Antibodies and molecules that immunospecifically bind to BTN1a1 and therapeutic uses thereof

Abstract

To provide a molecule having an antigen binding fragment that immunospecifically binds to BTN1A1, which is useful in cancer treatment or as a cancer diagnosis.SOLUTION: There is provided a molecule having an antigen binding fragment that immunospecifically binds to BTN1A1, for example, an antigen binding fragment that binds to glycosylated BTN1A1 with a Kd less than half of the Kd exhibited relative to unglycosylated BTN1A1, wherein optionally, the antigen binding fragment binds to glycosylated BTN1A1 with a Kd at least 10 times less than the Kd exhibited relative to unglycosylated BTN1A1, for example, an anti-glycosylated BTN1A1 antibody is provided.SELECTED DRAWING: None

Description

Technical Field

[0001] (1. Field) The present invention relates generally to the fields of cancer immunology and molecular biology. Provided herein are molecules having an antigen-binding fragment that immunospecifically binds to an anti-BTN1A1 antibody or BTN1A1, and their therapeutic uses.

Background Art

[0002] (2. Background) The immune systems of humans and other mammals defend them from infection and disease. A number of stimulatory and inhibitory ligands and receptors provide a strict regulatory system that maximizes the immune response to infection while restricting autoimmunity. Recently, therapies that modulate the immune response, such as anti-PD1 antibodies or anti-PDL1 antibodies, have been found to be effective in some cancer treatments. However, the development of new therapies that safely and effectively treat disease by modulating the immune system remains an urgent need, particularly for metastatic cancer. The compositions and methods described herein meet these needs and provide other related advantages.

Summary of the Invention

[0003] (3. Summary) Provided herein are molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1. In some embodiments, the molecule is an anti-BTN1A1 antibody.

[0004] In some embodiments, the molecule has an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1. In some embodiments, the antigen-binding fragment is at positions N55, N215, ​and / or binds immunospecifically to BTN1A1 glycosylated at N449. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at position N55. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at position N215. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at position N449. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at position N449. In some aspects the antigen-binding fragment binds immunospecifically to one or more glycosylation motifs. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at positions N55 and N215. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at positions N215 and N 449. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at positions N55 and N449. In some aspects the antigen-binding fragment binds immunospecifically to BTN1A1 glycosylated at positions N55, N215, and N449. In some embodiments, the molecule has an antigen-binding fragment that binds immunospecifically to glycosylated BTN1A1, where the antigen-binding fragment binds preferentially to glycosylated BTN1A1 over non-glycosylated BTN1A1. In some aspects

[0005] the antigen-binding fragment binds preferentially to BTN1A1 glycosylated at positions N55, N215, and / or N449 over non-glycosylated BTN1A1. In some aspects the antigen-binding fragment binds preferentially to glycosylated BTN1A1 over non-glycosylated BTN1A1. In some aspects the antigen-binding fragment binds preferentially to BTN1A1 glycosylated at positions N55, N215, and / or N449 over non-glycosylated BTN1A1. In some aspects the antigen-binding fragment binds preferentially to BTN1A1 glycosylated at positions N55, N215, and / or N449 over non-glycosylated BTN1A1. In some aspects the antigen-binding fragment binds preferentially to BTN1A1 glycosylated at positions N55, N215, and / or N449 over non-glycosylated BTN1A1. In some aspects Rather, it preferentially binds to BTN1A1 that is glycosylated at position N55. In some embodiments the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at position N215 rather than to non-glycosylated BTN1A1 In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at position N449 rather than to non-glycosylated BTN1A1 In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at one or more glycosylation motifs . In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at positions N55 and N215 rather than to non-glycosylated BTN1A1 . In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at positions N215 and N449 rather than to non-glycosylated BTN1A1 . In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at positions N55 and N449 rather than to non-glycosylated BTN1A1 . In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at positions N55, N215, and N449 rather than to non-glycosylated BTN1A1 . . . . .

[0006] In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is less than half of the Kd shown for non-glycosylated BTN1A1 . In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1 . .

[0007] In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 2-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 5-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55, N215, and / or N449. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N55. In some embodiments, the antigen-binding

[0008] fragment immunospecifically masks BTN1A1 glycosylation at position N215. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N449. In some embodiments, the antigen-binding fragment immunospecifically masks one or more glycosylation motifs of BTN1A1. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55 and N215. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N215 and N449. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55 and N449. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55, N215, and N449.

[0009] ​​​​​​In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and comprises a VH or VL domain of the mouse monoclonal antibody STC810 as shown in Table 2 . In one embodiment, the molecule comprises both a VH domain and a VL domain of the mouse monoclonal antibody STC810 as shown in Table 2 and can have an antigen-binding fragment. In another embodiment, the molecule can have an antigen-binding fragment comprising one or more VH CDRs having the amino acid sequence of any one of the VH CDRs of the mouse monoclonal antibody STC810 as shown in Table 2 . In another embodiment, the molecule can have an antigen-binding fragment comprising one or more VL CDRs having the amino acid sequence of any one of the VL CDRs of the mouse monoclonal antibody STC810 as shown in Table 2 . In yet another embodiment, the molecule can have an antigen-binding fragment comprising at least one VH CDR and at least one VL CDR of the mouse monoclonal antibody STC810 as shown in Table 2 . In some embodiments, the molecule provided herein comprises: (a) (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 10, 13, and 16; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, and 17; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V In yet another embodiment, the molecule comprises at least one VH CDR and at least one VL CDR of the mouse monoclonal antibody STC810 as shown in Table 2 and can have an antigen-binding fragment .

[0010] In some embodiments, the molecule provided herein comprises: (a) (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 10, 13, and 16; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, and 17; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V CDR1; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, and 17; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V H CDR1; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, and 17; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V CDR1; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 11, 14, and 17; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V H CDR2; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V CDR2; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 12, 15, and 18: and a heavy chain variable (V H iable (V iable (V H ​​region; or (b) (1) an amino acid selected from the group consisting of SEQ ID NO: 19, 22, 25, and 28 having a V L CDR1; (2) an amino acid having a sequence of V L CDR2; and (3) an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 24, 27, and 30 having a V L CDR3: comprising a light chain variable (V L ) region: having an antigen-binding fragment .

[0011] Also provided herein are the VH chain, VL chain, VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL C DR3 of the anti-BTN1A1 antibody described herein, isolated nucleic acid molecules encoding them. Further provided are vectors and host cells comprising these nucleic acid molecules .

[0012] In some embodiments, the molecules provided herein have an antigen-binding fragment that competitively blocks the BT N1A1 epitope described herein (e.g., in a dose-dependent manner). The BTN1A1 epitope can be the epitope of STC810 described herein . In some embodiments, the molecule can have an antigen-binding fragment that immunospecifically binds to the epitope of BTN1A1 described herein. The BTN1A1 epitope can be the epitope of STC810 described herein . In some embodiments , the BTN1A1 epitope has at least 5 consecutive amino acids of the amino acid sequence of SEQ ID NOs: 31-41 . .

[0013] In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is an anti-BTN1A1 antibody, including an anti-glycosylated BTN1A1 antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. The antibody can be a human antibody. The antibody can be IgG, IgM, or IgA. In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is an anti-BTN1A1 antibody, including an anti-glycosylated BTN1A1 antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. The antibody can be a human antibody. The antibody can be IgG, IgM, or IgA. In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is an anti-BTN1A1 antibody, including an anti-glycosylated BTN1A1 antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. The antibody can be a human antibody. The antibody can be IgG, IgM, or IgA. In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is an anti-BTN1A1 antibody, including an anti-glycosylated BTN1A1 antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. The antibody can be a human antibody. The antibody can be IgG, IgM, or IgA.

[0014] In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is an anti-BTN1A1 antibody, including an anti-glycosylated BTN1A1 antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. The antibody can be a human antibody. The antibody can be IgG, IgM, or IgA. In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is Fab', F(ab')2, F(ab')3, monovalent scFv, bivalent scFv, or a single-domain antibody.

[0015] In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is recombinantly produced. In some embodiments, the molecule is conjugated to an imaging agent, a chemotherapeutic agent, a toxin, or a radionuclide. In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is recombinantly produced. In some embodiments, the molecule is conjugated to an imaging agent, a chemotherapeutic agent, a toxin, or a radionuclide. In some embodiments, the molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 is recombinantly produced. In some embodiments, the molecule is conjugated to an imaging agent, a chemotherapeutic agent, a toxin, or a radionuclide.

[0016] Also provided herein is a composition comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and a pharmaceutically acceptable carrier. Further provided herein is a kit comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and an adjuvant. Also provided herein is a composition comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and a pharmaceutically acceptable carrier. Further provided herein is a kit comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and an adjuvant. Also provided herein is a kit comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and an adjuvant. Also provided herein is a kit comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and an adjuvant.

[0017] Also provided herein is an antibody-drug conjugate (ADC) comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 as described herein. Also provided herein is a method of conjugating a compound to a cell by contacting the cell with a molecule provided herein conjugated to the compound, thereby conjugating the compound to a cell expressing BTN1A1. Also provided herein is an antibody-drug conjugate (ADC) comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 as described herein. Also provided herein is a method of conjugating a compound to a cell by contacting the cell with a molecule provided herein conjugated to the compound, thereby conjugating the compound to a cell expressing BTN1A1. Also provided herein is an antibody-drug conjugate (ADC) comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 as described herein. Also provided herein is a method of conjugating a compound to a cell by contacting the cell with a molecule provided herein conjugated to the compound, thereby conjugating the compound to a cell expressing BTN1A1. Also provided herein is an antibody-drug conjugate (ADC) comprising a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 as described herein. Also provided herein is a method of conjugating a compound to a cell by contacting the cell with a molecule provided herein conjugated to the compound, thereby conjugating the compound to a cell expressing BTN1A1. A method of delivering to. The compound can be an imaging agent, therapeutic agent, poison described herein, or a radionuclide. The compound can be conjugated to an anti-BTN1A1 antibody. The conjugate can be any conjugate described herein, such as an ADC. The cell can be a cancer cell. The cell can also be a population of cells containing both cancer cells and normal cells.

[0018] Also provided herein is administering an effective amount of a molecule described herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 and contains an anti-BTN1A1 antibody, thereby regulating the immune response in a subject. Regulating the immune response can include (a) increasing T cell activation; (b) increasing T cell proliferation; and / or (c) increasing cytokine production.

