin, etoposide, paclitaxel, Armitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).
  • chemotherapeutic agent selected from carboplatin, cisplatin, etoposide, paclitaxel,
  • doxorubicin hydrochloride etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lur
  • the lung cancer patient exhibits enhanced effective subject response to the chemotherapy after being prepared by the method.
  • the effective subject response is shrinkage of tumor volume in the lung cancer patient.
  • the lung cancer patient does not exhibit any effective subject response to the chemotherapy without being prepared by the method.
  • the lung cancer is small cell lung cancer.
  • the chemotherapy comprises paclitaxel.
  • 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.
  • the lung cancer is small cell lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • a method for preparing a colorectal cancer patient for a chemotherapy comprising administering one or more chemotherapeutic agent selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, capecitabine, Camptosar (Irinotecan Hydrochloride), Eloxatin (Oxaliplatin), 5-FU (Fluorouracil NAI-1543197688v1 107 Attorney 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 (
  • the colorectal cancer patient exhibits enhanced effective subject response to the chemotherapy after being prepared by the method.
  • the effective subject response is shrinkage of tumor volume in the colorectal cancer patient.
  • the colorectal cancer patient does not exhibit any effective subject response to the chemotherapy without being prepared by the method.
  • the colorectal cancer is Stage I, Stage II, Stage III, or Stage IV colon cancer.
  • the chemotherapy comprises one or more chemotherapeutic agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine paclitaxel.
  • 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.
  • 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.
  • a chemotherapy comprising one or more chemotherapeutic agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, or capecitabine.
  • the chemotherapy is selected from FOLFOX, FOLIRI, and capecitabine.
  • 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. [00347] 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 108 Attorney Docket No.: 13532-031-228 4.5 Combination Therapy for Treating Cancer
  • 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.
  • 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.
  • the cancer cells have been previously treated with the chemotherapy or radiation therapy and developed resistance to the treatment.
  • 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.
  • the immune effector cells are T lymphocytes.
  • the T lymphocytes are CD8+ cells.
  • the CD8+ cells are T cells.
  • the CD8+ cells are cytotoxic T cells.
  • T lymphocytes are infiltrating lymphocytes in a tumor environment.
  • the T lymphocytes are CD4+ cells.
  • the CD4+ cells are T cells.
  • the CD4+ cells are helper T cells.
  • the cancer cell expresses BTN1A1.
  • the cancer cells lack expression of BTN1A1 and the immune effector cells express BTN1A1.
  • 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.
  • the immune effector cells lack expression of PD-L1.
  • expression of PD-L1 in the immune effector cells are below a PD-L1 reference level.
  • the immune effector cells express BTN1A1 and lack expression of PD-L1.
  • 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.
  • expression of BTN1A1 in the cancer is equal to or above NAI-1543197688v1 109 Attorney Docket No.: 13532-031-228 a BTN1A1 reference level.
  • the BTN1A1 reference level is the average or medium expression level of BTN1A1 in a population of healthy individuals.
  • the PD-L1 reference level is the average or medium expression level of PD-L1 in the population of healthy individuals.
  • 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.
  • the subject has been previously treated with the chemotherapy or radiation therapy and developed resistance to the treatment.
  • the subject has been previously treated with the chemotherapy or radiation therapy, and the cancer has relapsed from such treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 110 Attorney 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.
  • 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.
  • 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.
  • the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 is an BTN1A1 antagonist.
  • 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).
  • 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).
  • the molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1 is a molecule described in Section 4.3 (Antagonistic BTN1A1 Binding Molecules).
  • 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.
  • 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.
  • the subject has been previously treated with a second chemotherapy and cancer has relapsed from such treatment.
  • the first chemotherapy and the second chemotherapy are the same or different.
  • 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.
  • the cancer is a colorectal cancer.
  • 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.
  • 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 (
  • the cancer is small cell lung cancer.
  • the first chemotherapy and second chemotherapy for treating the small cell lung cancer are NAI-1543197688v1 113 Attorney Docket No.: 13532-031-228 independently selected from the group consisting of carboplatin, cisplatin, etoposide, paclitaxel, Armitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).
  • the cancer is colorectal cancer.
  • 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-
  • a subject with small cell lung cancer is administered a combination treatment.
  • the combination treatment comprises the molecule described herein and a first chemotherapy.
  • the combination treatment comprises hSTC810 and a first chemotherapy wherein the first chemotherapy is selected from the group consisting of: carboplatin, cisplatin, etoposide, paclitaxel, Armitor (everolimus), doxorubicin hydrochloride, etopophos (etoposide phosphate), etoposide phosphate, everolimus, hycamtin (topotecan hydrochloride), lurbinectedin, methotrexate sodium, topotecan hydrochloride, trexall (methotrexate sodium), and zepzelca (lurbinectedin).
  • a subject with small cell lung cancer is administered a combination treatment.
  • the combination treatment comprises the molecule described herein and the first chemotherapy is paclitaxel.
  • the combination treatment comprises hSTC810 and the first chemotherapy is paclitaxel.
  • a subject with colorectal cancer is administered a combination treatment.
  • the combination treatment comprises the molecule described herein and a first chemotherapy.
  • 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 114 Attorney Docket No.: 13532-031-228 and Tipiracil), Oxaliplatin, Ramucirumab Regorafenib, Stivarga (Regorafenib), Trifluridine and Tipiracil Hydrochloride, Tucatinib, Tukysa (Tucatinib), Xeloda (Capecita
  • a subject with colorectal cancer is administered a combination treatment.
  • 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.
  • the combination treatment comprises hSTC810 and the first chemotherapy comprises one or more agents selected from folinic acid, fluorouracil, oxaliplatin, irinotecan, and capecitabine.
  • a subject with colorectal cancer is administered a combination treatment.
  • 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.
  • 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.
  • a subject with colorectal cancer is administered a combination treatment.
  • 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.
  • 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)
  • GAL-1 Galectin-1
  • GAL-9 Galectin-9
  • NRP-2 NRP-2
  • BTLA B- and T-Lymphocyte Attenuator
  • BTLA B- and T-
  • 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.
  • 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.
  • at least NAI-1543197688v1 115 Attorney 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.
  • the molecule that immunospecifically binds to BTN1A1 comprises any anti-BTN1A1 antibody or antigen binding fragment thereof described herein.
  • the molecule that immunospecifically binds to BTN1A1 comprises hSTC810.
  • the molecule that immunospecifically binds to BTN1A1 comprises STC109.
  • 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.
  • folinic acid fluorouracil
  • oxaliplatin i
  • the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).
  • the antibody or antigen-binding fragment thereof that immunospecifically binds to VEGF comprises Bevacizumab (Avastin).
  • the antibody or antigen binding fragment thereof that specifically binds to VEGF is Ranibizumab (Lucentis).
  • 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.
  • 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.
  • 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
  • Lonsurf Trifluridine and Tipiracil
  • bevacizumab a therapeutically effective amount of bevacizumab
  • the molecule that immunospecifically binds to BTN1A1 comprises hSTC810. In specific embodiments, the molecule that immunospecifically binds to BTN1A1 comprises STC109. [00368] 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.
  • 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.
  • Lonsurf Trifluridine and Tipiracil
  • bevacizumab a therapeutically effective amount of bevacizumab
  • hSTC810 a therapeutically effective amount of hSTC810.
  • 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 ⁇ -rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells.
  • 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.
  • 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. [00372] 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. [00373]
  • the patient or subject with cancer has been previously treated for cancer with a radiation therapy.
  • the radiation therapy includes using ⁇ -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.
  • the anti-PD- 1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq).
  • the cancer is resistant to or relapsed from prior treatment with the second chemotherapy.
  • the cancer is resistant to or relapsed from prior treatment with the radiation therapy.
  • the cancer is resistant to or relapsed NAI-1543197688v1 118 Attorney Docket No.: 13532-031-228 from prior treatment with the anti-PD-1 therapy.
  • the cancer is resistant to or relapsed from prior treatment with the anti-PD-L1 therapy.
  • 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.
  • GAL-1 Galectin-1
  • GAL-9 Galectin-9
  • NRP-2 NRP-2
  • BTLA B- and T-Lymphocyte Attenuator
  • 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.
  • 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.
  • GAL-1 Galectin-1
  • 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.
  • the colorectal cancer is selected from Stage I, Stage II, Stage III, and Stage IV colon cancer.
  • 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.
  • the colorectal cancer is selected from Stage I, Stage II, Stage III, and Stage IV colon cancer.
  • 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 119
  • 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.
  • 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).
  • 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).
  • 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 Tipiraci
  • the molecule that immunospecifically binds to BTN1A1 comprises STC109.
  • 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.
  • the antibody that immunospecifically binds to VEGF comprises Bevacizumab (Avastin).
  • the chemotherapy comprises Lonsurf (Trifluridine and Tipiracil).
  • 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.
  • 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.
  • any remaining cancer e.g., cancer that the surgery failed to eliminate
  • compositions and Kit [00384]
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 121 Attorney 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.
  • 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.
  • compositions described herein are not limited by the particular nature of the therapeutic preparation.
  • such compositions can be provided in formulations together with physiologically tolerable liquid, gel, or solid carriers, diluents, and excipients.
  • 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.
  • 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.
  • the number of administrations of a preferred dosage and/or an effective amount can vary according to the response of the subject.
  • kits for treating cancer e.g., lung cancer or colorectal cancer
  • the kit comprises the presently disclosed therapeutic agents, e.g., in a container.
  • kits 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.
  • 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.
  • 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.
  • Example 1 Identification of BTN1A1 as a Target for Cancer Therapy [00393] 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 123 Attorney Docket No.: 13532-031-228 BTN1A1 was identified as a target that overexpresses under such conditions.
  • Na ⁇ ve T cells were isolated from a non-tumor bearing mouse and placed into a 96 well plate. The na ⁇ ve 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.
  • 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.
  • T cells isolated from irradiated vs. unirradiated animals were compared in the same in vitro suppression assay. Proliferation was suppressed in T cells treated with non-target control shRNAs whereas inactivation of target genes that negatively regulate (inhibit) the immune response resulted in an enhanced response (reduced suppression). Significantly better T cell proliferation (i.e., reduced T cell suppression) was observed in samples that contained knock-down of BTN1A1, supporting that BTN1A1 is involved in inhibition of T cell responses, when combined with suppressor cells isolated from an irradiated animal.
  • BTN1A1 was identified as targets for cancer therapy, in particular, as a target whose inhibition can activate patient’s own immune system by releasing the immunosuppressive effect by the stressed cancer cells. Furthermore, inhibition of BTN1A1 is expected to sensitize a tumor to additional therapies such as radiotherapy. 5.2
  • Example 2 BTN1A1 is Expressed in Various Cancer Types [00396] To assess BTN1A1 expression levels across different cancer types a cBioPortal search was performed. CBioPortal (Gao et al. (2013) Sci. Signal.6(269)pl1.; Cerami et al. (2012) Cancer Discov.2(5) 401-4) allows the mining of results from 150 published cancer genomics studies.
  • FIG.21 illustrates results from the cBioPortal search for BTN1A1.
  • the frequency of mutations (green), deletions (blue), and amplifications (red) was plotted by cancer type.
  • BTN1A1 was found to be expressed in a variety of cancer types, including breast cancer, NAI-1543197688v1 124 Attorney Docket No.: 13532-031-228 neuroendocrine prostate cancer (NEPC), diffuse large B-cell lymphoma, melanoma, National Cancer Institute cancer panel (NCI 60), uveal melanoma, pancreas cancer, ovarian cancer, uterine cancer, lung adenocarcinoma, desmoplastic small-round-cell tumor, bladder cancer, colorectal cancer, lung squamous cell carcinoma, liver cancer, lung cancer, stomach cancer, cholangiocarcinoma, esophagus squamous cell carcinoma, head and neck cancer, sarcoma, prostate cancer, liver cancer, pancreas cancer
  • Example 3 Identification of Galectin-1, Galectin-9 and Neuropilin-2 as BTN1A1 Ligands
  • a plasma membrane protein array was screened using RetrogenixTM cell microarray technology (Whaley Bridge, United Kingdom).
  • RetrogenixTM cell microarray technology Wang Bridge, United Kingdom.
  • expression vectors encoding plasma membrane proteins were arrayed on slides and reverse transfected into HEK293 cells to create microarrays of cells expressing candidate BTN1A1 ligands. Binding of BTN1A1-Fc to candidate BTN1A1 ligands was detected by fluorescence imaging.
  • BTN1A1 ligands were confirmed using the same cell microarray technology and secondary assays, including co-immunoprecipitation and surface- plasmon resonance assays (BiacoreTM). 5.3.1 Primary Screen and Reconfirmation [00400] 4550 expression vectors, each encoding a full-length human plasma membrane protein, were arrayed in duplicate across 13 microarray slides (“slide sets”). More than 3500 of the arrayed expression vectors encoded unique genes.
  • One expression vector control (pIRES- hEGFR-IRES-ZsGreen1) was spotted in quadruplicates on each slide to confirm that a minimal threshold of transfection efficiency was met or exceeded on each slide (mean ZsGreen signal from the pIRES-EGFR-ZsGreen vector over background of 1.5).
  • Human HEK293 cells were used for reverse transfection and protein expression.
  • BTN1A1-ECD-Fc was added to each slide as a test ligand at a final concentration of 20 ⁇ g/ml following cell fixation.
  • BTN1A1-Fc binding to HEK293 cell expressing BTN1A1 ligands or negative control cells was detected using an anti- IgG antibody and fluorescence imaging.
  • a primary ‘hit’ was defined as a duplicate spot on a microarray slide showing an increased signal relative to NAI-1543197688v1 125 Attorney Docket No.: 13532-031-228 background levels.
  • Primary hits were identified by visual inspection of images gridded by ImageQuant software. Primary hits were classified as ‘strong,’ ‘medium,’ ‘weak’ or ’very weak,’ based on the fluorescence intensity of duplicate spots. [00401] Primary hits were reconfirmed in the cell microarray assay. Vectors encoding the primary hits were arrayed on multiple slide sets.
  • Each slide in the confirmation assay also included CD86 positive control and EGFR negative control.
  • BTN1A1-Fc generally showed only low background binding to fixed untransfected HEK293 slides when tested at 2 ⁇ g/ml, 5 ⁇ g/ml, or 20 ⁇ g/ml. A total of 40 slides were screened in the primary screen (26 slides) and secondary confirmation assays (14 slides).
  • FIG.11 shows an image illustrating results of an exemplary reconfirmation assay. Strong binding signals were observed for the positive control interaction of CTLA4-hFc (soluble ligand) with CD86 (cellular membrane protein), which validated the assay conditions.
  • Gal-1 Three primary hits Galectin-1 (Gal-1), Galectin-9 (Gal-9), and Neuropilin-2 (NRP-2) showed specific binding with BTN1A1-Fc, but not with negative controls, in the reconfirmation assays. Thus, Gal-1, Gal-9, and Nrp2 were confirmed as BTN1A1-ligands. 5.3.2 Co-Immunoprecipitation [00404] Gal-1 and Gal-9 were further validated as BTN1A1 ligands by co- immunoprecipitation (co-IP). BTN1A1-Flag was expressed in HEK293T cells alone or in combination with Myc- and Flag-double tagged Gal-1 or Gal-9 (FIG.12A).
  • Immunoprecipitation was then performed with anti-Myc or anti-BTN1A1 antibodies (FIG.12B). Immunoprecipitates were analyzed by SDS-PAGE to probe the interaction between BTN1A1 and Gal-1 or Gal-9 (FIG.12C). Pull-down of Myc-tagged Gal-1 and Gal-9 using an NAI-1543197688v1 126 Attorney Docket No.: 13532-031-228 anti-Myc antibody resulted in co-IP of Flag-tagged BTN1A1 (FIG.12C).
  • BTN1A1 was pulled-down using the BTN1A1-specific antibody STC810.
  • BTN1A1 pull down with STC810 resulted in co- IP of Gal-1 and Gal-9 (FIG.12C).
  • Gal-1 and Gal-9 bona fide ligands of BTN1A1.
  • the BTN1A1-Gal-1 interaction was further analyzed in a surface plasmon resonance (BiacoreTM) binding assay.
  • FIGS.13A-D show exemplary BIAcore sensograms illustrating Gal-1-binding to glycosylated BTN1A1 wild type (BTN1A1, FIG.13A), non-glycosylated BTN1A1 mutant (BTN1A1-2NQ) or other members of the BTN1A1 family (BTN2A1 - FIG.13C; BTN3A2 - FIG.13D) Gal-1 was not found to detectably bind to an unglycosylated BTN1A1-2NQ mutant protein (FIG.13B), demonstrating that Gal-1 binds to BTN1A1 in a glycospecific manner.
  • Gal-1 was not found to detectably bind to other members of the BTN1A1 family, such as BTN2A1 (FIG.13C) or BTN3A2 (FIG.13D), demonstrating that Gal-1 is a selective ligand of BTN1A1 within the BTN1A1 family.
  • BTN2A1 FIG.13C
  • BTN3A2 FIG.13D
  • Gal-1 is a selective ligand of BTN1A1 within the BTN1A1 family.
  • Example 4 Identification of Galectin-1, Galectin-9 and Neuropilin-2 as BTN1A1 Ligands 5.4.1 ⁇ -Galactosidase Complementation Assay [00406] Chimeric proteins composed of proteins of interest fused to complementing ⁇ - galactosidase ( ⁇ -gal) deletion mutants are useful to analyze intracellular protein complexes.
  • FIG.14A shows a graph illustrating the design of a ⁇ -gal complementation assay.
  • ⁇ -gal galactosidase complementation assays are typically designed using two inactive fragments of ⁇ - galactosidase ( ⁇ -gal), the enzyme donor (ED) and the enzyme acceptor (EA), which combine to create an active ⁇ -gal enzyme.
  • ⁇ –galactosidase activity was measured as an indicator of a direct BTN1A1-BTN1A1-ligand interaction.
  • ⁇ –galactosidase complementation of BTN1A1-EA and BTLA-PK or Nrp-2-PK was observed (FIG.14B).
  • the results of the ⁇ -gal complementation assay show that BTLA and Nrp-2 interact with BTN1A1 in a cis-acting manner. 5.4.2 Co-Immunoprecipitation [00408] To validate BTN1A1 ligands identified in the ⁇ –Gal complementation screen BTN1A1 was co-transfected with BTLA and Nrp-2 and co-immunoprecipitated.
  • FIG.15 shows images of western blots with representative results of BTN1A1 – BTLA Co-IP experiments.
  • Co- IP was performed with anti-FLAG or anti-Myc antibodies as shown in FIG.5.
  • Precipitates of HEK293T cells expressing BTN1A1-Flag and BTLA-Myc or Nrp-2-Myc were analyzed by SDS-PAGE (Nrp-2 data not shown in FIG.15).
  • Co-IP with an anti-FLAG antibody resulted in co-precipitation of BTLA-Myc or Nrp-2-Myc.
  • FIG.16A shows a sensogram illustrating Gal-1 and BTLA binding to BTN1A1-Fc. Gal-1 binding is indicated by a positive response signal in the sensogram.
  • BTLA binding to immobilized BTN1A1-Fc on the BiacoreTM chip resulted in a reduction of the response signal in the sensogram (negative signal).
  • FIG.16B shows sensograms illustrating the dose-dependent decrease of response signals observed when injecting BTLA onto a BiacoreTM chip with immobilized BTN1A1-Fc at 0.4 ⁇ M, 0.8 ⁇ M, 1.6 ⁇ M, 3.2 ⁇ M, or 6.4 ⁇ M.
  • the observed NAI-1543197688v1 128 Attorney Docket No.: 13532-031-228 decrease in SPR signals resulting from BTLA binding to BTN1A1 indicates a conformational change, e.g., in BTN1A1 upon BTN1A1-BTLA complex formation.
  • FIG.17 shows sensograms illustrating the results of a bio-layer interferometry (BLI) experiment analyzing BTLA binding to BTN1A1-Fc on an Octet® system (FortéBio, Menlo Park, CA).
  • Anti-hIgG Fc capture (AHC) tips of a FortéBio Octet® RED96 system were coated with BTN1A1-Fc.
  • the coated biosensor tips were dipped into solutions of increasing concentrations of BTLA (0.8 ⁇ M, 1.6 ⁇ M, or 3.2 ⁇ M) and BTLA binding to BTN1A1 was monitored.
  • Table 3 shows results for the binding kinetics and dissociation constant of the BTN1A1-BTLA interaction individually determined for each BTN1A1 concentration.
  • An overall KD value was calculated by steady state analysis using FortéBio Data Analysis 9.0 software. According to this calculation, BTLA was determined to bind BTN1A1 with a KD of 17 ⁇ M ⁇ 0.81 ⁇ M of KD.
  • Table 3 Loading S ample ID Sample ID Conc. ( ⁇ M) Response KD (M) kon(1/Ms) kdis(1/s) RMax 5.5
  • Example 5 Production and Screening of Dimer-Specific BTN1A1 Monoclonal Antibodies [00411] Immunization.
  • BTN1A1-Fc dimer form of BTN1A1
  • Fc fusion vector pFUSE-hIgG1-Fc, Invivogen
  • HEK293T cells overexpressing BTN1A1 were were incubated with anti-BTN1A1 antibodies existing in hybridoma culture supernatant. After washing, secondary antibodies conjugated with FITC were added as detection agent. Fluorescence intensity (measured fluorescence intensity, MFI) was measured via FACS I flow cytometry analysis to assess the relative binding of the anti-BTN1A1 antibodies to membrane bound BTN1A1 WT on cells. Antibodies that exhibited significantly higher MFI on WT BTN1A1 were selected for further evaluation. Based on the binding analysis, sixty-seven candidate MAb-producing hybridomas were selected, grown in ADCF medium, and their supernatant containing monoclonal antibody was concentrated and purified.
  • MFI measured fluorescence intensity
  • ELISA In order to exclude the possibility that the observed binding was due to human Fc binding, ELISA was performed using human BTN1A1-Fc and human IgG1 control. The antigens BTN1A1-Fc and human IgG1 were coated onto ELISA plate. Antibodies were added to each well and binding was for each antibody determined by standard direct ELISA against the antigens. Human IgG1 binding antibodies were excluded from the candidates. [00414] Octet. To determine the binding affinity, the selected antibodies that showed high binding activity in FACS and ELISA were subjected to Octet kinetic analysis. Using a biosensor coated with anti-mouse Fc capture antibody, KD was determined by Kon and Koff.
  • Antibodies with higher affinity were selected.
  • Epitope binning is also used to categorize the epitope binding characteristics of panels of antibodies against a single target. This epitope binning experiment was designed to determine whether two different antibodies bind to the same epitope. If two antibodies bind to the same epitope of the antigen, then the binding of the first antibody will preclude the binding if the second antibody. If each antibody in a tested pair binds to a completely independent epitope, then binding of the first antibody will have no effect on the binding of the second. Through repeated testing, the antibodies are grouped according to epitope binding specificity.
  • variable region of the heavy chain (VH) and of the variable region (VL) of the light chain, which contains the complementarity determining regions (CDRs), were amplified using specific primer sets from the SMARTer® RACE cDNA Amplification Kit (Takara/Clontech), which was then used as the template in a PCR.
  • the product was ligated into the pRACE expression vector.
  • the PCR products ligated into pRACE in-fusion vectors were transformed into Top10 competent E. coli cells (ThermoFisher).
  • the cloned vectors were selected, purified, and sequenced.
  • the sequencing results were analyzed with the abYsis website (www.bioinf.org.uk/abysis2.7).
  • the CDR region peptide sequences were corroborated by three different prediction methods.
  • the sequences of the HC and LC of each antibody were aligned using Clustal Omega (www.ebi.ac.uk/Tools/msa/clustalo/).
  • the antibody sequencing results revealed that most of antibodies have the same sequences in heavy and light chain.
  • T cell killing assay is an effective minimized system in which to test the efficacy of immune checkpoint blockade agents, but BTN1A1 and its receptors may each be expressed by multiple cell types and T cells are only one component of the immune response to cancer. So, in order to develop an in vitro model that better represents the immune environment in which cancer cell killing must occur, STCube developed a cancer cell killing assay using T cells from whole, na ⁇ ve peripheral blood monocyte populations. To evaluate the killing of cancer cells by na ⁇ ve T cells, PC3 human prostate cancer cells were stably transfected with human BTN1A1, then plated into a 96 well plate. Isolated T cells were added to each well, along with the indicated concentration of BTN1A1 antibodies.
  • NAI-1543197688v1 133 Attorney Docket No.: 13532-031-228
  • a cell-permeable reagent which is fluorescent only after cleavage by Caspase 3/7 was added as an apoptosis indicator.
  • Apoptosis was enhanced in PC3 cells by the inclusion of STC2714 in the media, indicating that STC2714 blocks a suppressive signal mediated from the cancer cell to T cells in the context of the whole circulating immune component ( Figure 18).
  • Western blot for detection of dimer-specific BTN1A1 antibody Western blot for detection of dimer-specific BTN1A1 antibody.
  • STC2714 is a dimer-specific antibody.
  • the KD value of STC2714 was determined using a Biacore X-100 system (GE Healthcare Life Science). The KD value was obtained by the process of association and dissociation of BTN1A1-Fc (a dimer form) and BTN1A1-His (a monomer form) in the mobile phase to STC2714 bound to a gold sensor chip immobilized with anti-mouse IgG antibody.
  • FIG. 20A and 20B A representative association/ dissociation graph is shown in Figures 20A and 20B.
  • Efficacy of hSTC810 in Combination with Paclitaxel on SCLC Tumors 5.6.1 Materials and Methods Reagents [00419] Cells were cultured in Dulbecco’s modified eagle’s medium (DMEM)/F12 or RPMI- 1640 media (Gibco) supplemented with 10% fetal bovine serum (FBS) (Crystalgen). Antibodies used in this report were purchased from Cell Signaling, Sigma, and BioLegend, or were developed internally and stored at 4 o C.
  • DMEM Dulbecco
  • F12 RPMI- 1640 media
  • FBS fetal bovine serum
  • STcube Pharmaceuticals provided the mouse anti-human NAI-1543197688v1 134 Attorney Docket No.: 13532-031-228 BTN1A1, and Samsung Biologics (SBL) produced the clinical-grade test agent hSTC810.
  • Paclitaxel (PTX) was purchased from Sigma-Aldrich and originally dissolved in 100% DMSO and was then diluted to 15% DMSO using PBS. Matrigel was purchased from Corning.
  • Human peripheral blood mononuclear cells (PBMCs) were freshly isolated using Ficoll-Paque Plus (GE Healthcare) gradient centrifugation obtained from New York blood center according to the standard Ficoll density gradient centrifugation method.
  • SCLC Human small cell lung cancer
  • SCLC Spheroid Preparation NCI-H345 SCLC cell lines were cultured in DMEM/F-12 medium to reach a minimal confluency of 90% and prepared approximately 1 x 10 4 cells for making each SCLC spheroid. Each dome contained 50% of Matrigel and 50% of the cells (1 x 10 3 cells) with 10% FBS, 1% penicillin, and 1% NEAA complete medium (Gibco). Two domes were set to each well in a 12- well plate with 2 mL of the growth medium. Spheroid formation was monitored using Incucyte Live – Cell Analysis System (Sartorius).
  • the 3D stack and 2D projection images were captured using a 10x objective and a 10 ⁇ m focus step, with time-lapse imaging every six hours and an environmental temperature of 37 o C and 5% CO2.
  • BTN1A1 Expression of Immunohistochemistry (IHC) and Immunofluorescence (IF) of SCLC Tumors [00422]
  • IHC assays the ImmPRESS Excel Amplified HRP (peroxidase) Polymer Staining Kit (Vector Laboratories MP-7601) was used. Slides were deparaffinized in xylene and rehydrated with a graded ethanol-water series.
  • Antigen retrieval was performed in citrate buffer [citrate (pH 6.0), Dako K8005 Envision Flex Target Retrieval Solution Low pH (50x) DM829] using Dako PT link (97 o C for 20 minutes).
  • the slides were incubated in Bloxall (Vector Laboratories SP-6000-100) for 10 minutes to block endogenous peroxidase and alkaline phosphatase activity.
  • Bloxall Vector Laboratories SP-6000-100
  • slides were incubated in 2.5% normal horse NAI-1543197688v1 135 Attorney Docket No.: 13532-031-228 serum (Vector Laboratories, S-2012).
  • Antigen retrieval was performed in citrate buffer (pH 6.0) and Tris-EDTA buffer (pH 9.0) using microwave treatment at a low power setting for 15 minutes.
  • Six-plex panel multiplex immunofluorescence (mIF) was performed using the following antibodies: anti-BTN1A1 (STC43H11-1), anti-PD-L1 (clone E1L3N, dilution 1:200, Cell Signaling), anti-CD8 (clone C8/144B, dilution 1:200, DAKO), anti-Ki-67 (clone 8D5, dilution 1:1000, Cell Signaling), anti-CK (clone: AE1/AE3, dilution 1:2000, DAKO) and NAI-1543197688v1 136 Attorney Docket No.: 13532-031-228 DAPI.
  • TSA-conjugated fluorophores (PerkinElmer) were used to visualize each biomarker: Opal 690 (CK), Opal 650 (Ki-67), Opal 620 (PD-L1), Opal 570 (BTN1A1 and Opal 520 (CD8). Slides were mounted using VECTASHIELD ® HardSet TM Antifade Mounting Medium. Image acquisition was performed with a Vectra Quantitative Pathology Imaging System (Akoya Biosciences). [00424] For post-processing of scanned images, the first step of image processing includes extraction of each tissue as a unit of analysis, using InForm 2.6.0 image analysis software.
  • each of the five markers was separately counted phenotypically per the region of interest (ROI).
  • ROI region of interest
  • Phenotypic counts of the cell segmentation data analysis from the non-small cell lung cancer (NSCLC) and SCLC tumor tissues were performed.
  • An image analysis pipeline in the InForm 2.6.0 applies the classifier to create probability maps for each cell type individually, then segments, counts, and optionally measures features for each cell of each type.
  • Efficacy of hSTC810 in combination with Paclitaxel against SCLC Spheroids [00427] While the spheroid formation was monitored using Incucyte Live-Cell Analysis System for 8 days of incubation, the grown NCI-H345 SCLC cells-derived spheroid cultures were filtered to select a similar size ranging from 80 to 150 ⁇ m in diameter. Freshly isolated PBMCs ( ⁇ 1 x 10 5 ) or PBMCs with hSTC810 (200 ⁇ g/ml) were added to the pre-formed spheroids in each single well of a 12-well plate.