[0019] Also provided herein is enhancing the T cell-dependent apoptosis of cells expressing BTN1A1 by contacting the cells with an effective amount of a molecule described herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 and contains an anti-BTN1A1 antibody. Also provided herein is inhibiting the proliferation of cells expressing BTN1A1 by contacting the cells with an effective amount of a molecule described herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 and contains an anti-BTN1A1 antibody. The cell can be a cancer cell.

[0020] Furthermore, provided herein is immunospecific binding to BTN1A1 described herein Administering an effective amount of a molecule having an antigen-binding fragment to a subject to treat cancer in the subject is a method. In some embodiments, the molecule is an anti-BTN1A1 antibody. In some embodiments, the molecule is an anti-glycosylated BTN1A1 antibody. In some embodiments, the treatment can activate an immune response or promote the activation and proliferation of T cells in the subject. In some embodiments, the molecule binds to cancer cells and induces an immune response that results in the destruction of the cancer cells. In some embodiments, the destruction of the cancer cells is mediated by the ADCC activity of the molecule. In some embodiments, the destruction of the cancer cells is

[0021] mediated by the CDC activity of the molecule. In some embodiments, the subject has metastatic cancer. The cancer can be a hematological cancer or a solid tumor. In some embodiments, the cancer is a hematological cancer selected from the group consisting of leukemia, lymphoma, and myeloma. In some embodiments, the cancer is a solid tumor selected from the group consisting of breast cancer, lung cancer, thymic cancer, thyroid cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, brain tumor, liver cancer, bladder cancer,

[0022] kidney cancer, gastric cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer, and skin cancer. The skin cancer can be either melanoma skin cancer or non-melanoma skin cancer. . In some embodiments, the method comprises administering to the subject a second anti-cancer therapy , which can be a surgical therapy, chemotherapy, biological target therapy, small molecule target therapy, radiotherapy, cryo therapy, hormone therapy, immunotherapy, or cytokine therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] (4. BRIEF DESCRIPTION OF THE DRAWINGS) The following drawings form a part of this specification and are included to further illustrate certain aspects of the present invention and are included. The present invention can be better understood by referring to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein.

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[0031] Figure 7B - High induction of cell surface BTN1A1 in mouse T cells after activation by anti - CD3 / CD28 stimulation. Naïve mouse T cells were mock - stimulated (red) or stimulated with anti - CD3 (5 μg / ml) and anti - CD2 8 (5 μg / ml) (orange) for 2 days and subjected to flow cytometry analysis. The expression of BTN1A1 was compared to a control with secondary antibody only. Figure 7B shows high induction of cell surface BTN1A1 in CD3 / CD28 - stimulated cells compared to mock - treated cells. The blue curve is the isotype control.

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Mode for Carrying Out the Invention

[0046] (5. Detailed Description) Co-stimulatory molecules of the B7 family can promote the activation and inhibition of immune cells. Related family molecules - buryrophilin - also have immune regulatory functions similar to those of B7 family members. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. Similar to B7 family members, related family molecules - buryrophilin - also have immune regulatory functions. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. Butyrophilin, subfamily 1, member A1 ("BTN1A1") is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and has structural similarity to the B7 family. BTN1A1 is known as a major protein that regulates the formation of fat droplets in milk (Ogg et al., PNAS, 101(27):10084 - 10089 (2004)). BTN1A1 is expressed in immune cells including T cells. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents the animal model of EAE. It has been found to be practiced (Stefferl et al., J. Immunol. 165(5):2859-65(2000)).

[0047] BTN1A1 is specifically and highly expressed even in cancer cells. BTN1A1 in cancer cells is also glycosylated. Using the expression of BTN1A1, not only can it assist in cancer diagnosis, but it can also evaluate the effectiveness of cancer treatment.

[0048] Provided herein are anti-BTN1A1 antibodies and other molecules that can immunospecifically bind to BTN1A1, as well as their methods of use in providing cancer diagnosis, evaluating cancer treatment, or regulating the activity of immune cells, and in treating cancer.

[0049] (5.1. Definitions) As used herein and unless otherwise specified, the articles "a," "an," and "the" refer to one or more of the grammatical objects of the respective articles. By way of example, an antibody refers to one antibody or a plurality of antibodies.

[0050] As used herein and unless otherwise specified, the term "butyrophilin, subfamily 1, member A1" or "BTN1A1" refers to BTN1A1 derived from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys), dogs, and rodents (e.g., mice and rats). Unless otherwise specified, BTN1A1 refers to various BTN1A1 isoforms, related BTN1A1 polypeptides including their SNP variants, and, without limitation, including phosphorylated BTN1A1, glycosylated BTN1A1, and ubiquitinated BTN1A1, various forms of BTN1A1. ​​​​​​​​​Also included are various modified forms. As used herein, glycosylated BTN1A1 includes BTN1A1 having N55, N21 5, and / or N449 glycosylation.

[0051] An exemplary amino acid sequence of human BTN1A1 (BC096314.1 GI: 64654887) is provided below, with potential glycosylation sites in bold and underlined:

[0052] [Chemical formula]

[0053] An exemplary nucleic acid sequence encoding human BTN1A1 (BC096314.1 GI: 64654887) is provided below :

[0054] [Chemical formula]

[0055] As used herein, and unless otherwise specified, the term "antibody" refers to an immunoglobulin (or "Ig") class polypeptide product of B cells that can bind specifically to a molecular antigen and is composed of two identical polypeptide chain pairs (where 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 contains a variable region of about 100 - about 130 or more amino acids, and each carboxy terminal portion of each chain contains a constant region) (Borrebaeck (ed.) (1995) , Antibody Engineering, 2nd Edition, Oxford University Press.; K , Antibody Engineering, 2nd Edition, Oxford University Press.; K , Antibody Engineering, 2nd Edition, Oxford University Press.; K the literature of uby (1997), Immunology, 3rd Edition, W.H. Freeman and Company, New York is referred to). Here, the specific molecular antigen includes the target BTN1A1, which can be a BTN1A1 polypeptide, a BTN1A1 fragment, or a BTN1A1 epitope. The antibodies provided herein include, but are not limited to, monoclonal antibodies, synthetic antibodies, recombinantly produced antibodies, bispecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, anti-idiotype

[0056] When used herein and unless otherwise specified, the term "monoclonal antibody" refers to an antibody that is a product of a single cell clone or hybridoma or a population of cells derived from a single cell. Monoclonal antibodies are also intended to refer to antibodies produced by recombinant methods from the heavy and light chains encoding the immunoglobulin genes to produce a single molecular immunoglobulin species. The amino acid sequences of the antibodies within a monoclonal antibody preparation are substantially homogeneous, and the binding activities of the antibodies within such a preparation exhibit substantially the same antigen-binding activity. In contrast, polyclonal antibodies are obtained from various B cells within a population and are a combination of immunoglobulin molecules that bind to a specific antigen. Each of the immunoglobulins of a polyclonal antibody can bind to different epitopes of the same g Harbor Laboratory Press (1989) and Borrebaeck (ed.), Antibody Engineering: A Practical Guide, W.H. Freeman and Co., Publishers, N ew York, pp. 103-120 (1991)). ew York, pp. 103-120(1991))。

[0057] As used herein, and unless otherwise specified, the term "human antibody" refers to an antibody having human variable regions and / or human constant regions or portions thereof corresponding to human germline immunoglobulin sequences. Such human germline immunoglobulin sequences are described in Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242. Here, human antibodies can include antibodies encoded by nucleic acid sequences that are somatic variants of the native nucleic acid sequences of human germline immunoglobulin sequences and that bind to BTN1A1 and bat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242. Here, human antibodies can include antibodies encoded by nucleic acid sequences that are somatic variants of the native nucleic acid sequences of human germline immunoglobulin sequences and that bind to BTN1A1 and Publication No. 91-3242. Here, human antibodies can include antibodies encoded by nucleic acid sequences that are somatic variants of the native nucleic acid sequences of human germline immunoglobulin sequences and that bind to BTN1A1 and are encoded by nucleic acid sequences that are somatic variants of the native nucleic acid sequences of human germline immunoglobulin sequences and that bind to BTN1A1 and are encoded by nucleic acid sequences that are somatic variants of the native nucleic acid sequences of human germline immunoglobulin sequences and that bind to BTN1A1 and

[0058] As used herein, and unless otherwise specified, the term "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is derived from another species or is identical or homologous to the corresponding sequence in an antibody belonging to another antibody class or subclass, and also refers to fragments of such antibodies, provided that they exhibit the desired biological activity ( homologous to the corresponding sequence in an antibody belonging to another antibody class or subclass, and also refers to fragments of such antibodies, provided that they exhibit the desired biological activity ( homologous to the corresponding sequence in an antibody belonging to another antibody class or subclass, and also refers to fragments of such antibodies, provided that they exhibit the desired biological activity ( U.S. Patent No. 4,816,567; and the reference of Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851- 6855 (1984)).

[0059] As used herein, and unless otherwise specified, the term "humanized antibody" refers to a chimeric antibody that contains a human immunoglobulin (e.g., a recipient antibody) in which the native complementarity determining region ("CDR") residues are replaced with residues from the corresponding CDRs (e.g., donor antibodies) of a non-human species such as mouse, rat, rabbit, or non-human primate, which have the desired specificity, affinity, and capacity. Optionally, one or more FR region residues of the human immunoglobulin are replaced with the corresponding non-human residues. Further, a humanized antibody can have residues that are not found in either the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. The heavy or light chain of a humanized antibody can comprise substantially all of at least one or a plurality of variable regions, wherein all or substantially all of the CDRs in said variable regions correspond to the CDRs of a non-human immunoglobulin, and all or substantially all of the FRs are FRs of a human immunoglobulin sequence. The literature of r et al., Proc. Natl. Acd. Sci. USA 89:4285-4289(1992); and U.S. Patent Nos. 6,800,73 No. 8, 6,719,971, 6,639,055, 6,407,213, and 6,054,297 are referred to Yes.

[0060] As used herein, and unless otherwise specified, the term "recombinant antibody" refers to an antibody prepared, expressed, produced, or isolated by recombinant means. Recombinant antibodies include antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant combinatorial antibody library, antibodies isolated from transgenic and / or transchromosomal animals (e.g., mice or cows) for human immunoglobulin genes (see, e.g., the literature of Taylor, L.D. et al., Nucl. Acids Res .20:6287-6295(1992)), or antibodies prepared, expressed, produced, or isolated by any other means involving splicing to other DNA sequences of immunoglobulin gene sequences . Such recombinant antibodies can have variable and constant regions, including those derived from human germline immunoglobulin sequences (see the literature of Kabat, E.A. et al. (1991), Sequences of Proteins of Immunological Interest . 5th Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3 242). Recombinant antibodies can be subjected to in vitro mutagenesis (or trans for human Ig sequences . Recombinant antibodies can be those prepared, expressed, produced, or isolated by any other means involving splicing to other DNA sequences of immunoglobulin gene sequences. Such recombinant antibodies can have variable and constant regions, including those derived from human germline immunoglobulin sequences (see the literature of Kabat, E.A. et al. (1991), Sequences of Proteins of Immunological Interest . 5th Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3 ), 5th Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3 242). Recombinant antibodies can be subjected to in vitro mutagenesis (or trans for human Ig sequences When using a generic animal, it may undergo in vivo somatic mutagenesis , therefore, the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to the VH and VL sequences of the human germline, but may be sequences that do not naturally exist in the in vivo human antibody germline repertoire.

[0061] As used herein and unless otherwise specified, "neutralizing antibody" refers to an antibody that blocks the binding of BTN1A1 to its natural ligand and inhibits the signal transduction pathway and / or other biological activities mediated by BTN1A1. The IC50 of a neutralizing antibody refers to the concentration of the antibody required to neutralize 50% of BTN1A1 in a neutralization assay. The IC50 of a neutralizing antibody can range from 0.01 to 10 μg / ml in a neutralization assay.

[0062] As used herein and unless otherwise specified, the term "antigen-binding fragment" and similar terms refer to a portion of an antibody that immunospecifically binds to an antigen and contains the amino acid residues that confer 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, divalent, or multivalent.

[0063] Examples of molecules having an antigen-binding fragment include, for example, Fd, Fv, Fab, F(ab'), F(ab)2, F(ab')2, single-chain Fv (scFv), diabody, triabody, tetrabody, minibody, or single-domain antibody. The scFv can be a monovalent scFv or a divalent scFv. Other molecules having an antigen-binding fragment include, for example, those in which such an antigen-binding fragment retains its binding activity. ​​​​​​​​​​​​include heavy or light chain polypeptides, variable region polypeptides, or CDR polypeptides, or portions thereof. Such antigen-binding fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publisher; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 ow 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; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, New York, NY (1990). Antigen-binding fragments contain 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 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 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 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 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 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 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 A polypeptide can have an amino acid sequence of 150 consecutive amino acid residues, at least 175 consecutive amino acid residues, at least 20 0 consecutive amino acid residues, or at least 250 consecutive amino acid residues.

[0064] The heavy chain of an antibody refers to a polypeptide chain of about 50 - 70 kDa that contains a variable region of about 120 - 130 or more amino acids at the amino - terminal portion and a constant region at the carboxy - terminal portion. The constant region can be one of five different types, called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy - chain constant region. Different heavy chains are of different sizes: α, δ, and γ contain about 450 amino acids, while μ and ε contain about 550 amino acids. When combined with a light chain, these different types of heavy chains give rise to the five well - known classes of antibodies, namely IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG, i.e., IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0065] The light chain of an antibody refers to a polypeptide chain of about 25 kDa that contains a variable region of about 100 - about 110 or more amino acids at the amino - terminal portion and a constant region at the carboxy - terminal portion. The approximate length of the light chain is 211 - 217 amino acids. Based on the amino acid sequence of the constant domain, there are two different types, called kappa (κ) or lambda (λ). The light - chain amino acid sequences are well - known in the art. The light chain can be a human light chain.

[0066] ​​​​​​​​​​The variable domain or region of an antibody is usually located at the amino terminus of the light or heavy chain, and the heavy chain has a length of about 120-130 amino acids and the light chain has a length of about 100-110 amino acids, and refers to the portion of the light or heavy chain of an antibody that is used with respect to the binding and specificity of that particular antibody to its particular antigen. The variable domains vary greatly in sequence between different antibodies. The sequence variations are concentrated in the CDRs, while the regions with little variation within the variable domain are called framework regions (FRs). The CDRs of the light and heavy chains are mainly involved in the interaction between the antibody and the antigen. The numbering of amino acid positions used herein is according to Kabat et al. (1991), Sequences of proteins of immunological interest (U.S. Department of Health and Human Services, Washington, D.C.), 5th edition, as found in the EU index. The variable region can be a human variable region. The CDR refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of the antibody VL β-sheet framework. Thus, the CDR is a variable region sequence scattered within the framework region sequence. The CDR region is well-known to those skilled in the art and is defined, for example, by Kabat as the most hypervariable region within the antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609 ). ent of Health and Human Services, Washington, D.C.), 5th edition, as found in the EU index. The variable region can be a human variable region. The CDR refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of the antibody VL β-sheet

[0067] framework. Thus, the CDR is a variable region sequence scattered within the framework region sequence. The CDR region is well-known to those skilled in the art and is defined, for example, by Kabat as the most hypervariable region within the antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609 ). framework. Thus, the CDR is a variable region sequence scattered within the framework region sequence. The CDR region is well-known to those skilled in the art and is defined, for example, by Kabat as the most hypervariable region within the antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609 ). The CDR region is well-known to those skilled in the art and is defined, for example, by Kabat as the most hypervariable region within the antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609 ). -6616(1977); Kabat, Adv. Prot. Chem. 32:1-75(1978)). Also, the CDR region sequences are not part of the conserved β-sheet framework and can therefore adopt various conformations and are structurally defined by Chothia as residues that can take various conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917(1987)). Both nomenclatures are well recognized in the art. The positions of the CDRs within a standard 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)). Since the number of residues within the hypervariable regions varies among different antibodies, in the standard variable domain numbering system, additional residues relative to the standard positions have conventionally been numbered with letters such as a, b, c, etc. following the residue number (Al-Lazikani et al., supra(1997)). Such nomenclature systems are similarly well known to those skilled in the art. For example, the CDRs defined according to the standard notation are shown in Table 1 below. Table 1: CDR Definitions Moreover, one or more CDRs can be incorporated into a molecule covalently or non-covalently to make it an immunoadhesin. The immunoadhesin can incorporate the CDR as part of a larger polypeptide chain or covalently link the CDR to another polypeptide chain

[0068] [Table 1]

[0069] be incorporated non-covalently, or a CDR can be incorporated non-covalently. The CDR enables the hesin to bind to a specific antigen of interest.

[0070] The "framework" or "FR" residues refer to the variable domain residues adjacent to the CDR. The FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. The FR residues are variable domain residues other than the hypervariable region residues defined herein.

[0071] As used herein, and unless otherwise specified, the term "isolated" when used in the context of an antibody means that the antibody is substantially free of cellular material or other contaminating proteins and / or other contaminating components from the source of the cell or tissue from which the antibody is derived, or, when chemically synthesized, is substantially free of chemical precursors or other chemicals. The phrase "substantially free of cellular material" includes preparations of antibodies that are separated from the cellular components of the cells from which the antibody is isolated or recombinantly produced. Thus, preparations of antibodies that are substantially free of cellular material include antibodies having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as "contaminating protein"). In certain embodiments, when the antibody is recombinantly produced, it is substantially free of culture medium, e.g., the culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. In certain embodiments, when the antibody is produced by chemical synthesis, it is substantially free of chemical precursors or other chemicals, e.g., it is substantially free of protein. substantially free of protein. substantially free of chemical precursors or other chemicals, e.g., it is It is separated from chemical precursors or other chemicals involved in the synthesis of the substance. Thus, preparations of such antibodies have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. Contaminants include, but are not limited to, substances that interfere with the therapeutic use of the antibody, and can also include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In certain embodiments, the antibody is (1) greater than 95% by weight, e.g., up to 99% by weight, of the antibody as determined by the Lowry method (Lowry et al., J. Bio. Chem. 193: 265-275, 1951), (2) to a sufficient extent to obtain at least 15 residues of the N- terminal or internal amino acid sequence using a spinning cup sequenator, or (3) purified to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue staining or preferably silver staining. Since at least one component of the natural environment of the antibody is absent, isolated antibodies include antibodies in situ within recombinant cells. However, usually, isolated antibodies are prepared by at least one purification step. In a specific embodiment, the antibodies provided herein are isolated. As used herein and unless otherwise specified, the terms "polynucleotide", "nucleotide", "nucleic acid", "nucleic acid molecule" and other similar terms are used interchangeably and include DNA, RNA, mRNA, etc. As used herein and unless otherwise specified, in the context of nucleic acid molecules and when used

[0072] As used herein and unless otherwise specified, the terms "polynucleotide", "nucleotide", "nucleic acid", "nucleic acid molecule" and other similar terms are used interchangeably and include DNA, RNA, mRNA, etc. As used herein and unless otherwise specified, the terms "polynucleotide", "nucleotide", "nucleic acid", "nucleic acid molecule" and other similar terms are used interchangeably and include DNA, RNA, mRNA, etc. and include DNA, RNA, mRNA, etc.

[0073] As used herein and unless otherwise specified, in the context of nucleic acid molecules ​The term "isolated" as used herein means that the nucleic acid molecule is not present in the natural source of the nucleic acid molecule. "Isolated" refers to a nucleic acid molecule that is separated from other nucleic acid molecules. The nucleic acid molecule, e.g., a cDNA molecule, may be derived from other cellular material or produced by recombinant techniques. is substantially free of culture medium or, if chemically synthesized, free of chemical precursors The composition may be substantially free of any chemicals or other chemicals. In the present invention, nucleic acid molecules encoding the antibodies provided herein are isolated or purified.

[0074] As used herein, and unless otherwise specified, "couple" or "couple The term "interaction" refers to interactions between molecules. Interactions can be, for example, hydrogen bonds, ionic Non-covalent phases, including bonds, hydrophobic interactions, and / or van der Waals interactions. The interaction can be between an antibody and a single epitope of a target molecule, e.g., BTN1A1. The strength of the overall non-covalent interactions is the affinity of the antibody for its epitope. "Binding affinity" generally refers to the ability of a molecule (e.g., a binding protein, e.g., an antibody) to bind to a single The strength of the sum of the non-covalent interactions between a site and its binding partner (e.g., an antigen) Point.