  • Paclitaxel (PTX, 1 nM) was added to the PBMCs or PBMCs with hSTC810-treated spheroid cultures, respectively. All cellular behaviors, such as spheroid size, shape, and initial contact time with immune cells, were monitored and recorded every 6 hours for 15 days.
  • BTN1A1 expression levels were relatively higher in twenty-three SCLC cell lines, denoted by #, such as DMS 53 (16.7) and NCI-H146 (6.4) than other NSCLC cell lines ( Figure 1A).
  • # such as DMS 53 (16.7) and NCI-H146 (6.4) than other NSCLC cell lines
  • Figure 1A It was also determined that BTN1A1 nTPM and doubling time correlated with R- squared in lung cancer cell lines. In lung cancer cell lines, SCLC was marked with open circles, which was almost always higher than the trendline marked with closed circles (Figure 1B). These data indicate that the cell division speed in SCLC cells was slower than the normal speed observed for lung cancer cell lines, and at the same time, SCLC cells expressed a lot of BTN1A1.
  • BTN1A1 and PD-L1 Protein Expression in SCLC Tumors [00431] IHC-specific anti-BTN1A1 (STC43H11-1, 0.5 ⁇ g/ml) or PD-L1 (1:200) antibodies were processed with SCLC tumor tissues to determine the expression levels of BTN1A1 and PD- L1, respectively. Strong positive BTN1A1 staining was observed in Figure 2 panels A, C, and E. However, PD-L1 staining was faint as observed in Figure 2, panels B, D, and F. Figure 3 shows confocal single-optical section images showing BTN1A1 (red) and PD-L1 (green) in SCLC patient specimen.
  • BTN1A1-relevant phenotypic counts made of three markers were performed with non-small cell lung cancer (NSCLC) and SCLC tumor tissues, respectively ( Figure 5).
  • NSCLC non-small cell lung cancer
  • Ki-67 Ki-67 staining associates with rapid reproduction of cancer cells and early cancer cell growth. Focused on the relationship of BTN1A1 expression and Ki-67 marker, significant differences were shown between NSCLC and SCLC tissues.
  • the SCLC cells had a 70% BTN1A1 expression level consisting of CK + BTN1A1 + Ki-67- cells (69.1%) and CK + BTN1A1 + Ki-67 + cells (0.9%).
  • NSCLC cells had a 92.5% BTN1A1 expression level consisting of CK + BTN1A1 + Ki-67- cells (26.3%) and CK + BTN1A1 + Ki-67 + cells (66.2%).
  • Ki-67 + which is associated with the rapid reproduction of cancer cells and corresponds to early cancer cell growth
  • PBMC alone PBMC + hSTC810
  • PBCM + hSTC810 + Paclitaxel Three treatments were administered to the spheroids: PBMC alone, PBMC + hSTC810, and PBCM + hSTC810 + Paclitaxel. It was observed that with all three treatments, the PBMC cells attached to the SCLC spheroid hull 2-4 days after being administered to the spheroid culture system (as shown in subsets of Figures 6B, 6C, and 6D). Spheroid size and shape were monitored for 8 days. Treatment with the mixture of PBMC, hSTC810, and Paclitaxel showed the most dramatic changes in size and shape by disintegrating the SCLC spheroids into tiny pieces ( Figure 6D).
  • hSTC810 200 ⁇ g/mL was calculated based on a Phase I Clinical Trial dosing regimen (15 mg/kg) under the guidance of Anroop et al., “A simple practice guide for dose conversion between animals and human,” J Basic Clin Pharma., 27-31, (2016), the content of which is incorporated herein by reference in its entirety.
  • four different treatments including (1) PBMC alone, (2) PBMC + Paclitaxel, (3) PBMC + hSTC810, and (4) PBMC + hSTC810 + Paclitaxel were applied to the spheroids, and the volume ( ⁇ m 3 ) and shape of the spheroids was measured for 5 days.
  • the treatment NAI-1543197688v1 140 Attorney Docket No.: 13532-031-228 consisting of PBMC + hSTC810 + Paclitaxel showed the best efficacy indicating that hSTC810 could exert the best performance in combination with Paclitaxel.
  • the treatment of PBMC + hSTC810 showed better efficacy compared to PBMC + Paclitaxel or PBMC alone.
  • STC109 is a mouse syngeneic BTN1A1 antibody. STC109 in combination with TAS- 102 (Lonsurf) and anti-VEGF antibody was shown to be efficacious in the treatment of colon cancer in a CT26 mouse colon carcinoma xenograft model system. 5.7.1 Materials and Methods Mice [00439] Female Balb/c mice (Jackson Laboratory) were six to eight weeks old with a BW range of 18.0 to 22.0 g.
  • mice were fed ad libitum water (reverse osmosis, 1 ppm Cl), and an NIH 31 modified Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber.
  • the mice were housed on irradiated Enrich-o’cobs TM Laboratory Animal Bedding in static microisolators on a 12-hour light cycle at 20-22 o C (68-72 o F) and 40-60% humidity.
  • the STCube Animal Facility specifically complies with the recommendations of the Guide for Care and Use of Laboratory Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care.
  • Tumor Cell Culture [00441] CT26 mouse colon carcinoma cells were cultured in RPMI medium with Earle salt containing 100 units/mL penicillin G sodium, 100 ⁇ g/mL streptomycin, and 25 ⁇ g/mL gentamicin. The medium was supplemented with 10% fetal bovine serum and 2mM glutamine. The tumor cells were cultured in tissue culture flasks in a humidified incubator at 37 o C in an atmosphere of 5% CO2 and 95% air.
  • CT26 cells were harvested in the exponential growth phase and resuspended in cold phosphate-buffered saline (PBS) at a concentration of 2 x 10 7 cells/mL.
  • Xenografts were initiated by subcutaneously implanting 1 x 10 6 CT26 tumor cells (50 mL suspension) into the right flank of each test animal, and tumors were monitored as their volumes approached the target range of 50-80 mm 3 .
  • Ten days after tumor implantation, the animals were sorted into nine groups (n 10/group) with individual tumor volumes ranging from 50-80 mm 3 and group mean tumor volumes of 65 mm 3 .
  • Testing Agents [00443] STCube Pharmaceuticals provided the hybridoma cell line and BioXCell produced the test agent STC109 (13.29 mg/mL, Lot No.994924N1B).
  • Rat IgG1 Isotype control was purchased from BioXCell (5.67 mg/mL, Lot No.811224J1), and Rat IgG2a Isotype control was purchased from BioXCell (7.35 mg/mL, Lot No.686318F1).
  • Anti-VEGF antibody was purchased from BioXCell (9.05 mg/mL, Lot No.939723D1). All antibodies were stored at 4 o C, and all dosing solutions were diluted in vehicle (PBS) to the appropriate concentration that provided an appropriate dosage of 200 ⁇ g/animal of 100 ⁇ L/animal. The chemo was stored in powder form and dissolved in 0.5% HPMC (hydroxypropyl methylcellulose, Sigma Aldric) on the day of scheduled administration.
  • HPMC hydroxypropyl methylcellulose
  • Group 1 served as the control for this study and was treated with a rat IgG1 isotype control antibody at 200 ⁇ g/animal and a rat IgG2a isotype antibody at 100 ⁇ g/animal.
  • Group 2 received STC109 at 200 ⁇ g/animal.
  • Group 3 received STC109 at 200 ⁇ g/animal and TAS-102 (Lonsurf) at 150 mg/Kg.
  • Group 4 received STC109 at 200 ⁇ g/animal and TAS-102 (Lonsurf) at 150 mg/Kg and was followed by anti-mouse VEGF at 100 ⁇ g/animal. 5.7.2 Results [00445] Groups in this study were treated in accordance with the protocol, as shown in Figure 23.
  • Figure 24 illustrates plots of group mean tumor growth.
  • Figure 25 is a scatter plot showing the individual tumor volumes by the group at Day 23.
  • Figure 26 shows individual tumor growth in each group.
  • Group 1 mice received IgG1 isotype control at 200 ⁇ g/animal three times per week for one week and served as the control group for efficacy analysis of test agents.
  • the Group 1 mean tumor growth plot illustrates the highly consistent and progressive growth of the control CT26 tumors ( Figure 24). Any animal that died prior to the study end was assigned a death cause of either TR or NTRu Sbased on considerations including clinical observations, body weight loss, tumor size, and the number of deaths per group.
  • toxicity-related (TR) death causes were assigned when the tumor size was below 900 mm 3 at the time of death. Assignments of non-toxicity-related (NTRu) death causes were given for animals that exhibited no body weight loss before death or that had tumor sizes above 900 mm 3 at the time of death.
  • Response to STC109 (Group 2) [00447] Group 2 was treated with STC109 at 200 ⁇ g/animal, i.p., three times per week for one week. All Group 2 animals exhibited increase in tumor volume ( Figure 25).
  • Group 3 was treated with STC109 at 200 ⁇ g/animal, i.p., three times per week for one week. TAS-102 (Lonsurf) was then followed at 150 mg/Kg, p.o. five times per week for two weeks. All Group 3 animals exhibited slow increases in tumor volume ( Figure 25). Response to STC109, anti-mouse VEGF and TAS-102 (Group 4) [00449] Group 4 was treated with TAS-102 (Lonsurf) at 150 mg/Kg, p.o., five times per week for two weeks.
  • This study evaluated the therapeutic efficacy of hSTC810 (Nelmastobart), an anti- BTN1A1 antibody, in combination with TAS-102 and Bevacizumab (Avastin), for the treatment of colon cancer using patient derived organoid models. Leveraging advanced 3D culture and organoid system, the study provides critical insights into tumor biology, immune interactions, NAI-1543197688v1 144 Attorney Docket No.: 13532-031-228 and drug responses in a physiologically relevant environment.
  • hSTC810 significantly reduces tumor size, particularly when combined with TAS- 102 (Lonsurf) and Bevacizumab, highlighting a synergistic therapeutic potential. Furthermore, the use of 3D organoid systems allowed for a deeper understanding of the synergistic effect between TAS-102 (Lonsurf) and hSTC810, providing more insights into tumor progression and immune modulation.
  • the tube with the organoids was centrifuged again at 200 x g for 5 minutes at 4 o C and the supernatant was discarded.
  • the organoids were then resuspended in 30 ⁇ L of cold adDMEM/F12+++ culture medium before mixing the cell suspension with Matrigel. 20 ⁇ L of Matrigel was then added to the organoids suspension and the suspension was mixed well by gentle pipetting up and down several times.
  • the Matrigel-cell mixture was dispensed as 50 ⁇ L droplets ( ⁇ 15, 000 cells/drop) into one well of a 6-well plate (usually 5 droplets were plated into each well). The drops were then solidified for 15 minutes upside down at 37 o C and 5% CO2.
  • 3 mL of adDMEM/F12+++ was added for 3 days at 37°C and 5% CO2.
  • the Matrigel domes containing the organoids were scraped from one well of a 6-well cell culture plate using a P1000 pipette tip and transfer them into a 15 mL tube. The tube was then centrifuged at 200 ⁇ g for 5 min at 4°C. The supernatant was discarded, and the Matrigel was digested with 2 mL of TrypLE Express for ⁇ 5 min at 37°C on a shaking platform (60 rpm).
  • the trypsinization was stopped by adding 4 mL of cold adDMEM/F12+++ NAI-1543197688v1 145 Attorney Docket No.: 13532-031-228 supplemented with 20% FBS. The tube was then centrifuged at 200 ⁇ g for 5 min at 4°C. The supernatant was discarded and the cell pellet was washed with 10 mL of cold adDMEM/F12+++. [00458] Single cells were checked, and then 20 ⁇ L of Matrigel + 60 ⁇ L (100-150 colon cancer cells/well and anti-HLA-ABC/anti-HLA-DR each 5 ⁇ g/ml, final) into one well of a 96-round bottom plate.
  • PBMCs were then activated using anti-CD3/CD28 Dynabeads.
  • the anti-CD3/CD28 Dynabeads were resuspended in a vial and vortexed for 30 seconds.
  • a calculated volume of the anti-CD3/CD28 Dynabeads was transferred to a tube, and 1 mL of PBS was added to mix the Dynabeads (vortex for 5 seconds).
  • the tube was placed on a magnet for 1 minute and the supernatant was discarded.
  • the tube was removed from the magnet, and the anti-CD3/CD28 Dynabeads were resuspended in the same volume of culture medium (RPMI). The tube was placed on the magnet again, the supernatant was discarded, and the anti-CD3/CD28 Dynabeads were resuspended in 400 ⁇ L of culture medium (RPMI). [00461] The PBMCs were then activated 1 ⁇ 10 6 hPBMCs were suspended in 1 mL of medium (RPMI) in a 24-well tissue culture plate. 100 ⁇ L of the pre-washed and resuspended Dynabeads were added to the plate to obtain a bead-to-cell ration of 1:1.
  • RPMI culture medium
  • the Dynabeads and hPBMCs were incubated in a humidified CO 2 incubator at 37°C for two days.
  • the hPBMCs were harvested using a magnet and the hPBMCs were used directly for further assay.
  • 1 x 10 3 of the activated hPBMCs were added per well in the 96-round bottom plate that contained the Matrigel and the colon cancer cells. The plate was centrifuged at 200 x g for 5 minutes at 4 o C. The IncuCyte Spheroid program was then run.
  • Treatment Organoids were treated with PBMCs in combination with Bevacizumab, hSTC810, TAS-102 (Lonsurf), or some combination of the three therapeutics (Figure 27).
  • organoids treated with and without PBMCs There were 8 groups of organoids treated with and without PBMCs: 1) organoids only (received no treatment), 2) Bevacizumab 100 ⁇ g/mL, 3) hSTC810100 ⁇ g/mL, 4) Bevacizumab 100 ⁇ g/mL + hSTC810100 ⁇ g/mL, 5) TAS-102 (Lonsurf) 300 nM, 6) TAS-102 (Lonsurf) 300 nM + Bevacizumab 100 ⁇ g/mL, 7) TAS-102 (Lonsurf) 300 nM + hSTC810100 ⁇ g/mL, and 8) TAS-102 (Lonsurf) 300 NAI-1543197688v1 146 Attorney Docket No.: 13532-031-228 nM + Bevacizumab 100 ⁇ g/mL + hSTC810100 ⁇ g/mL.
  • the organoids were stimulated with 200ng/ml IFN ⁇ 1 day before the treatment.
  • the PBMCs were activated with anti-CD3/CD28 two days prior to adding to the organoid culture.
  • Each PBMC-treated or untreated group contained 10 organoids and the organoid sizes were measured daily for 5 consecutive days. 5.8.2 Results Immune Modulation in the Organoid-PBMC Co-culture System [00463] When the combination of each drug was treated without the PBMC co-culture, the groups containing the chemotherapeutic drug TAS-102 (Lonsurf) showed the best effect ( Figures 28 and 29).
  • Example 9 Efficacy of hSTC810 in Combination with Chemotherapy on Colon Cancer 5.9.1 Phase I Clinical Trial – Colon Cancer [00467] hSTC810 treatment was demonstrated to reverse drug resistance in human colon cancer patients previously treated with chemotherapy.
  • Patient #1 [00468] As shown in FIG.9A, a 75-year old male human patient was diagnosed with Stage IV ascending colon cancer on October 23, 2020. The patient underwent right hemicolectomy in November 2020, and was administered Folfox and Bevacizumab over a course of 12 cycles between December 2020 and July 2021. The patient had cancer recurrence, and thereafter underwent 9 cycles of treatment with folfiri and aflibercept between October 2021 and March 2022.