[0075] A binding molecule X, e.g., an antibody, and its binding partner Y, e.g., the antibody's cognate antigen The compatibility is usually expressed as the dissociation constant (K D Low affinity antibodies usually have a low affinity for the antigen. They tend to bind slowly and dissociate quickly, whereas high affinity antibodies usually bind antigens quickly. As a measure of binding affinity, Various methods are known in the art and any of these may be used for the purposes of the present disclosure and the "K" D or "K" D value can be measured by assays known in the art, for example by a binding assay. K D is measured, for example, by a radioimmunoassay (RIA) performed using a Fab-type antibody of interest and its antigen (Chen et al. (1999) J. Mol Biol 293:865-881). K or the "K" D value can also be measured, for example, by surface plasmon resonance assay by Biacore using a BIAcore T D M-2000 or BIAcore T M-3000 (BIAcore, Piscataway, NJ), or by biolayer interferometry using, for example, an Octet QK384 system (For teBio, Menlo Park, CA). As used herein and unless otherwise specified, a molecule "immunologically specifically binds" to a second molecule if such binding exhibits specificity and affinity for the cognate antigen of the antibody An antibody immunologically specifically binds to a target region or conformation (an "epitope") of an antigen if such binding involves the antigen recognition site of the antibody

[0076] An antibody that immunologically specifically binds to a particular antigen may bind with lower affinity to other antigens if the other antigens have a certain degree of sequence or conformational similarity recognized by the antigen recognition site as determined by, for example, an immunoassay, a BIACORE (registered trademark ) assay, or other assays known in the art An antibody generally does not bind to completely unrelated antigens Some antigens When determined by an immunoassay, a BIACORE assay, or other assays known in the art and having a certain degree of sequence or conformational similarity recognized by the antigen recognition site can bind with lower affinity The antibody (and its antigen-binding fragment) does not cross-react with other antigens. The antibody can also bind to other molecules in a non-immune-specific manner, for example, to an FcR receptor, thanks to other regions / domains of the antibody that do not contain the antigen recognition site, for example, the binding domain in the Fc region. The antibody or antigen-binding fragment that immunospecifically binds to an antigen or epitope of the antigen containing a glycosylation site can bind to both glycosylated and non-glycosylated forms of the antigen or epitope. In some embodiments, the antibody or antigen-binding fragment preferentially binds to the glycosylated antigen or epitope over the non-glycosylated antigen or epitope. Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 over non-glycosylated BTN1A1 can bind to glycosylated BTN1A1 with a Kd less than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than half of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of the Kd shown for non-glycosylated BTN1A1.

[0077] The antibody or antigen-binding fragment that immunospecifically binds to an antigen or epitope of the antigen containing a glycosylation site can bind to both glycosylated and non-glycosylated forms of the antigen or epitope. In some embodiments, the antibody or antigen-binding fragment preferentially binds to the glycosylated antigen or epitope over the non-glycosylated antigen or epitope. Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 over non-glycosylated BTN1A1 can bind to glycosylated BTN1A1 with a Kd less than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than half of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of the Kd shown for non-glycosylated BTN1A1. Preferential binding is determined by a binding assay and is, for example, determined by fluorescence intensity (“MFI”). In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than half of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of the Kd shown for non-glycosylated BTN1A1. Preferential binding is determined by a binding assay and is, for example, determined by fluorescence intensity (“MFI”). In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than half of the Kd shown for non-glycosylated BTN1A1.

[0078] Preferential binding is determined by a binding assay and is, for example, determined by fluorescence intensity (“MFI”). It can also be shown. For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 has a higher MFI when binding to glycosylated BTN1A1 than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 2-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 3-fold, at least 5-fold, at least 10-fold, at least 15-fold, or at least 20-fold higher than the MFI shown for

[0079] non-glycosylated BTN1A1. As used herein and unless otherwise specified, a molecule is said to "immunologically specifically mask" the glycosylation of an antigen or epitope, or a specific glycosylation site thereof, and refers to its ability to either (1) block the glycosylation site of a non-glycosylated antigen or epitope so that the antigen or epitope cannot be glycosylated, or (2) bind to a glycosylated antigen or epitope or at a specific glycosylation site of a glycosylated antigen or epitope and interfere with the physiological effect of glycosylation, such as the block the glycosylation site and prevent its glycosylation, or (2) bind to glycosylated BTN1A1 , and refers to an antibody or antigen-binding fragment that either prevents the physiological effects of glycosylation, such as the immunosuppressive effect mediated by glycosylation . As another example, an antibody or antigen-binding fragment that immunospecifically masks BTN1A1 glycosylation at N55 and N215 is one that (1) blocks N55 and N215 of non-glycosylated BTN1A1 and prevents glycosylation of N55 and N215, or (2) binds to BTN1A1 glycosylated at N55 and N215 and prevents the physiological effects of glycosylation, such as the immunosuppressive effect mediated by glycosylation . As another example, an antibody or antigen-binding fragment that immunospecifically masks BTN1A1 glycosylation at N55 and N215 is one that (1) blocks N55 and N215 of non-glycosylated BTN1A1 and prevents glycosylation of N55 and N215, or (2) binds to BTN1A1 glycosylated at N55 and N215 and prevents the physiological effects of glycosylation, such as the immunosuppressive effect mediated by glycosylation . As another example, an antibody or antigen-binding fragment that immunospecifically masks BTN1A1 glycosylation at N55 and N215 is one that (1) blocks N55 and N215 of non-glycosylated BTN1A1 and prevents glycosylation of N55 and N215, or (2) binds to BTN1A1 glycosylated at N55 and N215 and prevents the physiological effects of glycosylation, such as the immunosuppressive effect mediated by glycosylation, and refers to any antibody or antigen-binding fragment that does either

[0080] As used herein, and unless otherwise specified, the term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), excipient, stabilizer, or vehicle with which a therapeutic agent is administered . A "pharmaceutically acceptable carrier" is a carrier that is non-toxic to the cells or mammals exposed thereto at the dosages and concentrations utilized, and which can be a sterile liquid such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like . A "pharmaceutically acceptable carrier" is a carrier that is non-toxic to the cells or mammals exposed thereto at the dosages and concentrations utilized, and which can be a sterile liquid such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like . A "pharmaceutically acceptable carrier" is a carrier that is non-toxic to the cells or mammals exposed thereto at the dosages and concentrations utilized, and which can be a sterile liquid such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like

[0081] As used herein, and unless otherwise specified, the term "vector" refers to a substance used to introduce a nucleic acid molecule into a host cell . Suitable vectors for use include, for example, expression vectors, plasmids, phage vectors, viral vectors . Suitable vectors for use include, for example, expression vectors, plasmids, phage vectors, viral vectors Examples include plasmids, episomes, and artificial chromosomes, which can contain selectable sequences or markers operable for stable integration into the chromosome of a host cell. Further, the vector can contain 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 auxotrophy, or supply essential nutrients not present in the culture medium. Expression control sequences can include constitutive and inducible promoters, transcriptional enhancers, transcriptional terminators, etc., well known in the art. If two or more nucleic acid molecules (e.g., both the heavy and light chains of an antibody) are to be co-expressed, both nucleic acid molecules can be inserted, for example, into a single expression vector or separate expression vectors. For single vector expression, the coding nucleic acid can be operably linked to one common expression control sequence or to different expression control sequences, e.g., one inducible promoter and one constitutive promoter. Introduction of the nucleic acid molecule into the host cell can be confirmed using methods well known in the art . Such methods include, for example, nucleic acid analysis, e.g., Northern blotting of mRNA or polymerase chain reaction (PCR) amplification, or immunoblotting for expression of the gene product, or other suitable analytical methods for testing expression of the 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 an amount sufficient to produce the desired product (e.g., the anti-BTN 1A1 antibody provided herein), and it is further understood that the expression level can be optimized using methods well known in the art to obtain sufficient expression.

[0082] As used herein, unless otherwise specified, the term "host cell" refers to a particular target cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. The progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations that may occur in subsequent generations or environmental influences or integration of the nucleic acid molecule into the host cell genome.

[0083] As used herein, unless otherwise specified, the term "subject" refers to an animal that is the subject of treatment, observation, and / or experimentation. "Animal" includes vertebrates and invertebrates, such as fish, crustaceans, reptiles, birds, and particularly, mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, apes, and humans.

[0084] As used herein, unless otherwise specified, the term "cancer" or "cancerous" typically refers to a physiological state in a mammal characterized by unregulated cell proliferation. Examples of cancer include, but are not limited to, blood cancers and solid tumors.

[0085] As used herein, unless otherwise specified, when used in connection with a cancer patient, the terms "treat", "treating", "treatment" refer to an act of reducing the severity of cancer or preventing or slowing the progression of cancer, which includes (a) injuring the growth of cancer or stopping the onset of cancer, and (b) causing regression of cancer or Comprising delaying or minimizing one or more symptoms associated with the existence.

[0086] As used herein and unless otherwise specified, the term "therapeutically effective amount" refers to an amount of an agent (e.g., an antibody described herein or any other agent described herein) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder, or condition and / or the symptoms associated therewith. The therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary to (i) reduce or ameliorate the progression or advancement of a given disease, disorder, or condition, (ii) reduce or ameliorate the recurrence, onset, or occurrence of a given disease, disorder, or condition, and / or (iii) improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an antibody provided herein). The therapeutically effective amount of a substance / molecule / agent (e.g., an anti-BTN1A1 antibody) of the present disclosure can vary depending on factors such as the individual's medical condition, age, sex, and weight, as well as the ability of the substance / molecule / agent to induce a desired response in the individual. The therapeutically effective amount encompasses an amount in which any toxic or adverse effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects.

[0087]

[0087] As used herein and unless otherwise specified, the term "administer" or "administration" refers to the act of physically delivering a substance that exists in an external state to a patient, e.g., by injection or by any other physical delivery method described herein or known in the art, such as mucosal, intradermal, intravenous, intramuscular delivery, and / or. When treating a disease, disorder, or condition, or the symptoms thereof, the administration of the substance typically Performed after the onset of a disorder, or disease, or symptoms thereof. For preventing a disease, disorder, or disease , or symptoms thereof, administration of the substance is usually performed before the onset of the disease, disorder, or dise ase, or symptoms thereof.

[0088] (5.2 Molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1) Provided herein are molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1, comprising an anti-BTN1A1 antibody . In some embodiments, the antigen-binding fragment that immunospecifically binds to BTN1A1 binds to a fragment of BTN1A1, or an epitope. In some embodiments , the BTN1A1 epitope can be a linear epitope. In some embodiments , the BTN1A1 epitope can be a conformational epitope. In some embodiments , the molecules provided herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 inhibit the immunosuppressive function of BTN1A1 .