  • the patient received 3 cycles of treatment with hSTC810 at the dose of 0.3 mg/kg body weight between April and May 2022, and tumor assessment in May 2022 showed tumor growth from 15 mm to 23 mm in two target lesions, and no progression in 2 non- target lesions.
  • the patient was treated with 4 cycles of capecitabine between May and August 2022.
  • tumor assessment thereafter in August 2022 showed partial response (PR) maintenance and decrease in tumor markers.
  • PR partial response
  • the patient Upon completion of the 12 cycles, the patient still had a wide wedge resection of lung, RLL, and VATs. Subsequently, the patient received 12 cycles of capecitabine. [00471] The patient then received 15 cycles of FOLFOX between August 2021 and March 22. The patient then received 12 cycles of hSTC810 at the dose of 1 mg/kg between July 2022 and January 2023. The patient is currently going through 3 cycles of Folfiri. The patient showed about 20% reduction in the tumor volume. [00472] In this clinical study, two colon cancer patients who were treated with hSTC810 but discontinued due to disease progression.

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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 1 Attorney 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 2 Attorney 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 3 Attorney 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 4 Attorney 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 5 Attorney 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 6 Attorney 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 7 Attorney 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 8 Attorney 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 9 Attorney 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 10 Attorney 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 11 Attorney 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. [00100] FIGS.9A and 9B show the treatment history of two male colon cancer human patients, respectively. [00101] 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. [00102] 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 12 Attorney Docket No.: 13532-031-228 [00103] 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 (**). [00104] 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). [00105] 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. [00106] 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). [00107] 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. [00108] FIG.17 shows sensograms of BLI experiments in which soluble BTLA was contacted at indicated concentrations with immobilized BTN1A1-Fc. [00109] 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 13 Attorney Docket No.: 13532-031-228 [00110] 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. [00111] 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). [00112] 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. [00113] 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. [00114] 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 106 cells 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 14 Attorney 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. [00115] 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. [00116] 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. [00117] 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. [00118] 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. [00119] 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. [00120] 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. [00121] 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 15 Attorney Docket No.: 13532-031-228 4. DETAILED DESCRIPTION [00122] 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). [00123] 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. [00124] 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 16 Attorney 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). [00125] 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. [00126] 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 [00127] 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 17 Attorney Docket No.: 13532-031-228 4.2 Definitions [00128] 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. [00129] 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. [00130] 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) [00131] An exemplary encoding nucleic acid sequence of human BTN1A1 (BC096314.1 GI: 64654887), is provided below: NAI-1543197688v1 18 Attorney 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). [00132] An exemplary amino acid sequence of an exemplary dimeric BTN1A1 extracellular domain construct (BTN1A1-ECD-Fc) is provided below: NAI-1543197688v1 19 Attorney Docket No.: 13532-031-228 APFDVIGPPEPILAVVGEDAELPCRLSPNASAEHLELRWFRKKVSPAVLVHRDGREQEAE QMPEYRGRATLVQDGIAKGRVALRIRGVRVSDDGEYTCFFREDGSYEEALVHLKVAAL GSDPHISMQVQENGEICLECTSVGWYPEPQVQWRTSKGEKFPSTSESRNPDEEGLFTVA ASVIIRDTSAKNVSCYIQNLLLGQEKKVEISIPASSLPRDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:3). [00133] 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). [00134] 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). [00135] An exemplary encoding nucleic acid sequence of mouse BTN1A1 (GenBank: BC011497.1), is provided below: ATGGCAGTTCCCACCAACTCCTGCCTCCTGGTCTGTCTGCTCACCCTCACTGTCCTAC AGCTGCCCACGCTGGATTCGGCAGCTCCCTTCGATGTGACCGCACCTCAGGAGCCAG NAI-1543197688v1 20 Attorney 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). [00136] 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 21 Attorney 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). [00137] An exemplary amino acid sequence of human GAL-1 (NCBI Reference Sequence NP_002296), is provided below. MACGLVASNLNLKPGECLRVRGEVAPDAKSFVLNLGKDSNNLCLHFNPRFNAHGDAN TIVCNSKDGGAWGTEQREAVFPFQPGSVAEVCITFDQANLTVKLPDGYEFKFPNRLNLE AINYMAADGDFKIKCVAFD (SEQ ID NO:7). [00138] 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). [00139] 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 22 Attorney Docket No.: 13532-031-228 [00140] 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). [00141] 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) [00142] 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 23 Attorney 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). [00143] 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). [00144] 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 24 Attorney 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 25 Attorney Docket No.: 13532-031-228 TGACAGGAATTTCTTGCGGCTGCAGAGTGACAGCCAGAGAGAGGGCCAGTATGCCC GGCTCATCAGCCCCCCTGTCCACCTGCCCCGAAGCCCGGTGTGCATGGAGTTCCAGT ACCAGGCCACGGGCGGCCGCGGGGTGGCGCTGCAGGTGGTGCGGGAAGCCAGCCA GGAGAGCAAGTTGCTGTGGGTCATCCGTGAGGACCAGGGCGGCGAGTGGAAGCACG GGCGGATCATCCTGCCCAGCTACGACATGGAGTACCAGATTGTGTTCGAGGGAGTG ATAGGGAAAGGACGTTCCGGAGAGATTGCCATTGATGACATTCGGATAAGCACTGA TGTCCCACTGGAGAACTGCATGGAACCCATCTCGGCTTTTGCAGTGGACATCCCAGA AATACATGAGAGAGAAGGATATGAAGATGAAATTGATGATGAATACGAGGTGGACT GGAGCAATTCTTCTTCTGCAACCTCAGGGTCTGGCGCCCCCTCGACCGACAAAGAAA AGAGCTGGCTGTACACCCTGGATCCCATCCTCATCACCATCATCGCCATGAGCTCAC TGGGCGTCCTCCTGGGGGCCACCTGTGCAGGCCTCCTGCTCTACTGCACCTGTTCCT ACTCGGGCCTGAGCTCCCGAAGCTGCACCACACTGGAGAACTACAACTTCGAGCTCT ACGATGGCCTTAAGCACAAGGTCAAGATGAACCACCAAAAGTGCTGCTCCGAGGCA TGA (SEQ ID NO:12). [00145] 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. [00146] 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). [00147] An exemplary nucleic acid sequence of human BTLA is provided below (NCBI Reference Sequence NM_001085357.1 (coding sequence)): NAI-1543197688v1 26 Attorney Docket No.: 13532-031-228 ATGAAGACATTGCCTGCCATGCTTGGAACTGGGAAATTATTTTGGGTCTTCTTCTTAA TCCCATATCTGGACATCTGGAACATCCATGGGAAAGAATCATGTGATGTACAGCTTT ATATAAAGAGACAATCTGAACACTCCATCTTAGCAGGAGATCCCTTTGAACTAGAAT GCCCTGTGAAATACTGTGCTAACAGGCCTCATGTGACTTGGTGCAAGCTCAATGGAA CAACATGTGTAAAACTTGAAGATAGACAAACAAGTTGGAAGGAAGAGAAGAACATT TCATTTTTCATTCTACATTTTGAACCAGTGCTTCCTAATGACAATGGGTCATACCGCT GTTCTGCAAATTTTCAGTCTAATCTCATTGAAAGCCACTCAACAACTCTTTATGTGAC AGGAAAGCAAAATGAACTCTCTGACACAGCAGGAAGGGAAATTAACCTGGTTGATG CTCACCTTAAGAGTGAGCAAACAGAAGCAAGCACCAGGCAAAATTCCCAAGTACTG CTATCAGAAACTGGAATTTATGATAATGACCCTGACCTTTGTTTCAGGATGCAGGAA GGGTCTGAAGTTTATTCTAATCCATGCCTGGAAGAAAACAAACCAGGCATTGTTTAT GCTTCCCTGAACCATTCTGTCATTGGACCGAACTCAAGACTGGCAAGAAATGTAAAA GAAGCACCAACAGAATATGCATCCATATGTGTGAGGAGTTAAG (SEQ ID NO:14). [00148] 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. [00149] 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 27 Attorney Docket No.: 13532-031-228 [00150] 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. [00151] 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. [00152] 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. [00153] In some embodiments, the anti-PD-1 therapy includes an anti-PD-1 antibody provided in International Application No. PCT/US2016/64394. [00154] 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. [00155] 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. [00156] 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 28 Attorney 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. [00157] “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. [00158] 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. [00159] 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 29 Attorney 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. [00160] 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)). [00161] 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 30 Attorney Docket No.: 13532-031-228 [00162] 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)). [00163] 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. [00164] 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 31 Attorney 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. [00165] 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 32 Attorney 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. [00166] 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. [00167] 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 33 Attorney 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. [00168] 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. [00169] 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. [00170] 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 34 Attorney 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. [00171] 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. [00172] 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.) 5th ed. A variable region can be a human variable region. [00173] 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 35 Attorney 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. [00174] 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 36 Attorney Docket No.: 13532-031-228 [00175] 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 n oncova 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. [00177] 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. [00178] 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. [00179] 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 37 Attorney 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. [00180] 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. [00181] 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. [00182] 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. [00183] 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 38 Attorney 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. [00184] 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. [00185] 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. [00186] 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 39 Attorney 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). [00187] 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). [00188] 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. [00189] 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 40 Attorney 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. [00190] 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 41 Attorney 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 42 Attorney Docket No.: 13532-031-228 [00191] 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. [00192] 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. [00193] 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 43 Attorney 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. [00194] 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. [00195] 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 44 Attorney 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. [00196] 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. [00197] 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. [00198] 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 45 Attorney 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. [00199] 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). [00200] 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. [00201] 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%. [00202] 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 46 Attorney Docket No.: 13532-031-228 [00203] 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. [00204] 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. [00205] 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. [00206] 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. [00207] “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 47 Attorney Docket No.: 13532-031-228 [00208] 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. [00209] 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. [00210] 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. [00211] 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 48 Attorney 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). [00212] 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. [00213] 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. [00214] 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. [00215] 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. [00216] 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. [00217] “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 49 Attorney 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. [00218] “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)). [00219] 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 50 Attorney Docket No.: 13532-031-228 [00220] 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. [00221] 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). [00222] 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. [00223] 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). [00224] 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. [00225] The term “composition” is intended to encompass a product containing the specified ingredients (e.g., an antibody provided herein) in, optionally, the specified amounts. [00226] “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 51 Attorney 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. [00227] 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. [00228] 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 52 Attorney 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. [00229] 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. [00230] “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%. [00231] 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. [00232] 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. [00233] 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. [00234] 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 53 Attorney 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. [00235] 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. [00236] 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.” [00237] 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. [00238] 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 [00239] 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 54 Attorney 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. [00240] 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 55 Attorney Docket No.: 13532-031-228 plasmon resonance, biolayer interferometry, co-immunoprecipitation, FRET, or TR-FRET assay, or an ELISA. [00241] 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. [00242] In some embodiments, the BTN1A1 binding molecule includes an antigen-binding domain that binds to the extracellular domain (ECD) of BTN1A1. [00243] 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. [00244] 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. [00245] 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 56 Attorney 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. [00246] 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. [00247] 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 KD less than 50% of the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD that is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of 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. [00248] 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 57 Attorney 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. [00249] 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. [00250] 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 58 Attorney 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. [00251] 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 KD less than half of the KD exhibited 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 KD at 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 KD at least 15 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 20 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 25 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 30 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 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 KD that is about 75% of the KD exhibited 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 59 Attorney 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 KD that is about 10% of the KD exhibited 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 KD that is about 2.5% of the KD exhibited relative to unglycosylated BTN1A1. In some embodiments, the antigen binding fragment binds to glycosylated BTN1A1 with KD that is about 1% of the KD exhibited relative to unglycosylated BTN1A1. [00252] 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 60 Attorney 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. [00253] 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. [00254] 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 61 Attorney 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). [00255] 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 KD less than 50% of the KD exhibited 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 KD that is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% of the KD exhibited 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 KD at least 10 times less than the KD exhibited relative to a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) [00256] 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. [00257] 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 62 Attorney 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). [00258] 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. [00259] 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 63 Attorney 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). [00260] 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. [00261] 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. [00262] 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 64 Attorney 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. [00263] 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 [00264] 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 65 Attorney 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. [00265] 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). [00266] 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. [00267] 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 66 Attorney Docket No.: 13532-031-228 [00268] 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. [00269] 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. [00270] 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. [00271] 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 67 Attorney Docket No.: 13532-031-228 [00272] 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. [00273] 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. [00274] 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. [00275] 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 68 Attorney 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. [00276] 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. [00277] 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. [00278] 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. [00279] 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 69 Attorney 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. [00280] 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 70 Attorney 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. [00281] 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). [00282] 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 71 Attorney 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 72 Attorney 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. [00283] 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). [00284] 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. [00285] 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 73 Attorney 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%). [00286] 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. [00287] 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%). [00288] 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 74 Attorney Docket No.: 13532-031-228 [00289] 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. [00290] 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%). [00291] 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. [00292] 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 75 Attorney 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. [00293] 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. [00294] 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%). [00295] 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 76 Attorney Docket No.: 13532-031-228 [00296] 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. [00297] 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)2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (sdFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody and minibody. [00298] 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 77 Attorney Docket No.: 13532-031-228 [00299] 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 78 Attorney 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 79 Attorney 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 S NAI-1543197688v1 80 Attorney Docket No.: 13532-031-228 Table 1C: Mouse anti-human BTN1A1 Antibody (STC810) VH and VL Sequences VH (SEQ ID NO:35) EVQLQQSGPELVKPGASVKISCKASGYTFTHYNMDWVKQSHGKSLEWIGYIYPSNGG D P NAI-1543197688v1 81 Attorney Docket No.: 13532-031-228 Table 2A: BTN1A1 Antibody (STC109) CDR Sequences Kabat Heavy Chain DFAMA NAI-1543197688v1 82 Attorney Docket No.: 13532-031-228 Table 2B: Mouse anti-BTN1A1 Antibody (STC109) VH and VL Amino Acid Sequences VH (SEQ ID NO:59) N P NAI-1543197688v1 83 Attorney 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 T NAI-1543197688v1 84 Attorney Docket No.: 13532-031-228 Table 2D: STC109 VH Leader, Framework, and Tail Sequences Sequence Region Sequence Fragment Residues Length ID NAI-1543197688v1 85 Attorney Docket No.: 13532-031-228 Table 2E: STC109 VL Leader, Framework, and Tail Sequences Sequence Region Sequence Fragment Residues Length ID NAI-1543197688v1 86 Attorney Docket No.: 13532-031-228 4.4 Methods for Sensitizing Responsiveness of Cancer Cells [00300] 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. [00301] 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). [00302] 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). [00303] 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 87 Attorney 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. [00304] 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). [00305] 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 88 Attorney Docket No.: 13532-031-228 reference level is the average or medium expression level of PD-L1 in the population of healthy individuals. [00306] 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. [00307] 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. [00308] 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 89 Attorney 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. [00309] 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. [00310] 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 90 Attorney 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. [00311] 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. [00312] 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. [00313] 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. [00314] 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 91 Attorney 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. [00315] 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 92 Attorney 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. [00316] 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. [00317] 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. [00318] 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. [00319] 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 93 Attorney 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 94 Attorney 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. [00320] 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). [00321] 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. [00322] 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 95 Attorney Docket No.: 13532-031-228 [00323] 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. [00324] 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. [00325] 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. [00326] 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. [00327] 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. [00328] 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 96 Attorney 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. [00329] 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. [00330] 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. [00331] 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. [00332] 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 97 Attorney 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 98 Attorney 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 99 Attorney 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. [00333] 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 100 Attorney 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. [00334] 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 101 Attorney 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 102 Attorney 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 103 Attorney Docket No.: 13532-031-228 [00335] 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. [00336] 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. [00337] 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 104 Attorney 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. [00338] 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. [00339] 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 105 Attorney 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. [00340] 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. [00341] 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. [00342] 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 106 Attorney 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. [00343] 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. [00344] 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. [00345] 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 107 Attorney 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. [00346] 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. [00347] 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 108 Attorney Docket No.: 13532-031-228 4.5 Combination Therapy for Treating Cancer [00348] 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. [00349] 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 109 Attorney 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. [00350] 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. [00351] 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. [00352] 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 110 Attorney 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. [00353] 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. [00354] 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. [00355] 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 111 Attorney 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. [00356] 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. [00357] 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 112 Attorney 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. [00358] 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 113 Attorney 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). [00359] 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. [00360] 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). [00361] 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. [00362] 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 114 Attorney 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. [00363] 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. [00364] 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. [00365] 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 115 Attorney 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. [00366] 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 116 Attorney Docket No.: 13532-031-228 [00367] 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. [00368] 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. [00369] 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. [00370] 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 117 Attorney Docket No.: 13532-031-228 the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. [00371] 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. [00372] 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. [00373] 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. [00374] 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). [00375] 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 118 Attorney 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. [00376] 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. [00377] 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. [00378] 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. [00379] 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. [00380] 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 119 Attorney 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). [00381] 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. [00382] 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). [00383] 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 120 Attorney Docket No.: 13532-031-228 after the regression of primary cancer to prevent metastasis. 4.6 Compositions and Kit [00384] 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. [00385] 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. [00386] 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. [00387] 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 121 Attorney 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. [00388] 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 122 Attorney Docket No.: 13532-031-228 determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. [00389] 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. [00390] 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. [00391] 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 [00392] 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 [00393] 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 123 Attorney 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. [00394] 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. [00395] The responses of T cells isolated from irradiated vs. unirradiated animals were compared in the same in vitro suppression assay. Proliferation was suppressed in T cells treated with non-target control shRNAs whereas inactivation of target genes that negatively regulate (inhibit) the immune response resulted in an enhanced response (reduced suppression). Significantly better T cell proliferation (i.e., reduced T cell suppression) was observed in samples that contained knock-down of BTN1A1, supporting that BTN1A1 is involved in inhibition of T cell responses, when combined with suppressor cells isolated from an irradiated animal. Accordingly, BTN1A1 was identified as targets for cancer therapy, in particular, as a target whose inhibition can activate patient’s own immune system by releasing the immunosuppressive effect by the stressed cancer cells. Furthermore, inhibition of BTN1A1 is expected to sensitize a tumor to additional therapies such as radiotherapy. 5.2 Example 2: BTN1A1 is Expressed in Various Cancer Types [00396] To assess BTN1A1 expression levels across different cancer types a cBioPortal search was performed. CBioPortal (Gao et al. (2013) Sci. Signal.6(269)pl1.; Cerami et al. (2012) Cancer Discov.2(5) 401-4) allows the mining of results from 150 published cancer genomics studies. [00397] FIG.21 illustrates results from the cBioPortal search for BTN1A1. The frequency of mutations (green), deletions (blue), and amplifications (red) was plotted by cancer type. BTN1A1 was found to be expressed in a variety of cancer types, including breast cancer, NAI-1543197688v1 124 Attorney Docket No.: 13532-031-228 neuroendocrine prostate cancer (NEPC), diffuse large B-cell lymphoma, melanoma, National Cancer Institute cancer panel (NCI 60), uveal melanoma, pancreas cancer, ovarian cancer, uterine cancer, lung adenocarcinoma, desmoplastic small-round-cell tumor, bladder cancer, colorectal cancer, lung squamous cell carcinoma, liver cancer, lung cancer, stomach cancer, cholangiocarcinoma, esophagus squamous cell carcinoma, head and neck cancer, sarcoma, prostate cancer, liver cancer, pancreas cancer, pheochromocytoma and paraganglioma (PCPG), cervical cancer, glioma, and acute myeloid leukemia (AML). 5.3 Example 3: Identification of Galectin-1, Galectin-9 and Neuropilin-2 as BTN1A1 Ligands [00398] To identify BTN1A1 ligands a plasma membrane protein array was screened using RetrogenixTM cell microarray technology (Whaley Bridge, United Kingdom). [00399] In brief, expression vectors encoding plasma membrane proteins were arrayed on slides and reverse transfected into HEK293 cells to create microarrays of cells expressing candidate BTN1A1 ligands. Binding of BTN1A1-Fc to candidate BTN1A1 ligands was detected by fluorescence imaging. Identified BTN1A1 ligands were confirmed using the same cell microarray technology and secondary assays, including co-immunoprecipitation and surface- plasmon resonance assays (BiacoreTM). 5.3.1 Primary Screen and Reconfirmation [00400] 4550 expression vectors, each encoding a full-length human plasma membrane protein, were arrayed in duplicate across 13 microarray slides (“slide sets”). More than 3500 of the arrayed expression vectors encoded unique genes. One expression vector control (pIRES- hEGFR-IRES-ZsGreen1) was spotted in quadruplicates on each slide to confirm that a minimal threshold of transfection efficiency was met or exceeded on each slide (mean ZsGreen signal from the pIRES-EGFR-ZsGreen vector over background of 1.5). Human HEK293 cells were used for reverse transfection and protein expression. BTN1A1-ECD-Fc was added to each slide as a test ligand at a final concentration of 20 μg/ml following cell fixation. BTN1A1-Fc binding to HEK293 cell expressing BTN1A1 ligands or negative control cells was detected using an anti- IgG antibody and fluorescence imaging. Two replicate slides were screened for each of the 13 microarray slides of the primary screen slide set. Fluorescent images were analyzed and quantitated (for transfection efficiency) using ImageQuant software (GE). A primary ‘hit’ was defined as a duplicate spot on a microarray slide showing an increased signal relative to NAI-1543197688v1 125 Attorney Docket No.: 13532-031-228 background levels. Primary hits were identified by visual inspection of images gridded by ImageQuant software. Primary hits were classified as ‘strong,’ ‘medium,’ ‘weak’ or ’very weak,’ based on the fluorescence intensity of duplicate spots. [00401] Primary hits were reconfirmed in the cell microarray assay. Vectors encoding the primary hits were arrayed on multiple slide sets. Each slide in the confirmation assay also included CD86 positive control and EGFR negative control. Candidate BTN1A1-ligands were expressed in HEK293 cells and the cells were fixed. Different slides were then treated with 20 μg/ml BTN1A1-Fc, 20 μg/ml CTLA4-Fc, or no ligand (detection antibody only) (n=2 slides per treatment). [00402] BTN1A1-Fc generally showed only low background binding to fixed untransfected HEK293 slides when tested at 2 μg/ml, 5 μg/ml, or 20 μg/ml. A total of 40 slides were screened in the primary screen (26 slides) and secondary confirmation assays (14 slides). Transfection efficiencies exceeded the targeted transfection efficiency threshold. In the primary screen, 11 duplicate hits (expression vector clones) were identified. The 11 primary hits covered a range of spot intensities (signal to background) from very weak to strong. Identified vectors were sequenced to confirm the identities of candidate BTN1A1 ligands. Vectors encoding the 11 hits, CD86/ZsGreen1 (positive control) or EGFR/ZsGreen1 (negative control) were tested in secondary confirmation assays. [00403] FIG.11 shows an image illustrating results of an exemplary reconfirmation assay. Strong binding signals were observed for the positive control interaction of CTLA4-hFc (soluble ligand) with CD86 (cellular membrane protein), which validated the assay conditions. Three primary hits Galectin-1 (Gal-1), Galectin-9 (Gal-9), and Neuropilin-2 (NRP-2) showed specific binding with BTN1A1-Fc, but not with negative controls, in the reconfirmation assays. Thus, Gal-1, Gal-9, and Nrp2 were confirmed as BTN1A1-ligands. 