[0089] N-glycosylation is a post-translational modification that starts in the endoplasmic reticulum (ER) and is then processed in the Golgi (Schwarz and Aebi, Curr. Opin. Struc. Bio., 21(5): 576-582 (2011 ))). This type of modification transfers a pre-formed glycan composed of oligosaccharides to the asparagine (Asn) side-chain acceptor located within the NXT motif (-Asn-X-Ser / Thr-), first catalyzed by the membrane-associated oligosaccharyltransferase (OST) complex (Cheung and Reithmeier, Methods, 41: 451-459 (2007); Helenius and Aebi, Scie nce, 320: 271-277 (2008)). nce, 320: 271-277 (2008)). nce, 291(5512):2364-9(2001)). Addition or removal of saccharides from preformed glycans and cleavage tightly regulate the N-glycosylation cascade in a cell- and location-dependent manner, respectively It is mediated by a group of glycosyltransferases and glycosidases.

[0090] In some embodiments, the molecule is selected for one or more glycosylation motifs of BTN1A1. In some embodiments, the antigen-binding fragment selectively binds to the antigen. Binds immunospecifically to glycopeptides containing glycosylation motifs and adjacent peptides In some embodiments, the antigen-binding fragment has a glycosylation motif in three dimensions. It immunospecifically binds to one or more closely located peptide sequences.

[0091] In some embodiments, the antigen-binding fragment is expressed against non-glycosylated BTN1A1. The glycosylation product has a Kd that is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% less than the Kd of the glycosylation product. In one embodiment, the antigen-binding fragment binds to unglycosylated BTN1A1. BTN1A1 binds glycosylated BTN1A1 with a Kd that is less than 50% of the Kd shown for BTN1A1. In embodiments, the antigen-binding fragment has a Kd greater than or equal to 1%, 2% or 3% of the Kd exhibited for unglycosylated BTN1A1. ,3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% less Kd In a further embodiment, the antigen-binding fragment binds to glycosylated BTN1A1 at a non-glycosylated Binds to glycosylated BTN1A1 with a Kd at least 10-fold lower than the Kd shown for glycosylated BTN1A1 do.

[0092] The specific glycosylation sites of a particular BTN1A1 isoform or variant may vary from the amino acids at positions 55, 215, or 449 of that particular BTN1 A1 isoform or variant. In these situations, one of ordinary skill in the art would be able to determine the glycosylation sites of any particular BTN1A1 isoform or variant corresponding to N55, N215, and N449 of human BTN1A1 exemplified above based on sequence alignment and other common knowledge in the art. Therefore, provided herein is also a molecule having an antigen-binding fragment that immunospecifically binds to a glycosylated form of a BTN1A1 isoform or variant as compared to a non-glycosylated BTN1A1 isoform or variant. The glycosylation sites of the BTN1A1 isoform or variant can be the corresponding sites of N55, N215, and N449 of the human BTN1A1 sequence provided above. In some embodiments, the molecule has an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55, N215, and / or N449. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N215. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N449. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position 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.

[0093] In some embodiments, the molecule has an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55, N215, and / or N449. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N215. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N215. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N449. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position 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. ​and the antigen-binding fragment immunospecifically binds to one or more glycosylation motifs. Several In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55 and N215. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N215 and N 449. In some embodiments the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55 and N449. In some embodiments, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55, N215, and N449.

[0094] In some embodiments, the molecule has an antigen-binding fragment that immunospecifically binds to glycosylated BTN1A1, wherein the antigen-binding fragment preferentially binds to glycosylated BTN1A1 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55, N215, and / or N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N55 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N215 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to one or more glycosylation motifs. binds to. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55 and N215 over non-glycosylated BTN1A1. In some embodiments , the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N215 and N449 over non-glycosylated BTN1A1. In some embodiments , the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55 and N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55, N215, and N449 over non-glycosylated BTN1A1. Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1 A1 can bind to glycosylated BTN1A1 with a Kd less than the Kd shown for non-glycosylated BTN1A1. In some embodiments , the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than half of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment

[0095] binds to glycosylated BTN1A1 with a Kd at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 75% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 50% of the Kd shown for non-glycosylated BTN1A1. In some embodiments , the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than the Kd shown for non-glycosylated BTN1A1. In some embodiments , the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than half of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 75% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 50% of the Kd shown for non-glycosylated BTN1A1. In some embodiments binds to glycosylated BTN1A1 with a Kd less than the Kd shown for non-glycosylated BTN1A1. In some embodiments binds to glycosylated BTN1A1 with a Kd that is about 75% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 50% of the Kd shown for non-glycosylated BTN1A1. In some embodiments , the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd less than the Kd shown for non-glycosylated BTN1A1. In some embodiments binds to glycosylated BTN1A1 with a Kd that is about 50% of the Kd shown for non-glycosylated BTN1A1. In some embodiments wherein the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 25% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 10% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 5% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 2.5% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 1% of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is about 1% of the Kd shown for non-glycosylated BTN1A1. Preferred binding can be determined, for example, in a binding assay indicated by fluorescence intensity ("MFI"). For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1A1 can bind to glycosylated BTN1A1 with an MFI higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 2-fold higher than the MFI shown for non-glycosylated BTN1A1.

[0096] In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 3-fold higher than the MFI shown for non-glycosylated BTN1A1. It binds to glycosylated BTN1A1 with an MFI at least 5 times higher than that of MFI. In some embodiments the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 10 times higher than that shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 15 times higher than that shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment binds to glycosylated BTN1A1 with an MFI at least 20 times higher than that shown for non-glycosylated BTN1A1.

[0097] In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55, N215, and / or N449. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N55. In some embodiments the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N215. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N449. In some embodiments, the antigen-binding fragment immunospecifically masks one or more glycosylation motifs of BTN1A1. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N55 and N215. In some embodiments, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at positions N215 and N449. In some embodiments, the antigen-binding fragment is at the position Specifically mask the BTN1A1 glycosylation in N55 and N449. In some embodiments wherein the antigen-binding fragment specifically masks the BTN1A1 glycosylation at positions N55, N215, and N449.

[0098] (5.2.1. Antibodies and Other Molecules Having Antigen-Binding Fragments) In some embodiments, the anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody can be IgG, IgM, IgA, IgD, or IgE. The anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody can also be a chimeric antibody, an affinity matured antibody, a humanized antibody, or a human antibody. The anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody can also be a camelized antibody, an intrabody, an anti-idiotype (anti-Id) antibody. In some embodiments, the anti-BTN1A1 antibody or the anti-glycosylated BTN1A1 antibody can be a polyclonal antibody or a monoclonal antibody.

[0099] Antibodies can be produced from any animal source, including birds and mammals. In some embodiments, the antibodies are those of sheep, rodents (e.g., mice and rats), rabbits, goats, guinea pigs, camels, horses, or chickens. Furthermore, newer techniques enable the development and screening of human antibodies from human combinatorial antibody libraries. For example, bacteriophage antibody expression technology enables the production of specific antibodies in the absence of animal immunization, as described in U.S. Patent No. 6,946,546, which is incorporated herein by reference in its entirety. These techniques are described in Marks (1992); Stem enable the development and screening of human antibodies from human combinatorial antibody libraries. For example, bacteriophage antibody expression technology enables the production of specific antibodies in the absence of animal immunization, as described in U.S. Patent No. 6,946,546, which is incorporated herein by reference in its entirety. wherein specific antibodies are produced in the absence of animal immunization, as described in U.S. Patent No. 6,946,546, which is incorporated herein by reference in its entirety. ​​​​​​​​​​Literature by er (1994); Literature by Gram et al. (1992); Literature by Barbas et al. (1994); and Literature by Schier et al. (1996 ) are further described therein; these literatures are hereby incorporated herein by reference in their entirety .

[0100] Methods for producing polyclonal antibodies in various animal species, as well as methods for producing various types of monoclonal antibodies, including humanized, chimeric, and fully human, are well known in the art . For example, the following U.S. patents provide a practical description of such methods and are hereby incorporated herein by reference: U.S. Patent No. 3,817,837; 3,850,752; 3,939,350 ; 3,996,345; 4,196,265; 4,275,149; 4,277,437; 4,366,241; 4,469,7 97; 4,472,509; 4,606,855; 4,703,003; 4,742,159; 4,767,720; 4,8 16,567; 4,867,973; 4,938,948; 4,946,778; 5,021,236; 5,164,296; 5,196,066; 5,223,409; 5,403,484; 5,420,253; 5,565,332; 5,571,69 8; 5,627,052; 5,656,434; 5,770,376; 5,789,208; 5,821,337; 5,84 4,091; 5,858,657; 5,861,155; 5,871,907; 5,969,108; 6,054,297; 6,165,464; 6,365,157; 6,406,867; 6,709,659; 6,709,873; 6,753,407 ; 6,753,407 No.; No. 6,814,965; No. 6,849,259; No. 6,861,572; No. 6,875,434; No. 6,891,024; No. 7,407 ,659; and No. 8,178,098 (these documents are hereby incorporated by reference in their entirety into this specification) .

[0101] Molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1 or particularly glycosylated BTN1A1, including anti-BTN1A1 antibodies or anti-glycosylated BTN1A1 antibodies, can be produced by any method known in the art useful for the production of polypeptides, e.g., in vitro synthesis, recombinant DNA production, etc. Humanized antibodies can be produced by recombinant DNA technology. The antibodies described in this specification can also be produced using recombinant immunoglobulin expression technology. The recombinant production of immunoglobulin molecules containing humanized antibodies is described in U.S. Patent No. 4,816,397 (Boss et al.), U.S. Patents Nos. 6,331,415 and 4,816,567 (both to Cabilly et al.), British Patent GB 2,188,638 (Winter et al.), and British Patent GB 2,209,757; these documents are hereby incorporated by reference in their entirety into this specification. Techniques for the recombinant expression of immunoglobulins containing humanized immunoglobulins can also be found in the literature of Goeddel et al., Gene Expression Technology, Methods in Enzymology, Vol. 185, Academic Press (1991), and the literature of Borreback, Antibody Engineering, W. H. Freeman (1992); these documents are hereby incorporated by reference in their entirety into this specification. ​​​​​​​​​​​​It is incorporated. Further information regarding the production, design, and expression of recombinant antibodies can be found in the literature of Mayforth, Designing Antibodies, Academic Press, San Diego (1993).