5.3.2 Co-Immunoprecipitation [00404] Gal-1 and Gal-9 were further validated as BTN1A1 ligands by co- immunoprecipitation (co-IP). BTN1A1-Flag was expressed in HEK293T cells alone or in combination with Myc- and Flag-double tagged Gal-1 or Gal-9 (FIG.12A). Immunoprecipitation (pull-down) was then performed with anti-Myc or anti-BTN1A1 antibodies (FIG.12B). Immunoprecipitates were analyzed by SDS-PAGE to probe the interaction between BTN1A1 and Gal-1 or Gal-9 (FIG.12C). Pull-down of Myc-tagged Gal-1 and Gal-9 using an NAI-1543197688v1 126 Attorney Docket No.: 13532-031-228 anti-Myc antibody resulted in co-IP of Flag-tagged BTN1A1 (FIG.12C). To further confirm the specificity of the BTN1A1-Gal-1 and BTN1A1–Gal9 interactions, BTN1A1 was pulled-down using the BTN1A1-specific antibody STC810. BTN1A1 pull down with STC810 resulted in co- IP of Gal-1 and Gal-9 (FIG.12C). These results further validated Gal-1 and Gal-9 as bona fide ligands of BTN1A1. [00405] The BTN1A1-Gal-1 interaction was further analyzed in a surface plasmon resonance (BiacoreTM) binding assay. BTN1A1-Fc fusion proteins were captured on a protein A-coated CM5 chip, and Gal-1 ligand was injected onto the CM5 chip at five or more different concentrations. FIGS.13A-D show exemplary BIAcore sensograms illustrating Gal-1-binding to glycosylated BTN1A1 wild type (BTN1A1, FIG.13A), non-glycosylated BTN1A1 mutant (BTN1A1-2NQ) or other members of the BTN1A1 family (BTN2A1 - FIG.13C; BTN3A2 - FIG.13D) Gal-1 was not found to detectably bind to an unglycosylated BTN1A1-2NQ mutant protein (FIG.13B), demonstrating that Gal-1 binds to BTN1A1 in a glycospecific manner. In addition, Gal-1 was not found to detectably bind to other members of the BTN1A1 family, such as BTN2A1 (FIG.13C) or BTN3A2 (FIG.13D), demonstrating that Gal-1 is a selective ligand of BTN1A1 within the BTN1A1 family. 5.4 Example 4: Identification of Galectin-1, Galectin-9 and Neuropilin-2 as BTN1A1 Ligands 5.4.1 β-Galactosidase Complementation Assay [00406] Chimeric proteins composed of proteins of interest fused to complementing β- galactosidase (β-gal) deletion mutants are useful to analyze intracellular protein complexes. β- Gal activity resulting from a forced interaction of nonfunctional weakly complementing β-gal peptides (Δα and Δω) can serve as a measure of the extent of interaction of non-β-gal portions of the chimeras. Using β-gal complementation, cis-acting protein–protein interactions occurring at the plasma membrane can be detected. [00407] FIG.14A shows a graph illustrating the design of a β-gal complementation assay. β- Galactosidase complementation assays are typically designed using two inactive fragments of β- galactosidase (β-gal), the enzyme donor (ED) and the enzyme acceptor (EA), which combine to create an active β-gal enzyme. An N-terminal 45 amino acid fragment ProLinker (designated PK) as an ED was fused to a candidate BTN1A1 ligand protein and the BTN1A1 was fused to EA. Interactions between the two proteins can promote complementation between PK and EA, NAI-1543197688v1 127 Attorney Docket No.: 13532-031-228 resulting in formation of an active β-gal enzyme that cleaves a substrate to generate chemiluminescent signal. BTN1A1-EA cell lines were engineered to stably express large β-gal enzyme reporter fragment EA (enzyme acceptor). BTN1A1-ligand candidates fused to PK were transfected into the EA parental cell lines. β–galactosidase activity was measured as an indicator of a direct BTN1A1-BTN1A1-ligand interaction. β–galactosidase complementation of BTN1A1-EA and BTLA-PK or Nrp-2-PK was observed (FIG.14B). The results of the β-gal complementation assay show that BTLA and Nrp-2 interact with BTN1A1 in a cis-acting manner. 5.4.2 Co-Immunoprecipitation [00408] To validate BTN1A1 ligands identified in the β–Gal complementation screen BTN1A1 was co-transfected with BTLA and Nrp-2 and co-immunoprecipitated. FIG.15 shows images of western blots with representative results of BTN1A1 – BTLA Co-IP experiments. Co- IP was performed with anti-FLAG or anti-Myc antibodies as shown in FIG.5. Precipitates of HEK293T cells expressing BTN1A1-Flag and BTLA-Myc or Nrp-2-Myc were analyzed by SDS-PAGE (Nrp-2 data not shown in FIG.15). Co-IP with an anti-FLAG antibody resulted in co-precipitation of BTLA-Myc or Nrp-2-Myc. To confirm the specificity of observed BTN1A1- BTN1A1-ligand interactions, an anti-Myc antibody was used to pull-down BTLA-Myc or Nrp-2- My from cell lysates. BTN1A1-Flag was found to co-precipitate with BTLA-Myc or Nrp-2-My, demonstrating that BTLA and Nrp-2 are bona fide ligands of BTN1A1. 5.4.3 Surface Plasmon Resonance [00409] The interaction between BTN1A1 and BTLA was further analyzed in a BiacoreTM assay. BTN1A1-Fc fusion proteins were captured on a protein A-coated CM5 chip, and BTLA or Gal-1 were injected onto the chip at 3.2 μM. FIG.16A shows a sensogram illustrating Gal-1 and BTLA binding to BTN1A1-Fc. Gal-1 binding is indicated by a positive response signal in the sensogram. BTLA binding to immobilized BTN1A1-Fc on the BiacoreTM chip resulted in a reduction of the response signal in the sensogram (negative signal). FIG.16B shows sensograms illustrating the dose-dependent decrease of response signals observed when injecting BTLA onto a BiacoreTM chip with immobilized BTN1A1-Fc at 0.4 μM, 0.8 μM, 1.6 μM, 3.2 μM, or 6.4 μM. Without being bound by a particular theory, it is believed that the observed NAI-1543197688v1 128 Attorney Docket No.: 13532-031-228 decrease in SPR signals resulting from BTLA binding to BTN1A1 indicates a conformational change, e.g., in BTN1A1 upon BTN1A1-BTLA complex formation. 5.4.4 Biolayer Interferometry [00410] FIG.17 shows sensograms illustrating the results of a bio-layer interferometry (BLI) experiment analyzing BTLA binding to BTN1A1-Fc on an Octet® system (FortéBio, Menlo Park, CA). Anti-hIgG Fc capture (AHC) tips of a FortéBio Octet® RED96 system were coated with BTN1A1-Fc. The coated biosensor tips were dipped into solutions of increasing concentrations of BTLA (0.8 μM, 1.6 μM, or 3.2 μM) and BTLA binding to BTN1A1 was monitored. Table 3 shows results for the binding kinetics and dissociation constant of the BTN1A1-BTLA interaction individually determined for each BTN1A1 concentration. An overall KD value was calculated by steady state analysis using FortéBio Data Analysis 9.0 software. According to this calculation, BTLA was determined to bind BTN1A1 with a KD of 17 µM ± 0.81 µM of KD. Table 3 Loading Sample ID Sample ID Conc. (µM) Response KD (M) kon(1/Ms) kdis(1/s) RMax 5.5 Example 5: Production and Screening of Dimer-Specific BTN1A1 Monoclonal Antibodies [00411] Immunization. To generate dimer-specific BTN1A1 monoclonal antibodies, a dimer form of BTN1A1 (BTN1A1-Fc) was produced by inserting the extracellular domain of the gene into Fc fusion vector (pFUSE-hIgG1-Fc, Invivogen). Hybridomas producing monoclonal antibodies generated against dimer form of BTN1A1 were obtained by the fusion of SP2/0 murine myeloma cells with spleen cells isolated from human BTN1A1-Fc -immunized BALB/c mice (n=6) (Antibody Solution, Inc.) according to standardized protocol. Before fusion, sera from the immunized mice were validated for binding to the BTN1A1 immunogen using FACS analysis. The hybridomas that produced antibodies were again tested for specificity. NAI-1543197688v1 129 Attorney Docket No.: 13532-031-228 [00412] FACS. To identify anti-BTN1A1-Fc MAbs that were specific for and which preferentially bound human BTN1A1-Fc antigen, different types of assays were performed. In a screening assay to detect preferential binding of MAbs to BTN1A1, antibody binding was determined based on the measurement of fluorescence intensity through FACS analysis (using cell membrane bound proteins). By way of example, the assay was performed using the HEK293T human embryonic kidney cell line. Illustratively, HEK293T cells overexpressing BTN1A1were were incubated with anti-BTN1A1 antibodies existing in hybridoma culture supernatant. After washing, secondary antibodies conjugated with FITC were added as detection agent. Fluorescence intensity (measured fluorescence intensity, MFI) was measured via FACS I flow cytometry analysis to assess the relative binding of the anti-BTN1A1 antibodies to membrane bound BTN1A1 WT on cells. Antibodies that exhibited significantly higher MFI on WT BTN1A1 were selected for further evaluation. Based on the binding analysis, sixty-seven candidate MAb-producing hybridomas were selected, grown in ADCF medium, and their supernatant containing monoclonal antibody was concentrated and purified. [00413] ELISA. In order to exclude the possibility that the observed binding was due to human Fc binding, ELISA was performed using human BTN1A1-Fc and human IgG1 control. The antigens BTN1A1-Fc and human IgG1 were coated onto ELISA plate. Antibodies were added to each well and binding was for each antibody determined by standard direct ELISA against the antigens. Human IgG1 binding antibodies were excluded from the candidates. [00414] Octet. To determine the binding affinity, the selected antibodies that showed high binding activity in FACS and ELISA were subjected to Octet kinetic analysis. Using a biosensor coated with anti-mouse Fc capture antibody, KD was determined by Kon and Koff. Antibodies with higher affinity (nanomolar range) were selected. Epitope binning is also used to categorize the epitope binding characteristics of panels of antibodies against a single target. This epitope binning experiment was designed to determine whether two different antibodies bind to the same epitope. If two antibodies bind to the same epitope of the antigen, then the binding of the first antibody will preclude the binding if the second antibody. If each antibody in a tested pair binds to a completely independent epitope, then binding of the first antibody will have no effect on the binding of the second. Through repeated testing, the antibodies are grouped according to epitope binding specificity. This experiment was performed using the Octet Red96 System (Pall ForteBio) with Bio-Layer Interferometry (BLI) to detect and analyze the interaction of biological NAI-1543197688v1 130 Attorney Docket No.: 13532-031-228 molecules. Antigen was bound to the disposable sensors, then additional binding of antibody to the antigen was measured by change in delay of the reflection of the light passing through the sensor. A longer delay is indicative of more mass bound to the sensor, and this value is used to determine the degree of protein-antibody interaction. In this experiment, antibodies were categorized by 5 different classes that do not share the binding site. Table 4: Screening Results of Antibodies by FACS, ELISA and Octet. Code FACS ELISA ELISA (MFI) (Native Ag) (Denatured Ag) Octet (KD) NAI-1543197688v1 131 Attorney Docket No.: 13532-031-228 STC2730 985 0.932 0.395 STC2731 1703 1.204 0.933 NAI-1543197688v1 132 Attorney Docket No.: 13532-031-228 STC2772 6434 1.937 1.485 1.27E-09 STC2773 4604 2.116 1.626 4.45E-09 . , was isolated from hybridoma cells using the RNeasy Mini RNA kit (Qiagen) and cDNA was generated using SuperScript II One-Step RT-PCR system (ThermoFisher). The variable region of the heavy chain (VH) and of the variable region (VL) of the light chain, which contains the complementarity determining regions (CDRs), were amplified using specific primer sets from the SMARTer® RACE cDNA Amplification Kit (Takara/Clontech), which was then used as the template in a PCR. The product was ligated into the pRACE expression vector. The PCR products ligated into pRACE in-fusion vectors were transformed into Top10 competent E. coli cells (ThermoFisher). The cloned vectors were selected, purified, and sequenced. The sequencing results were analyzed with the abYsis website (www.bioinf.org.uk/abysis2.7). The CDR region peptide sequences were corroborated by three different prediction methods. The sequences of the HC and LC of each antibody were aligned using Clustal Omega (www.ebi.ac.uk/Tools/msa/clustalo/). The antibody sequencing results revealed that most of antibodies have the same sequences in heavy and light chain. [00416] T cell -Mediated Killing of Cancer Cells. T cell killing assay is an effective minimized system in which to test the efficacy of immune checkpoint blockade agents, but BTN1A1 and its receptors may each be expressed by multiple cell types and T cells are only one component of the immune response to cancer. So, in order to develop an in vitro model that better represents the immune environment in which cancer cell killing must occur, STCube developed a cancer cell killing assay using T cells from whole, naïve peripheral blood monocyte populations. To evaluate the killing of cancer cells by naïve T cells, PC3 human prostate cancer cells were stably transfected with human BTN1A1, then plated into a 96 well plate. Isolated T cells were added to each well, along with the indicated concentration of BTN1A1 antibodies. NAI-1543197688v1 133 Attorney Docket No.: 13532-031-228 Finally, a cell-permeable reagent which is fluorescent only after cleavage by Caspase 3/7 was added as an apoptosis indicator. Apoptosis was enhanced in PC3 cells by the inclusion of STC2714 in the media, indicating that STC2714 blocks a suppressive signal mediated from the cancer cell to T cells in the context of the whole circulating immune component (Figure 18). [00417] Western blot for detection of dimer-specific BTN1A1 antibody. To determine the conformational specificity, Western blot analysis was performed using both dimer form of BTN1A1 (Fc fusion protein extracellular domain of BTN1A1) and monomer form of BTN1A1 (His-tagged protein of extracellular domain of BTN1A1). Proteins were treated with DTT (a reducing agent) and boiling or without reducing and denaturing by boiling. After running the proteins on SDS-PAGE, Western blot was performed by a standard protocol (Figure 19). In a native condition (without a reducing agent and boiling), STC2714 recognized only Fc fusion protein, a dimerized form of BTN1A1 ECD, but not His-tagged protein, a monomer form of BTN1A1 ECD. Reduced BTN1A1-Fc also could be detected by STC2714, suggesting that this protein could be restored to a dimer form on the membrane during incubation. This result proposed that STC2714 is a dimer-specific antibody. [00418] Binding Affinity of STC2714 to dimer form of BTN1A1. The KD value of STC2714 was determined using a Biacore X-100 system (GE Healthcare Life Science). The KD value was obtained by the process of association and dissociation of BTN1A1-Fc (a dimer form) and BTN1A1-His (a monomer form) in the mobile phase to STC2714 bound to a gold sensor chip immobilized with anti-mouse IgG antibody. A representative association/ dissociation graph is shown in Figures 20A and 20B. STC2714 binds BTN1A1-Fc with high affinity (KD = 2.5 nM); while this antibody has 31.4 nM of KD to BTN1A1-His. This suggests that STC2714 has stronger affinity to a dimer form of BTN1A1 than to a monomer form of BTN1A1. 