[0102] In certain embodiments, the anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody is a human antibody. Human antibodies can be produced by various methods known in the art, including the phage display methods described above using antibody libraries derived from human immunoglobulin sequences (see U.S. Pat. Nos. 4,444,887 and 4,716,111; and International Publications WO 98 / 46645, WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 33735, and WO 91 / 10741). Human antibodies cannot express functional endogenous immunoglobulins, but can be produced using transgenic mice that can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, in addition to the human heavy and light chain genes, the human variable regions, constant regions, and diversity regions can be introduced into mouse embryonic stem cells. The mouse heavy and light chain immunoglobulin genes can be made non-functional individually or simultaneously by introduction of the human immunoglobulin locus by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. Subsequently, the chimeric ​​​​​​​​​​​​​​Mate the Ramus to produce homozygous progeny that express human antibodies. The transgene The transgenic mice are immunized with a selected antigen, e.g., all or a portion of a BTN1A1 polypeptide or a glycosylated BTN1A1 polypeptide, using conventional methods. Monoclonal antibodies against the antigen can be obtained from the immunized transgenic mice using conventional hybridoma technology (see, e.g., U.S. Patent No. 5,916,771). The human immunoglobulin transgene carried by the transgenic mice rearranges during B cell differentiation and then undergoes class switching and somatic mutation. Thus, using such techniques, therapeutically useful IgG, IgA, IgM, and IgE antibodies can be produced. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93, which is incorporated herein by reference in its entirety). For a detailed discussion of this technology for producing human and human monoclonal antibodies and the protocols for producing such antibodies, see, e.g., International Publication Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Patent Nos. 5, 413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,8 06, 5,814,318, and 5,939,598, which are incorporated herein by reference in their entirety. Further, companies such as Abgenix (Freemont , Calif.) and Medarex (Princeton, N.J.) use techniques similar to the above-described techniques and then, after that, class switching and somatic mutation. Thus, using such techniques, therapeutically useful IgG, IgA, IgM, and IgE antibodies can be produced. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93, which is incorporated herein by reference in its entirety). For a detailed discussion of this technology for producing human and human monoclonal antibodies and the protocols for producing such antibodies, see, e.g., International Publication Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Patent Nos. 5, 413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,8 06, 5,814,318, and 5,939,598, which are incorporated herein by reference in their entirety. Further, companies such as Abgenix (Freemont , Calif.) and Medarex (Princeton, N.J.) use techniques similar to the above-described techniques and the protocols for producing such antibodies, see, for example, International Publication Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Patent Nos. 5, 413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,8 06, 5,814,318, and 5,939,598, which are incorporated herein by reference in their entirety. Further, companies such as Abgenix (Freemont , Calif.) and Medarex (Princeton, N.J.) use techniques similar to the above-described techniques to produce human antibodies. For a detailed discussion of this technology for producing human antibodies and the protocols for producing such antibodies, see, for example, International Publication Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Patent Nos. 5, , Calif.) and Medarex (Princeton, N.J.) use techniques similar to the above-described techniques and can be tasked with providing a human antibody against the selected antigen.

[0103] In some embodiments, the anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody is a chimeric antibody, e.g., an antibody in which the antigen-binding sequence from a non-human donor is grafted into a heterologous non-human, human, or humanized sequence (e.g., a framework and / or constant domain sequence). In one embodiment, the non-human donor is a rat. In one embodiment, the antigen-binding sequence is synthetic, e.g., obtained by mutagenesis (e.g., phage display screening of a human phage library, etc.). In one embodiment, the chimeric antibody can have a murine V region and a human C region. In one embodiment, the murine light chain V region is fused to a human κ light chain. In one embodiment, the murine heavy chain V region is fused to a human IgG1 C region. Methods for producing chimeric antibodies are known in the art. See, e.g., Morrison, 1985

[0104] , Science 229:1202; Oi et al., 1986, BioTechniques 4:214; Gillies et al., 1989 , J. Immunol. Methods 125:191-202; and U.S. Patent Nos. 6,311,415, 5,807,715, 4,816,567, and 4,816,397; all of which are hereby incorporated by reference in their entirety into this specification. Chimeric antibodies that include one or more CDRs from a non-human species and framework regions from a human immunoglobulin molecule can be made, e.g., by CDR-grafting (EP 239,400 ​​No.; International Publication WO 91 / 09967; and U.S. Patents Nos. 5,225,539, 5,530,101, and 5,585,0 89); benylation or resurfacing (EP 592,106; EP 519,596; Padlan literature , 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka et al. literature, 1994, Protein E ngineering 7:805; and Roguska et al. literature, 1994, Proc. Natl. Acad. Sci. USA 91:969), as well as chain shuffling (U.S. Patent No. 5,565,332), can be produced using various techniques known in the art; all of these documents are hereby incorporated by reference in their entirety herein.

[0105] An exemplary process for the production of recombinant chimeric anti-BTN1A1 antibodies is as follows: a) By conventional molecular biology methods, encoding the CDRs and variable regions of a mouse anti-BTN1A1 (or anti-glycosylated BTN1A1) monoclonal antibody fused to an Fc region derived from a human immunoglobulin to obtain an antibody heavy chain, and constructing an expression vector for expressing it, thereby producing a vector for the expression of a chimeric antibody heavy chain; b) By conventional molecular biology methods, encoding the antibody light chain of a mouse anti-BTN1A1 (or anti-glycosylated BTN1A1) monoclonal antibody, and constructing an expression vector for expressing it, thereby producing a vector for the expression of a chimeric antibody light chain; c) Transferring these expression vectors into host cells by conventional molecular biology methods to produce transfected host cells for the expression of a chimeric antibody; and d) Producing a chimeric antibody by these transfected host cells. ​As described above, it is possible to culture transfected cells by conventional cell culture techniques. It can be included.

[0106] Exemplary processes for the production of recombinant humanized anti-BTN1A1 antibodies include the following: a) By conventional methods of molecular biology, the minimum portion of the variable region framework required to retain the CDR and donor antibody binding specificities is derived from a non-human immunoglobulin such as a murine anti-BTN1A1 (or anti-glycosylated BTN1A1) monoclonal antibody, and the remaining portion of the antibody encodes a heavy chain of an antibody derived from human immunoglobulin and constructs an expression vector that expresses it, thereby producing a vector for the expression of a humanized heavy chain; b) By conventional methods of molecular biology, the minimum portion of the variable region framework required to retain the CDR and donor antibody binding specificities is derived from a non-human immunoglobulin such as a murine anti-BTN1A1 (or anti-glycosylated BTN1A1) monoclonal antibody, and the remaining portion of the antibody encodes a light chain of an antibody derived from human immunoglobulin and constructs an expression vector that expresses it, thereby producing a vector for the expression of a humanized light chain; c) Transferring these expression vectors into host cells by conventional methods of molecular biology to produce transfected host cells for the expression of humanized antibodies; and d) It can include culturing the transfected cells by conventional cell culture techniques to produce humanized antibodies. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers. As described above, it is possible to co-transfect such expression vectors into host cells, and these expression vectors contain different selectable markers.

[0107] For either of the exemplary methods, such expression vectors can be co-transfected into host cells, and these expression vectors contain different selectable markers. For either of the exemplary methods, such expression vectors can be co-transfected into host cells, and these expression vectors contain different selectable markers. It is possible, but preferably identical except for the sequences encoding the heavy and light chains. This procedure results in equivalent expression of the heavy chain polypeptide and the light chain polypeptide. Alternatively, a single vector encoding both the heavy chain polypeptide and the light chain polypeptide may be used. The coding sequences for the heavy and light chains can include cDNA or genomic DNA or both. The host cell used to express the recombinant antibody can be either bacterial cells such as Escherichia coli (E. coli), or more preferably, eukaryotic cells (e.g., Chinese hamster ovary (CHO) cells or HEK-293 cells). The choice of expression vector depends on the choice of host cell and can be selected to have the desired expression and regulatory characteristics in the selected host cell. Other cell lines that can be used include, but are not limited to, CHO-K1, NSO , and PER.C6 (Crucell, Leiden, Netherlands). Further, when selecting a host cell that occupies a species-specific codon usage bias and enhances protein expression, codon usage can be optimized. For example, in the case of CHO cell expression , the DNA encoding the antibody can incorporate codons preferentially used by Cricetulus griseus (Chinese hamster ovary cells are derived from this) . The use of codon optimization methods can facilitate the improvement of expression by the desired host cell (e.g., Wohlgemuth, I. et al., Philos. Trans. R. Soc. Lond. B Biol. Sci. 366(1580):2979-2986(2011); Jestin, J. L. et al., J. Mol. Evol. 69(5) . For example, in the case of CHO cell expression, the DNA encoding the antibody can incorporate codons preferentially used by Cricetulus griseus (Chinese hamster ovary cells are derived from this). The DNA encoding the antibody can incorporate codons preferentially used by Cricetulus griseus (Chinese hamster ovary cells are derived from this). The use of codon optimization methods can facilitate the improvement of expression by the desired host cell. (e.g., Wohlgemuth, I. et al., Philos. Trans. R. Soc. Lond. B Biol. Sci. 366(1580):2979-2986(2011); Jestin, J. L. et al., J. Mol. Evol. 69(5) : 452-457 (2009); see Bollenbach, T. et al., Genome Res. 17(4):401-404 (2007); Kurland , C. G. et al., Prog. Nucleic Acid Res. Mol. Biol. 31:191-219 (1984); Grosjean, H. et al., Gene 18(3): 199-209 (1982)).

[0108] In some embodiments, the anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody can be a monoclonal antibody. In some embodiments, the anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody can be a polyclonal antibody. To produce an antibody specific for a BTN1A1 polypeptide or glycosylated BTN1A1 polypeptide, an animal can be inoculated with an antigen, for example, a BTN1A1 polypeptide or glycosylated BTN1A1 polypeptide. Often, the antigen is conjugated to another molecule to enhance the immune response. The conjugate can be any peptide, polypeptide, protein, or non-proteinaceous substance that binds to the antigen used to induce an immune response in an animal. The antibodies produced in an animal in response to antigen inoculation have various non-identical molecules (polyclonal antibodies) made from various individual antibody-producing B lymphocytes. Given the exact conditions for polyclonal antibody production in an animal, most of the antibodies in the animal's serum recognize the collective epitopes on the antigenic compound against which the animal was immunized. This specificity can be further enhanced by affinity purification to recognize the antigen or epitope of interest

[0109] and Only the antibodies to be selected can be used. The method for producing monoclonal antibodies (MAbs) can be started in the same way as the method for preparing polyclonal antibodies. In some embodiments rodents such as mice and rats are used in the production of monoclonal antibodies. In some embodiments rabbits, sheep, or frog cells are used in the production of monoclonal antibodies. The use of rats is well known and can provide certain advantages . Mice (e.g., BALB / c mice) are routinely used and usually produce a high proportion of stable fusions . The hybridoma technology involves the fusion of a single B lymphocyte derived from a mouse immunized with a BTN1A1 polypeptide or a glycosylated BTN1A1 polypeptide with an immortal myeloma cell (usually a mouse myeloma). This technology provides a method for growing a single antibody-producing cell through an unlimited number of generations so that an unlimited amount of structurally identical antibodies (monoclonal antibodies) with the same antigen or epitope specificity can be produced

[0110] . In one embodiment, the antibody is a single variable domain of an immunoglobulin derived from a camelid antibody lacking a light chain, preferably derived from a heavy chain camelid antibody, which is a VH domain sequence or known as Nanobodies (trademark). Nanobody (trademark) (Nb) is the smallest functional fragment or single variable domain (VH) of a naturally occurring single-chain antibody and is well known to those skilled in the art . These are derived from antibodies with only heavy chains found in camelids (Hamers-Caster

[0111] . In one embodiment, the antibody is a single variable domain of an immunoglobulin derived from a camelid antibody lacking a light chain, preferably derived from a heavy chain camelid antibody, which is a VH domain sequence or known as Nanobodies (trademark). Nanobody (trademark) (Nb) is the smallest functional fragment or single variable domain (VH) H of a naturally occurring single-chain antibody and is well known to those skilled in the art . These are derived from antibodies with only heavy chains found in camelids (Hamers-Caster H and are well known to those skilled in the art. These are derived from antibodies with only heavy chains found in camelids (Hamers-Caster and are well known to those skilled in the art. These are derived from antibodies with only heavy chains found in camelids (Hamers-Caster The literature of Man et al., Nature, 363(6428):446-8(1993); the literature of Desmyter et al., Nat Struct Biol., 3(9):803-11.(1996)). In the family of "Camelidae", immune globulins lacking light polypeptide chains are found. "Camelidae" includes Old World camels (Bactrian camel (Camelus bactrianus) and Dromedary camel (Camelus dromedarius)) and New World camels ( for example, alpaca (Lama paccos), llama (Lama glama), guanaco (Lama guanicoe), and vicuña (Lama vicugna)). Single variable domain heavy chain antibodies are herein referred to as N anobody (trademark) or V H antibody. The small size and unique biophysical properties of Nb H surpass conventional antibody fragments with respect to the recognition of general or hidden epitopes and binding into the cavity or active site of protein targets. Furthermore, Nb can be designed as a multispecific and multivalent antibody, conjugated to a reporter molecule, or humanized. Nb is stable, persists in the gastrointestinal system, and can be easily manufactured. When two antigen-binding sites with different specificities are integrated into a single construct, the bispecific antibody can bring together two separate antigens with excellent specificity, and therefore has great potential as a therapeutic agent. Bispecific antibodies can be produced by fusing two hybridomas that can each produce different immunoglobulins. Bispecific antibodies can connect two scFv antibody fragments while simultaneously being a complete immunoglobulin

[0112] ​​​​​​It can also be produced by deleting the Fc portion present in the robulin. Each scFv unit in such a construct is connected to each other by a synthetic polypeptide linker and is composed of one variable domain derived from each of the heavy (VH) and light (VL) antibody chains, the latter of which is often genetically modified to minimize immunogenicity while retaining maximum resistance to proteolysis. Each scFv unit is connected by one of several techniques including the incorporation of a short (usually less than 10 amino acids) polypeptide spacer that crosslinks two scFv units, thereby enabling the generation of bispecific single-chain antibodies. Thus, the resulting bispecific single-chain antibody is a species containing two VH / VL pairs with different specificities on a single polypeptide chain, where the VH domain and VL domain in each scFv unit are separated by a polypeptide linker long enough to allow intramolecular association between these two domains, and the scFv units thus formed are linked to each other in close proximity by a polypeptide spacer kept short enough to prevent unwanted association between the VH domain of one scFv unit and the VL of the other scFv unit.

[0113] Examples of molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1 include: (i) a Fab fragment consisting of VL, VH, CL, and CH1 domains; (ii) an "Fd" fragment consisting of VH and CH1 domains; (iii) an "Fv" fragment consisting of the VL and VH domains of a single antibody; (iv) a "dAb" fragment consisting of the VH domain; (v) an isolated CDR region; (vi) a bivalent fragment containing two linked Fab fragments; (v) a "dAb" fragment consisting of the VH domain; (vi) a bivalent The F(ab')2 fragment which is a fragment; (vii) The VH domain and the VL domain are linked by a peptide linker that enables these two domains to associate to form a binding domain, a single-chain Fv molecule ("scFv"); (viii) A bispecific single-chain Fv dimer (refer to U.S. Patent No. 5,091,513) ; and (ix) A diabody which is a multivalent or multispecific fragment constructed by gene fusion (U.S. Patent Application Publication No. 20050214860), but is not limited thereto. Fv, scF v, or diabody molecules can be stabilized by incorporating disulfide bridges that link the VH domain and the VL domain. Mini-bodies in which scFv is connected to the CH3 domain can also be prepared (Hu et al., Cancer Res., 56(13):3055-61(1996)). Antibody-like binding peptide mimetics are also contemplated in the embodiments. In the literature of Murali et al., Cell Mol. Biol., 49(2):209-216(2003), "antibody-like binding peptide mimetics" (ABiPs), which are peptides that act as light-chain antibodies and have specific advantages such as a longer serum half-life and a less cumbersome synthetic method, are described. This literature is incorporated herein by reference in its entirety.

[0114] (5.2.2. Anti-BTN1A1 Antibody) A total of 68 monoclonal antibodies that specifically bind immunologically to BTN1A1 were cloned and characterized (Table 4 below). For example, the antibody designated STC810 (also called STC838) showed glycosylation-specific binding with high affinity (the KD between STC810 and hBTN1A1-Fc, according to Biacore, was

[0115] (5.2.2. Anti-BTN1A1 Antibody) A total of 68 monoclonal antibodies that specifically bind immunologically to BTN1A1 were cloned and characterized (Table 4 below). For example, the antibody designated STC810 (also called STC838) showed glycosylation-specific binding with high affinity (the KD between STC810 and hBTN1A1-Fc, according to Biacore, 1.81 nM, as determined by Octet to be 2.12 nM). As described in detail below, treatment with the monoclonal anti-BTN1A1 antibody, e.g., STC810, enhanced T cell-dependent apoptosis of cancer cells, inhibited cancer cell proliferation, and resulted in glycosylation-dependent internalization of BTN1A1 into lysosomes. The epitope of STC810 is also provided herein. Accordingly, anti-BTN1A1 antibodies having specific sequence characteristics, anti-BTN1A1 antibodies that immunospecifically bind to a specific epitope, and their uses in cancer treatment are also provided herein. In certain embodiments, the anti-BTN1A1 antibodies provided herein comprise the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of the monoclonal antibody STC810, or a humanized variant thereof described herein. In certain embodiments, the anti-BTN1A1 antibody can further comprise VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof. In certain embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. In some embodiments, the antibody comprises, consists of, or consists of 1, 2, 3, 4, or 5 CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody is the monoclonal antibody described herein. In one embodiment, the anti-BTN1A1 antibody provided herein is the monoclonal antibody STC810 described herein, or a VH domain, VL domain, VH CDR1,

[0116] In one embodiment, the anti-BTN1A1 antibody provided herein is the monoclonal antibody STC810 described herein, or a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of its humanized variant. In one embodiment, the anti-BTN1A1 antibody can further comprise VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof. In one embodiment, the anti-BTN1A1 antibody comprises less than 6 CDRs. In some embodiments, the antibody comprises, consists of, or consists of 1, 2, 3, 4, or 5 CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody is the monoclonal antibody described herein. In one embodiment, the anti-BTN1A1 antibody provided herein is the monoclonal antibody STC810 described herein, or a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of its humanized variant. In one embodiment, the anti-BTN1A1 antibody can further comprise VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof.

[0117] In one embodiment, the anti-BTN1A1 antibody comprises less than 6 CDRs. In some embodiments, the antibody comprises, consists of, or consists of 1, 2, 3, 4, or 5 CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In a specific embodiment, the antibody is the monoclonal antibody described herein. In one embodiment, the anti-BTN1A1 antibody provided herein is the monoclonal antibody STC810 described herein, or a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of its humanized variant. In one embodiment, the anti-BTN1A1 antibody can further comprise VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of a human germline immunoglobulin amino acid sequence or a variant thereof. One, two, three, four, or five CDRs selected from the group consisting of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of antibody STC810 or its humanized variant or consists of these. In a specific embodiment, the antibody is a human germline immunoglobulin linear amino acid sequence or further comprises VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 of its variant.

[0118] In a specific embodiment, the antibody is a humanized antibody, monoclonal antibody, recombinant antibody , antigen-binding fragment, or any combination thereof. In a particular embodiment, the antibody is a humanized monoclonal antibody or its antigen-binding fragment.

[0119] In some embodiments, provided herein is (i) the anti-BTN1A1 antibody provided herein competes with (e.g., in a dose-dependent manner) the binding of the BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN 1A1), BTN1A1 fragment, or BTN1A1 epitope, and / or (ii) binds to the BTN1A1 epitope bound by the anti-BTN1A1 antibody provided herein (e.g., humanized anti-BTN1A1 antibody), an antibody comprising a humanized antibody. In other embodiments, the antibody is the monoclonal antibody STC810 or its humanized variant provided herein competes with (e.g., in a dose manner) the binding of the BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), BTN1A1 fragment, or BTN1A1 epitope. In other embodiments, the antibody is the monoclonal antibody STC810 or its humanized variant provided herein competes with (e.g., in a dose manner) the binding of the BTN1A1 polypeptide (e.g., cell surface-expressed or soluble BTN1A1), BTN1A1 fragment, or BTN1A1 epitope. ​​interfere competitively in a dependent manner. In other embodiments, the antibody binds to (e.g., recognizes) a BTN1A1 epitope bound by the monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein. The monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein binds to (e.g., recognizes) a BTN1A1 epitope bound by the monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein. binds to (e.g., recognizes) a BTN1A1 epitope bound by the monoclonal antibody BTN1A1 or a humanized variant thereof (e.g., a humanized anti-BTN1A1 antibody) described herein. Table 2a: Sequences of the heavy chain variable (VH) region and light chain variable (VL) region of the mouse monoclonal anti-human BTN1A1 antibody STC810 ) region [Table 2] Table 2b: CDR sequences of the mouse monoclonal anti-human BTN1A1 antibody STC810 [Table 3]

[0120] Accordingly, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics. In some embodiments, the molecule provided herein comprises (a) a heavy chain variable (VH) region comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and / or (b) a light chain variable (VL) region comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, provided herein What is provided is a heavy chain variable (VH) region comprising: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12 , 15, or 18; and / or (b) a light chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20 , 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. The antibody has a variable light (VL) region. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0121] In some embodiments, the molecule provided herein has an antigen-binding fragment having a heavy chain variable (VH) region comprising: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; and (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 1 3, or 16; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; and (2) a VH C DR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 1 3, or 16; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18. In some embodiments, the heavy chain variable (VH) region comprises: (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18 ​It includes a VH CDR3 having the amino acid sequence of. In some embodiments, provided herein the molecule is (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; and (3) VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18: and has an antigen-binding fragment having a heavy chain variable (VH) region.