5.6 Example 6: Efficacy of hSTC810 in Combination with Paclitaxel on SCLC Tumors 5.6.1 Materials and Methods Reagents [00419] Cells were cultured in Dulbecco’s modified eagle’s medium (DMEM)/F12 or RPMI- 1640 media (Gibco) supplemented with 10% fetal bovine serum (FBS) (Crystalgen). Antibodies used in this report were purchased from Cell Signaling, Sigma, and BioLegend, or were developed internally and stored at 4oC. STcube Pharmaceuticals provided the mouse anti-human NAI-1543197688v1 134 Attorney Docket No.: 13532-031-228 BTN1A1, and Samsung Biologics (SBL) produced the clinical-grade test agent hSTC810. Paclitaxel (PTX) was purchased from Sigma-Aldrich and originally dissolved in 100% DMSO and was then diluted to 15% DMSO using PBS. Matrigel was purchased from Corning. Human peripheral blood mononuclear cells (PBMCs) were freshly isolated using Ficoll-Paque Plus (GE Healthcare) gradient centrifugation obtained from New York blood center according to the standard Ficoll density gradient centrifugation method. Mallone et al., “Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses: position statement of the T-Cell Workshop Committee of the Immunology of Diabetics Society,” Clin Exp Immunol., 163, pp.33-49 (2011). SCLC Cell Lines and Culture Conditions [00420] Human small cell lung cancer (SCLC) cell lines, NCI-H345 was obtained from the Lombardi Cancer Center at Georgetown University (Washington D.C.). NCI-H345 cells were cultured in DMEM and incubated in a humidified air atmosphere containing 5% CO2 at 37oC. SCLC Spheroid Preparation [00421] NCI-H345 SCLC cell lines were cultured in DMEM/F-12 medium to reach a minimal confluency of 90% and prepared approximately 1 x 104 cells for making each SCLC spheroid. Each dome contained 50% of Matrigel and 50% of the cells (1 x 103 cells) with 10% FBS, 1% penicillin, and 1% NEAA complete medium (Gibco). Two domes were set to each well in a 12- well plate with 2 mL of the growth medium. Spheroid formation was monitored using Incucyte Live – Cell Analysis System (Sartorius). The 3D stack and 2D projection images were captured using a 10x objective and a 10 μm focus step, with time-lapse imaging every six hours and an environmental temperature of 37oC and 5% CO2. BTN1A1 Expression of Immunohistochemistry (IHC) and Immunofluorescence (IF) of SCLC Tumors [00422] For IHC assays, the ImmPRESS Excel Amplified HRP (peroxidase) Polymer Staining Kit (Vector Laboratories MP-7601) was used. Slides were deparaffinized in xylene and rehydrated with a graded ethanol-water series. Antigen retrieval was performed in citrate buffer [citrate (pH 6.0), Dako K8005 Envision Flex Target Retrieval Solution Low pH (50x) DM829] using Dako PT link (97oC for 20 minutes). The slides were incubated in Bloxall (Vector Laboratories SP-6000-100) for 10 minutes to block endogenous peroxidase and alkaline phosphatase activity. To block non-specific binding, slides were incubated in 2.5% normal horse NAI-1543197688v1 135 Attorney Docket No.: 13532-031-228 serum (Vector Laboratories, S-2012). Primary antibodies (0.5 μg/ml) specific for BTN1A1 (STC43H11-1), PD-L1 (1:200) (Cell Signaling E1L3N XP® Rabbit mAb #13684), or rabbit control IgG (0.5 μg/ml) [Cell Signaling Rabbit (DA1E) mAb IgG XP® Isotype Control #3900] were diluted in 2.5% normal horse serum and then incubated for 60 minutes in a humidified chamber at room temperature. After incubating with the Amplifier for 15 minutes, slides were incubated for 30 minutes with the ImmPRESS Polymer Reagent. Each target was detected using ImmPACT DAB EqV working solution (development time: approximately 2-10 minutes). All slides were then mounted using Vecta® Mount Permanent Mounting Medium (Vector Labs H- 5000) and scanned with a Vectra 3 aging System (Akoya Biosciences). For IF staining, slides were deparaffinized in xylene and rehydrated with a graded ethanol-water series. Antigen retrieval was performed in citrate buffer [citrate (pH 6.0), Dako K8005 Envision Flex Target Retrieval Solution Low pH (50x) DM829] using Dako PT link (97oC for 20 minutes). The slides were incubated in Bloxall (Vector Laboratories SP-6000-100) for 10 minutes to block endogenous peroxidase and alkaline phosphatase activity. To block non- specific binding, slides were incubated in 2.5% normal horse serum (Vector Laboratories, S- 2012). Primary antibodies (0.5 μg/ml) specific for BTN1A1 (STC43H11-1) and PD-L1 (1:200, Abcam, CAL10, ab279304) were diluted in 2.5% normal horse serum and then incubated for 2 hours in a humidified chamber at room temperature. After 2 hours, slides were incubated for 1 hour with Alexa-488 and -647 (1:2000, Thermo Fisher Scientific) for anti-mouse and anti-rabbit, respectively. All slides were then mounted using Vecta® Mount Permanent Mounting Medium (Vector Labs H-5000) and scanned with a Nikon Eclipse Ti microscope with the A1 confocal module. BTN1A1 Expression of Opal Staining of SCLC Tumors [00423] For multiplex IHC (mIHC) using the Opal protocol (OPAL 4-color Automation IHC kit, Akoya Biosciences NEL82001KT NEL794001KT), the sections were deparaffined in xylene and rehydrated with a graded ethanol series. Antigen retrieval was performed in citrate buffer (pH 6.0) and Tris-EDTA buffer (pH 9.0) using microwave treatment at a low power setting for 15 minutes. Six-plex panel multiplex immunofluorescence (mIF) was performed using the following antibodies: anti-BTN1A1 (STC43H11-1), anti-PD-L1 (clone E1L3N, dilution 1:200, Cell Signaling), anti-CD8 (clone C8/144B, dilution 1:200, DAKO), anti-Ki-67 (clone 8D5, dilution 1:1000, Cell Signaling), anti-CK (clone: AE1/AE3, dilution 1:2000, DAKO) and NAI-1543197688v1 136 Attorney Docket No.: 13532-031-228 DAPI. TSA-conjugated fluorophores (PerkinElmer) were used to visualize each biomarker: Opal 690 (CK), Opal 650 (Ki-67), Opal 620 (PD-L1), Opal 570 (BTN1A1 and Opal 520 (CD8). Slides were mounted using VECTASHIELD® HardSetTM Antifade Mounting Medium. Image acquisition was performed with a Vectra Quantitative Pathology Imaging System (Akoya Biosciences). [00424] For post-processing of scanned images, the first step of image processing includes extraction of each tissue as a unit of analysis, using InForm 2.6.0 image analysis software. The individual image marker analysis from the panel was merged at the end using the X and Y coordinated of each cell by the program Phenoptr script from R studio (Akoya Biosciences). [00425] Further characterization of TME, immune cells with BTN1A1 and PD-L1 immunophenotypes were followed below. After quantifying the amount of tumor-infiltrating immune cells with certain immunophenotypes, the numbers/densities of each cell type can be counted. In addition, unsupervised or supervised hierarchical clustering based on the numbers/densities of each cell type can be useful for finding out whether distinct TME subgroups exist within the study population. Based on the cell segmentation data analysis, each of the five markers was separately counted phenotypically per the region of interest (ROI). [00426] Phenotypic counts of the cell segmentation data analysis from the non-small cell lung cancer (NSCLC) and SCLC tumor tissues were performed. An image analysis pipeline in the InForm 2.6.0 (Akoya Biosciences) applies the classifier to create probability maps for each cell type individually, then segments, counts, and optionally measures features for each cell of each type. Efficacy of hSTC810 in combination with Paclitaxel against SCLC Spheroids [00427] While the spheroid formation was monitored using Incucyte Live-Cell Analysis System for 8 days of incubation, the grown NCI-H345 SCLC cells-derived spheroid cultures were filtered to select a similar size ranging from 80 to 150 μm in diameter. Freshly isolated PBMCs (~1 x 105) or PBMCs with hSTC810 (200 μg/ml) were added to the pre-formed spheroids in each single well of a 12-well plate. After 24 hours of incubation, Paclitaxel (PTX, 1 nM) was added to the PBMCs or PBMCs with hSTC810-treated spheroid cultures, respectively. All cellular behaviors, such as spheroid size, shape, and initial contact time with immune cells, were monitored and recorded every 6 hours for 15 days. Statistical and Graphical Analysis NAI-1543197688v1 137 Attorney Docket No.: 13532-031-228 [00428] GraphPad Prism 9.0 (GraphPad) or Excel (Microsoft) was used to prepare graphical representations of study results and for the statistical analysis thereof. Two-tailed statistical analyses were conducted at a significance level of p=0.05. Statistical tests were not adjusted for multiple comparisons. Prism summarizes test results as not significant (ns) at p>0.05, significant (symbolized by ‘*’) at 0.01 < p ≤ 0.05, very significant (“**”) at 0.001 < p ≤ 0.01, and extremely significant (“***”) at p ≤ 0.001. 5.6.2 BTN1A1 Expression Levels in Lung Cancer Cell Lines [00429] The normalized transcript expression values, denoted normalized transcript per million (nTPM), were calculated for BTN1A1 gene expression in a total of seventy-four small cell lung cancer (SCLC) cell lines via the website of “The Human Protein Atlas” (www.proteinatlas.org). The BTN1A1 expression levels were relatively higher in twenty-three SCLC cell lines, denoted by #, such as DMS 53 (16.7) and NCI-H146 (6.4) than other NSCLC cell lines (Figure 1A). [00430] It was also determined that BTN1A1 nTPM and doubling time correlated with R- squared in lung cancer cell lines. In lung cancer cell lines, SCLC was marked with open circles, which was almost always higher than the trendline marked with closed circles (Figure 1B). These data indicate that the cell division speed in SCLC cells was slower than the normal speed observed for lung cancer cell lines, and at the same time, SCLC cells expressed a lot of BTN1A1. 5.6.3 BTN1A1 and PD-L1 Protein Expression in SCLC Tumors [00431] IHC-specific anti-BTN1A1 (STC43H11-1, 0.5 μg/ml) or PD-L1 (1:200) antibodies were processed with SCLC tumor tissues to determine the expression levels of BTN1A1 and PD- L1, respectively. Strong positive BTN1A1 staining was observed in Figure 2 panels A, C, and E. However, PD-L1 staining was faint as observed in Figure 2, panels B, D, and F. Figure 3 shows 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. These data demonstrate that BTN1A1 expression in SCLC tumor tissues was at a higher level, and that BTN1A1 expression and PD-L1 expression were mutually exclusive with respect to one another in SCLC tumor tissues. NAI-1543197688v1 138 Attorney Docket No.: 13532-031-228 5.6.4 Automated Digital Analysis in SCLC Tumor Tissues [00432] Formalin-fixed paraffin-embedded (FFPE) SCLC tumor tissues were characterized using a multiplex immunohistochemistry (mIHC) technique. On a single FFPE slide, five markers of immune cells and tumor cells were performed with multiparametric fluorescent staining of BTN1A1 (green), PD-L1 (cyan), CD8 (orange), Ki-67 (magenta), and Pan-Keratin (red), respectively. The whole slides were digitally scanned after each cycle was completed. Interpretation of the mIHC data sets was made with computer-assisted image analysis using publicly available software. With accurate visualization of immune and tumor cells in the mIHC analysis under the tumor microenvironment (TME) of SCLC tissues, BTN1A1 expression levels were clearly observed in green colors (Figure 4). Again, these data demonstrate that BTN1A1 expression in SCLC tumor tissues was at a higher level, and that BTN1A1 expression and PD-L1 expression were mutually exclusive with respect to one another in SCLC tumor tissues. Additionally, Ki-67, which is a marker for rapidly proliferating cells, tends to co-locate with PD- L1, but not with BTN1A1, evidencing that BTN1A1 is largely expressed on slow-growing cells. 5.6.5 Cell segmentation Analysis from NSCLC and SCLC Tumor Tissues [00433] Based on the cancer cell segmentation analysis, the BTN1A1-relevant phenotypic counts made of three markers (BTN1A1, CK, and Ki-67) were performed with non-small cell lung cancer (NSCLC) and SCLC tumor tissues, respectively (Figure 5). CK is a general marker for cancer cells, while Ki-67 staining associates with rapid reproduction of cancer cells and early cancer cell growth. Focused on the relationship of BTN1A1 expression and Ki-67 marker, significant differences were shown between NSCLC and SCLC tissues. In particular, the SCLC cells had a 70% BTN1A1 expression level consisting of CK+ BTN1A1+ Ki-67- cells (69.1%) and CK+ BTN1A1+ Ki-67+ cells (0.9%). In contrast, NSCLC cells had a 92.5% BTN1A1 expression level consisting of CK+ BTN1A1+ Ki-67- cells (26.3%) and CK+ BTN1A1+ Ki-67+ cells (66.2%). The marker Ki-67+ (which is associated with the rapid reproduction of cancer cells and corresponds to early cancer cell growth) was closely associated with BTN1A1 expression in the NSCLC tissue. In contrast, only a tiny portion of BTN1A1 expressing cells was Ki-67+ in the SCLC tissue, indicating that the majority of cancer cells belonging to the relatively late growth stage expressed BTN1A1 at a high level in SCLC. Overall, both tissues derived from lung tumors showed much different cancer cell distribution patterns. These results indicates that it NAI-1543197688v1 139 Attorney Docket No.: 13532-031-228 would be beneficial to use hSTC810 antibody alone or in combination with paclitaxel to treat lung cancers. 5.6.6 SCLC Spheroid Formation and Efficacy of hSTC810 and Paclitaxel [00434] A 3D spheroid cell culture platform mimicking the tumor microenvironment was used to model clinically relevant tumor physiology. Anti-tumor T-cell activity is a driving force of cancer immunotherapy treatments. The effectiveness of T-cell mediated immunotherapy was investigated with hSTC810 in combination with Paclitaxel, which was administered to the spheroids co-cultured with freshly isolated PBMCs. NCL-H345 SCLC spheroid formation was monitored using the Incucyte Live-Cell Analysis System for 8 days ranging from 80-150 μm in diameter (Figure 6A). Three treatments were administered to the spheroids: PBMC alone, PBMC + hSTC810, and PBCM + hSTC810 + Paclitaxel. It was observed that with all three treatments, the PBMC cells attached to the SCLC spheroid hull 2-4 days after being administered to the spheroid culture system (as shown in subsets of Figures 6B, 6C, and 6D). Spheroid size and shape were monitored for 8 days. Treatment with the mixture of PBMC, hSTC810, and Paclitaxel showed the most dramatic changes in size and shape by disintegrating the SCLC spheroids into tiny pieces (Figure 6D). The dose of hSTC810 (200 μg/mL) was calculated based on a Phase I Clinical Trial dosing regimen (15 mg/kg) under the guidance of Anroop et al., “A simple practice guide for dose conversion between animals and human,” J Basic Clin Pharma., 27-31, (2016), the content of which is incorporated herein by reference in its entirety. [00435] Next, four different treatments including (1) PBMC alone, (2) PBMC + Paclitaxel, (3) PBMC + hSTC810, and (4) PBMC + hSTC810 + Paclitaxel were applied to the spheroids, and the volume (μm3) and shape of the spheroids was measured for 5 days. As controls, no treatment or treatment with hSTC810 alone were also monitored, and the volume (μm3) and shape of the spheroids was measured also for 5 days. As shown, treatment with hSTC810 alone showed no apparent efficacy comparing to the blank control in the in vitro setting (Figure 7A), demonstrating that anti-tumor efficacy of hSTC810 was through immunomodulation. With the treatment of the triple combination of PBMC, hSTC810, and Paclitaxel, the volume of the spheroid increased until 24 hours, which was the shortest period of tumor growth among all treatment groups; then the volume of the spheroid gradually decreased to zero around 72 hours, which was the fastest tumor clearance among all treatment groups (Figure 7B). The treatment NAI-1543197688v1 140 Attorney Docket No.: 13532-031-228 consisting of PBMC + hSTC810 + Paclitaxel showed the best efficacy indicating that hSTC810 could exert the best performance in combination with Paclitaxel. The treatment of PBMC + hSTC810 showed better efficacy compared to PBMC + Paclitaxel or PBMC alone. These data demonstrate that combination treatment with both hSTC810 and paclitaxel exhibited synergistic effects in inhibiting tumor growth that was significantly better comparing to treatment with either hSTC810 or paclitaxel alone. 5.6.7 Phase I Clinical Trial - SCLC [00436] A humanized version of STC810 antibody (hSTC810) demonstrated encouraging anti-tumor activity against solid tumors in a phase I clinical trial. In particular, the extensive stage (ES)-SCLC patient treated with hSTC810 showed progression-free survival (PFS) of 5.5 months with treatment still ongoing. [00437] Using a patient sample tissue, there was a significant amount of BTN1A1 observed through IHC staining, while the expression pattern of PD-L1 was comparatively lower (Figure 8). This data showed that BTN1A1 expression in SCLC tumor tissues were at higher levels. 5.7 Example 7: Therapeutic Efficacy of STC109 in Combination with TAS-102 (Lonsurf) and Anti-VEGF Antibody in CT26 Mouse Tumor Model [00438] STC109 is a mouse syngeneic BTN1A1 antibody. STC109 in combination with TAS- 102 (Lonsurf) and anti-VEGF antibody was shown to be efficacious in the treatment of colon cancer in a CT26 mouse colon carcinoma xenograft model system. 5.7.1 Materials and Methods Mice [00439] Female Balb/c mice (Jackson Laboratory) were six to eight weeks old with a BW range of 18.0 to 22.0 g. The animals were fed ad libitum water (reverse osmosis, 1 ppm Cl), and an NIH 31 modified Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. The mice were housed on irradiated Enrich-o’cobsTM Laboratory Animal Bedding in static microisolators on a 12-hour light cycle at 20-22oC (68-72oF) and 40-60% humidity. The STCube Animal Facility specifically complies with the recommendations of the Guide for Care and Use of Laboratory Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care. NAI-1543197688v1 141 Attorney Docket No.: 13532-031-228 [00440] Tumor Cell Culture [00441] CT26 mouse colon carcinoma cells were cultured in RPMI medium with Earle salt containing 100 units/mL penicillin G sodium, 100 μg/mL streptomycin, and 25 μg/mL gentamicin. The medium was supplemented with 10% fetal bovine serum and 2mM glutamine. The tumor cells were cultured in tissue culture flasks in a humidified incubator at 37oC in an atmosphere of 5% CO2 and 95% air. In Vivo Implantation [00442] On the day of tumor implantation, CT26 cells were harvested in the exponential growth phase and resuspended in cold phosphate-buffered saline (PBS) at a concentration of 2 x 107 cells/mL. Xenografts were initiated by subcutaneously implanting 1 x 106 CT26 tumor cells (50 mL suspension) into the right flank of each test animal, and tumors were monitored as their volumes approached the target range of 50-80 mm3. Tumors were measured in two perpendicular dimensions using calipers, and volume was calculated using the formula: ^^ଶ × ^^ ^^^^^^^^^^ ^^^^^^^^^^^^ = 2 where w=width and l=length, in weight may be estimated with the assumption that 1 mg is equivalent to 1 mm3 of tumor volume. Ten days after tumor implantation, the animals were sorted into nine groups (n=10/group) with individual tumor volumes ranging from 50-80 mm3 and group mean tumor volumes of 65 mm3. Testing Agents [00443] STCube Pharmaceuticals provided the hybridoma cell line and BioXCell produced the test agent STC109 (13.29 mg/mL, Lot No.994924N1B). Rat IgG1 Isotype control was purchased from BioXCell (5.67 mg/mL, Lot No.811224J1), and Rat IgG2a Isotype control was purchased from BioXCell (7.35 mg/mL, Lot No.686318F1). Anti-VEGF antibody was purchased from BioXCell (9.05 mg/mL, Lot No.939723D1). All antibodies were stored at 4oC, and all dosing solutions were diluted in vehicle (PBS) to the appropriate concentration that provided an appropriate dosage of 200 μg/animal of 100 μL/animal. The chemo was stored in powder form and dissolved in 0.5% HPMC (hydroxypropyl methylcellulose, Sigma Aldric) on the day of scheduled administration. NAI-1543197688v1 142 Attorney Docket No.: 13532-031-228 Treatment [00444] On Day 0 of the study, mice were sorted into four groups (n=10), and dosing was initiated according to the treatment plan summarized in Figure 23. Chemo treatment was performed five times per week for two weeks, and the antibody treatment was administered three times per week for one week. Antibodies were administered i.p. in a fixed volume of 100 μL/animal, and chemo was administered p.o. in a fixed volume of 200 μL/animal. Group 1 served as the control for this study and was treated with a rat IgG1 isotype control antibody at 200 μg/animal and a rat IgG2a isotype antibody at 100 μg/animal. Group 2 received STC109 at 200 μg/animal. Group 3 received STC109 at 200 μg/animal and TAS-102 (Lonsurf) at 150 mg/Kg. Group 4 received STC109 at 200 μg/animal and TAS-102 (Lonsurf) at 150 mg/Kg and was followed by anti-mouse VEGF at 100 μg/animal. 5.7.2 Results [00445] Groups in this study were treated in accordance with the protocol, as shown in Figure 23. Figure 24 illustrates plots of group mean tumor growth. Figure 25 is a scatter plot showing the individual tumor volumes by the group at Day 23. Figure 26 shows individual tumor growth in each group. Growth of CT26 tumors in Control Mice (Group 1) [00446] Group 1 mice received IgG1 isotype control at 200 μg/animal three times per week for one week and served as the control group for efficacy analysis of test agents. The Group 1 mean tumor growth plot illustrates the highly consistent and progressive growth of the control CT26 tumors (Figure 24). Any animal that died prior to the study end was assigned a death cause of either TR or NTRu Sbased on considerations including clinical observations, body weight loss, tumor size, and the number of deaths per group. Generally, toxicity-related (TR) death causes were assigned when the tumor size was below 900 mm3 at the time of death. Assignments of non-toxicity-related (NTRu) death causes were given for animals that exhibited no body weight loss before death or that had tumor sizes above 900 mm3 at the time of death. Response to STC109 (Group 2) [00447] Group 2 was treated with STC109 at 200 μg/animal, i.p., three times per week for one week. All Group 2 animals exhibited increase in tumor volume (Figure 25). Response to STC109 and TAS-102 (Group 3) NAI-1543197688v1 143 Attorney Docket No.: 13532-031-228 [00448] Group 3 was treated with STC109 at 200 μg/animal, i.p., three times per week for one week. TAS-102 (Lonsurf) was then followed at 150 mg/Kg, p.o. five times per week for two weeks. All Group 3 animals exhibited slow increases in tumor volume (Figure 25). Response to STC109, anti-mouse VEGF and TAS-102 (Group 4) [00449] Group 4 was treated with TAS-102 (Lonsurf) at 150 mg/Kg, p.o., five times per week for two weeks. STC109 was then followed at 200 μg/animal, i.p., three times per week for one week. Anti-mouse VEGF was also administered intrapenetoneally one time per week for two weeks. Among the four study groups, Group 4 exhibited the most pronounced beneficial therapeutic outcomes (Figures 24, 25, and 26). All animals in Group 4 exhibited slow increases in tumor volume. 5.7.3 Summary [00450] The present study was designed to evaluate the efficacy of combination treatment of TAS-102 (Lonsurf) and STC109 in the CT26 mouse colon carcinoma xenograft model system. Tumors were measured three times weekly until the study was terminated. All evaluable data showed positive outcomes in the therapy groups relative to control. Specifically, STC109, in combination with TAS-102 (Lonsurf), achieved highly significant reductions in tumor growth relative to the control group. In summary, all therapies tested were active in the CT26 tumor model in mice. 5.8 Example 8: Therapeutic efficacy of hSTC810 (Nelmastobart), an anti- BTN1A1 antibody in combination with TAS-102 (Lonsurf) and Bevacizumab (Avastin), for the treatment of colon cancer using patient-derived organoid models. [00451] Three-dimensional (3D) cell culture systems offer a more physiologically relevant model by closely mimicking the structural and functional characteristics of the original parental tissue, such as the tumor microenvironment. These systems also replicate the intricate interactions between patient-derived colon cancer cells and their surrounding microenvironment, which are often lost in traditional two-dimensional (2D) culture models. [00452] This study evaluated the therapeutic efficacy of hSTC810 (Nelmastobart), an anti- BTN1A1 antibody, in combination with TAS-102 and Bevacizumab (Avastin), for the treatment of colon cancer using patient derived organoid models. Leveraging advanced 3D culture and organoid system, the study provides critical insights into tumor biology, immune interactions, NAI-1543197688v1 144 Attorney Docket No.: 13532-031-228 and drug responses in a physiologically relevant environment. Unlike traditional 2D culture systems, 3D cultures better mimic the structural and functional complexities of the tumor microenvironment, including cell-cell and cell-matrix interactions. These features are essential for accurately replicating the in vivo tumor conditions and predicting clinical outcomes. [00453] hSTC810 significantly reduces tumor size, particularly when combined with TAS- 102 (Lonsurf) and Bevacizumab, highlighting a synergistic therapeutic potential. Furthermore, the use of 3D organoid systems allowed for a deeper understanding of the synergistic effect between TAS-102 (Lonsurf) and hSTC810, providing more insights into tumor progression and immune modulation. 5.8.1 Materials and Methods Organoid Preparation [00454] Colon organoids were thawed and washed with 10 mL of cold advanced DMEM/F12 with supplementary (adMDEM/F12+++, containing Penicillin/Streptomycin 1x, GlutaMAX supplement 1x, HEPES 1x, B-27 supplement 1x, R-Spondin-1500 ng/ml, Noggin 100 ng/ml, N- 2-MAX 1x, PGE210 μM, Gastrin 10 μM, EGF 100 ng/ml, N-Acetylcysteine 1.25 mM, Nicotinamide 10 mM, SB20219010 μM, A83-01500 nM). The tube with the organoids was centrifuged again at 200 x g for 5 minutes at 4oC and the supernatant was discarded. [00455] The organoids were then resuspended in 30 μL of cold adDMEM/F12+++ culture medium before mixing the cell suspension with Matrigel. 20 μL of Matrigel was then added to the organoids suspension and the suspension was mixed well by gentle pipetting up and down several times. [00456] The Matrigel-cell mixture was dispensed as 50 μL droplets (∼15, 000 cells/drop) into one well of a 6-well plate (usually 5 droplets were plated into each well). The drops were then solidified for 15 minutes upside down at 37oC and 5% CO2. 3 mL of adDMEM/F12+++ was added for 3 days at 37°C and 5% CO2. [00457] After 3 days, the Matrigel domes containing the organoids were scraped from one well of a 6-well cell culture plate using a P1000 pipette tip and transfer them into a 15 mL tube. The tube was then centrifuged at 200 × g for 5 min at 4°C. The supernatant was discarded, and the Matrigel was digested with 2 mL of TrypLE Express for ∼5 min at 37°C on a shaking platform (60 rpm). The trypsinization was stopped by adding 4 mL of cold adDMEM/F12+++ NAI-1543197688v1 145 Attorney Docket No.: 13532-031-228 supplemented with 20% FBS. The tube was then centrifuged at 200 × g for 5 min at 4°C. The supernatant was discarded and the cell pellet was washed with 10 mL of cold adDMEM/F12+++. [00458] Single cells were checked, and then 20 μL of Matrigel + 60 μL (100-150 colon cancer cells/well and anti-HLA-ABC/anti-HLA-DR each 5 µg/ml, final) into one well of a 96-round bottom plate. The plate was centrifuged at 200 x g for 5 min at 4°C, and the plate was incubated in the incubator for 2 days at 37°C and 5% CO2. [00459] PBMCs were then activated using anti-CD3/CD28 Dynabeads. The anti-CD3/CD28 Dynabeads were resuspended in a vial and vortexed for 30 seconds. A calculated volume of the anti-CD3/CD28 Dynabeads was transferred to a tube, and 1 mL of PBS was added to mix the Dynabeads (vortex for 5 seconds). [00460] The tube was placed on a magnet for 1 minute and the supernatant was discarded. The tube was removed from the magnet, and the anti-CD3/CD28 Dynabeads were resuspended in the same volume of culture medium (RPMI). The tube was placed on the magnet again, the supernatant was discarded, and the anti-CD3/CD28 Dynabeads were resuspended in 400 μL of culture medium (RPMI). [00461] The PBMCs were then activated 1 × 106 hPBMCs were suspended in 1 mL of medium (RPMI) in a 24-well tissue culture plate. 100 μL of the pre-washed and resuspended Dynabeads were added to the plate to obtain a bead-to-cell ration of 1:1. The Dynabeads and hPBMCs were incubated in a humidified CO2 incubator at 37°C for two days. The hPBMCs were harvested using a magnet and the hPBMCs were used directly for further assay. [00462] 1 x 103 of the activated hPBMCs were added per well in the 96-round bottom plate that contained the Matrigel and the colon cancer cells. The plate was centrifuged at 200 x g for 5 minutes at 4oC. The IncuCyte Spheroid program was then run. Treatment Organoids were treated with PBMCs in combination with Bevacizumab, hSTC810, TAS-102 (Lonsurf), or some combination of the three therapeutics (Figure 27). There were 8 groups of organoids treated with and without PBMCs: 1) organoids only (received no treatment), 2) Bevacizumab 100 μg/mL, 3) hSTC810100 μg/mL, 4) Bevacizumab 100 μg/mL + hSTC810100 μg/mL, 5) TAS-102 (Lonsurf) 300 nM, 6) TAS-102 (Lonsurf) 300 nM + Bevacizumab 100 μg/mL, 7) TAS-102 (Lonsurf) 300 nM + hSTC810100 μg/mL, and 8) TAS-102 (Lonsurf) 300 NAI-1543197688v1 146 Attorney Docket No.: 13532-031-228 nM + Bevacizumab 100 μg/mL + hSTC810100 μg/mL. The organoids were stimulated with 200ng/ml IFNγ 1 day before the treatment. For the organoids cultured with PBMCs, the PBMCs were activated with anti-CD3/CD28 two days prior to adding to the organoid culture. Each PBMC-treated or untreated group contained 10 organoids and the organoid sizes were measured daily for 5 consecutive days. 5.8.2 Results Immune Modulation in the Organoid-PBMC Co-culture System [00463] When the combination of each drug was treated without the PBMC co-culture, the groups containing the chemotherapeutic drug TAS-102 (Lonsurf) showed the best effect (Figures 28 and 29). When co-cultured with activated with PBMCs, activated for the purpose of T-cell activation and proliferation, treatment resulted in greater size destruction in organoid assays, reflecting increased PBMC-mediated cytotoxicity. The effects of the non-PBMC and PBMC co-culture groups on day 5 are further shown in Figure 30. BTN1A1, Bevacizumab, and TAS-102 Drug Synergy [00464] Combination therapies of hSTC810 with TAS-102 (Lonsurf) or Bevacizumab showed enhanced efficacy compared to monotherapies of the original combination of TAS-102 (Lonsurf) and Bevacizumab. These findings highlight the potential of BTN1A1-targeting therapies to overcome resistance mechanisms, particularly in colon cancers. 5.8.3 Summary [00465] The present study elucidates the multifaceted role of BTN1A1 as a pivotal immune checkpoint regulator and its intricate interplay with Bevacizumab and TAS-102 (Lonsurf) treatment in the oncogenic milieu of colorectal cancer. Our findings reveal that BTN1A1 inhibition, mediated through hSTC810, exerts a dual mechanism of action by enhancing Bevacizumab and TAS102-driven therapy while concurrently potentiating T cell-mediated immunosurveillance. These effects culminate in robust tumor growth suppression and enhanced cytotoxicity, underscoring the therapeutic promise of targeting BTN1A1. [00466] Moreover, the synergistic interactions observed between hSTC810 Bevacizumab, and chemotherapeutic agents TAS-102 (Lonsurf) accentuate the translational relevance of this strategy. This therapeutic approach offers a means to circumvent tumor immune evasion and mitigate resistance to conventional therapies. These results provide compelling evidence for BTN1A1 as a novel therapeutic axis in cancer immunotherapy. Future investigations hold NAI-1543197688v1 147 Attorney Docket No.: 13532-031-228 significant potential to advance the therapeutic landscape for refractory and advanced colorectal malignancies, paving the way for more efficacious and durable treatment paradigms. 5.9 Example 9: Efficacy of hSTC810 in Combination with Chemotherapy on Colon Cancer 5.9.1 Phase I Clinical Trial – Colon Cancer [00467] hSTC810 treatment was demonstrated to reverse drug resistance in human colon cancer patients previously treated with chemotherapy. Patient #1 [00468] As shown in FIG.9A, a 75-year old male human patient was diagnosed with Stage IV ascending colon cancer on October 23, 2020. The patient underwent right hemicolectomy in November 2020, and was administered Folfox and Bevacizumab over a course of 12 cycles between December 2020 and July 2021. The patient had cancer recurrence, and thereafter underwent 9 cycles of treatment with folfiri and aflibercept between October 2021 and March 2022. Upon completion of the 9 cycles, there was no decrease in the size of the tumor (data not shown). [00469] Subsequently, the patient received 3 cycles of treatment with hSTC810 at the dose of 0.3 mg/kg body weight between April and May 2022, and tumor assessment in May 2022 showed tumor growth from 15 mm to 23 mm in two target lesions, and no progression in 2 non- target lesions. Subsequently, the patient was treated with 4 cycles of capecitabine between May and August 2022. Surprisingly, tumor assessment thereafter in August 2022 showed partial response (PR) maintenance and decrease in tumor markers. Particularly, as shown in Figure 10A, the first post-treatment scan showed a 32% tumor reduction in target lesions. Immunohistochemistry analysis also revealed that BTN1A1 protein expression was high whereas PD-L1 protein expression was low (Figure 10B) in colon tissue sample taken from this patient. Patient #2 [00470] As shown in Figure 9B, a 67-year old male human patient was diagnosed with Stage IIIB rectosigmoid colon cancer on August 16, 2017. The patient had a laparoscopic anterior of the rectum in August 2017, and was administered Folfox over a course of 12 cycles between September 2017 and March 2018. The patient had wide wedge resection of lung, RLL, and VATs, and thereafter underwent 12 cycles of treatment with folfiri and cetuzimab between NAI-1543197688v1 148 Attorney Docket No.: 13532-031-228 February 2019 and September 2019. Upon completion of the 12 cycles, the patient still had a wide wedge resection of lung, RLL, and VATs. Subsequently, the patient received 12 cycles of capecitabine. [00471] The patient then received 15 cycles of FOLFOX between August 2021 and March 22. The patient then received 12 cycles of hSTC810 at the dose of 1 mg/kg between July 2022 and January 2023. The patient is currently going through 3 cycles of Folfiri. The patient showed about 20% reduction in the tumor volume. [00472] In this clinical study, two colon cancer patients who were treated with hSTC810 but discontinued due to disease progression. However, immediately after the discontinuation, these patients were administered a chemotherapy (one with capecitabine and the other with folfiri), and both patients had significant reduction in their tumors following the chemotherapy. These results are very surprising because both patients had prior history of chemotherapy and developed resistance (stopped responding to the chemotherapy or had tumor recurrence after the chemotherapy), and it would have been virtually impossible for these patients to have responded to another chemotherapy. [00473] These results suggested that BTN1A1 is involved in the development of resistance to chemotherapy in cancer patients, and that inhibiting BTN1A1 (e.g., with an anti-BTN1A1 antibody disclosed herein) can reverse such drug resistance. These data suggest that combination therapy of one or more chemotherapeutic agent together with an anti-BTN1A1 agent can be more effective in treating cancer comparing to the chemotherapy alone, particularly in cancer patients who have been previously treated with such chemotherapy and developed or partially developed resistance thereto. To achieve the desirable treatment effect, the chemotherapeutic agent can be administered together with the anti-BTN1A1 agent, or shortly after administration of the anti-BTN1A1 agent. [00474] Throughout this application various publications have been referenced. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this disclosure pertains. While examples of certain particular embodiments are provided herein, it will be apparent to those skilled in the art that various changes and modifications may be made. Such modifications are also intended to fall within the scope of the appended claims. NAI-1543197688v1 149

Claims

Attorney Docket No.: 13532-031-228 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 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. 2. The method of claim 1, wherein BTN1A1 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 BTN1A1 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 any one of claims 11 to 4, wherein at least about 50% of cancer cells in a sample taken from the subject are Ki-67 negative. 6. The method of any one of claims 11 to 4, 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-L1 therapy. 10. The method of claim 9, wherein the anti-PD-1 therapy or anti-PD-L1 therapy is selected from Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinizi), and Atezolizumab (Tecentriq). NAI-1543197688v1 150 Attorney Docket No.: 13532-031-228 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-L1 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 (Regorafenib), 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. NAI-1543197688v1 151 Attorney Docket No.: 13532-031-228 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 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, and wherein the cancer is resistant to or relapsed from prior treatment with anti-PD-1 or anti-PD-L1 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 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. 26. The method of claim 25, wherein BTN1A1 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. NAI-1543197688v1 152 Attorney Docket No.: 13532-031-228 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 (Regorafenib), 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). NAI-1543197688v1 153 Attorney Docket No.: 13532-031-228 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 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. 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. NAI-1543197688v1 154 Attorney Docket No.: 13532-031-228 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 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). 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 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). 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 NAI-1543197688v1 155 Attorney Docket No.: 13532-031-228 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-L1 therapy. 57. The method of claim 56, wherein the anti-PD-1 therapy or anti-PD-L1 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-L1 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 BTN1A1 relative to monomeric BTN1A1. 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. NAI-1543197688v1 156 Attorney Docket No.: 13532-031-228 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 hSTC810. 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 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; NAI-1543197688v1 157 Attorney Docket No.: 13532-031-228 (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. NAI-1543197688v1 158 Attorney Docket No.: 13532-031-228 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 comprising the amino acid sequence of 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: NAI-1543197688v1 159 Attorney Docket No.: 13532-031-228 (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 least 95% 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, wherein 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. 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 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. NAI-1543197688v1 160
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