[0122] In some embodiments, the molecule provided herein is SEQ ID NO: 7, 10, 13, or also has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR1 having the amino acid sequence of 16. VH CDR1 can have the amino acid sequence of SEQ ID NO: 7. VH CDR1 can have the amino acid sequence of SEQ ID NO: 10. VH CDR1 can have the amino acid sequence of SEQ ID NO: 13. VH CDR1 can have the amino acid sequence of SEQ ID NO: 16.

[0123] In some embodiments, the molecule provided herein is SEQ ID NO: 8, 11, 14, or also has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR2 having the amino acid sequence of 17. VH CDR2 can have the amino acid sequence of SEQ ID NO: 8. VH CDR2 can have the amino acid sequence of SEQ ID NO: 11. VH CDR2 can have the amino acid sequence of SEQ ID NO: 14. VH CDR2 can have the amino acid sequence of SEQ ID NO: 17.

[0124] In some embodiments, the molecule provided herein is SEQ ID NO: 9, 12, 15, or also has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of 18. It can be done. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 9. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 12. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 15. The VH CDR3 can have the amino acid sequence of SEQ ID NO: 20.

[0125] In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 7; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 8; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 9. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 10; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 11; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 15. It has.

[0126] In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 18. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 10; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 11; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 15. It has.

[0127] In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 15. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 18. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 15. It has.

[0128] In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 18. In some embodiments, the molecules provided herein are: (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and / or (3) an antigen-binding fragment having a heavy chain variable (VH) region comprising VH CDR3 having the amino acid sequence of SEQ ID NO: 18. An antigen-binding fragment having a heavy-chain variable (VH) region containing a VH CDR3 having the amino acid sequence of SEQ ID NO: 18 has.

[0129] In some embodiments, the molecule provided herein has an antigen-binding fragment having a heavy-chain variable (VH) region having the amino acid sequence of SEQ ID NO: 3. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. has. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. and.

[0130] In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. ; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. ; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. has.

[0131] In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; ; and (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; has. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; ; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; ; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; has. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; ; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. In some embodiments, the molecule provided herein has an antigen-binding fragment having a light-chain variable (VL) region comprising: (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; (3) a VL CDR2 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. The antigen-binding fragment has a light chain variable (VL) region comprising: CDR3:

[0132] In some embodiments, the molecules provided herein are selected from the group consisting of SEQ ID NOs: 19, 22, 25, or The present invention relates to an antigen-binding fragment having a light chain variable (VL) region including a VL CDR1 having a sequence of 28 amino acids. The VL CDR1 can have the amino acid sequence of SEQ ID NO: 19. The VL CDR1 can have the amino acid sequence of SEQ ID NO: The VL CDR1 can have the amino acid sequence of SEQ ID NO:25. The VL CDR1 may have the amino acid sequence of SEQ ID NO:28.

[0133] In some embodiments, the molecules provided herein are selected from the group consisting of SEQ ID NOs: 20, 23, 26, or The present invention relates to an antigen-binding fragment having a light chain variable (VL) region including a VL CDR2 having a sequence of 29 amino acids. The VL CDR2 can have the amino acid sequence of SEQ ID NO: 23. The VL CDR2 can have the amino acid sequence of SEQ ID NO: The VL CDR2 can have the amino acid sequence of SEQ ID NO:29. It is possible.

[0134] In some embodiments, the molecules provided herein are selected from SEQ ID NOs: 21, 24, 27, or The present invention relates to an antigen-binding fragment having a light chain variable (VL) region including a VL CDR3 having a sequence of 30 amino acids. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 21. The VL CDR3 may have the amino acid sequence of SEQ ID NO: The VL CDR3 can have the amino acid sequence of SEQ ID NO:27. It can be done. The VL CDR3 can have the amino acid sequence of SEQ ID NO: 30.

[0135] In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 19; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 20; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 21. An antigen-binding fragment having In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 22; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 23; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 24. An antigen-binding fragment having

[0136] In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 25; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 27. An antigen-binding fragment having In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 30. An antigen-binding fragment having

[0137] In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 30. An antigen-binding fragment having In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 30. An antigen-binding fragment having

[0138] In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 30. An antigen-binding fragment having In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NO: 28; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (3) a light chain variable (VL) region having VL CDR3 having the amino acid sequence of SEQ ID NO: 30. An antigen-binding fragment having

[0139] In some embodiments, the molecule provided herein has an antigen-binding fragment having a variable light (VL) region with the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0140] In some embodiments, the molecule provided herein has an antigen-binding fragment having a variable heavy (VH) region comprising: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7, 10, 13, or 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8, 11, 14, or 17; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9, 12, 15, or 18; and (b) a variable light (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19, 22, 25, or 28; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, 23, 26, or 29; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, 24, 27, or 30. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0141] In some embodiments, the molecule provided herein has an antigen-binding fragment having a variable heavy (VH) region comprising: (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 7; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 8; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 9; and (b) a variable light (VL) region comprising: (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 19; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20; and / or (3) ​​​​​​​​​​​​​​or (3) a light chain variable (VL) region comprising a VL CDR3 having the amino acid sequence of SEQ ID NO: 21, and having an antigen-binding fragment of an anti- proximal binding fragment. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0142] In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 10; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 11; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 12, in a heavy chain variable (VH) region; and (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 22; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 23; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 24, in a light chain variable (VL) region, and having an antigen-binding fragment. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 15, in a heavy chain variable (VH) region; and (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 25; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 27, in a light chain variable (VL) region, and having an antigen-binding fragment. The molecule can be an antibody. The antibody can be a monoclonal antibody.

[0143] In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 15, in a heavy chain variable (VH) region; and (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 25; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 27, in a light chain variable (VL) region, and having an antigen-binding fragment. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 13; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 15, in a heavy chain variable (VH) region; and (b) (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 25; (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 26; It can be a body. The antibody can be a humanized antibody.

[0144] In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises (a) (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 16; (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 18: a heavy chain variable (VH) region; and (b) (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: an antigen-binding fragment having a light chain variable (VL) region. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0145] In some embodiments, the molecule provided herein comprises an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 3 and a VL region having the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 3 and a VL region having the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 3 and a VL region having the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, the molecule provided herein comprises an antigen-binding fragment having a VH region having the amino acid sequence of SEQ ID NO: 3 and a VL region having the amino acid sequence of SEQ ID NO: 5. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0146] In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC810 or a humanized antibody version thereof. The humanized STC810 antibody can have the VH region of STC810, the VL region of STC810, or both the VH region and the VL region as described herein. The humanized STC810 antibody can have the six CDR regions of STC810 (VH CDR1, VH C In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC810 or a humanized antibody version thereof. The humanized STC810 antibody can have the VH region of STC810, the VL region of STC810, or both the VH region and the VL region as described herein. The humanized STC810 antibody can have the six CDR regions of STC810 (VH CDR1, VH C In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC810 or a humanized antibody version thereof. The humanized STC810 antibody can have the VH region of STC810, the VL region of STC810, or both the VH region and the VL region as described herein. The humanized STC810 antibody can have the six CDR regions of STC810 (VH CDR1, VH C In some embodiments, the molecule provided herein is a murine monoclonal antibody designated STC810 or a humanized antibody version thereof. The humanized STC810 antibody can have the VH region of STC810, the VL region of STC810, or both the VH region and the VL region as described herein. The humanized STC810 antibody can have the six CDR regions of STC810 (VH CDR1, VH C It can also have DR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). The humanized STC810 antibody can also have less than 6 CDR regions of STC810. In some embodiments, the humanized STC810 antibody can have 1, 2, 3, 4, or 5 CDR regions (VH CDR1, VH CDR 2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of STC810.

[0147] For example, using standard techniques known to those skilled in the art, including site-directed mutagenesis and PCR-mediated mutagenesis that cause amino acid substitutions, mutations can be introduced into the nucleotide sequences encoding the antigen-binding fragments or antibodies provided herein. In certain embodiments, the derivative contains less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions compared to the original molecule. In a specific embodiment, the derivative has conservative amino acid substitutions made at one or more predicted non-essential amino acid residues. "Conservative amino acid substitution" is a substitution in which an amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Families of amino acid residues having side chains with similar charges are defined in the art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), and amino acids having uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine . "Conservative amino acid substitution" is a substitution in which an amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Amino acid residues having side chains with similar charges are defined in the art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), and amino acids having uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine . "Conservative amino acid substitution" is a substitution in which an amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Amino acid residues having side chains with similar charges are defined in the art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains tain), amino acids having non-polar side chains (e.g., alanine, valine, leucine, isole cine, proline, phenylalanine, methionine, tryptophan), amino acids having β-branched side chains (e.g., threonine, valine, isoleucine), and amino acids having aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, for example, by saturation mutagenesis, and the resulting mutants can be screened for biological activity to identify mutants that retain activity. After mutagenesis, the encoded protein can be expressed and the activity of the protein can be determined.

[0148] In one embodiment, the molecule provided herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 is the mouse monoclonal antibody STC810, or an antigen-binding fragment thereof, for example, an amino acid sequence of the VH domain or VL domain that is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical. In one embodiment, the molecule provided herein has an amino acid sequence that is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% identical to the amino acid sequence shown in SEQ ID NO: 3 or 5. , at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical amino acid sequences. In yet another embodiment, the molecules provided in the present specification have at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity with the VH CDR amino acid sequences and / or VL CDR amino acid sequences shown in Table 2 above. In some embodiments, the molecules provided herein are under stringent conditions

[0149] (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) for DNA bound to a filter at about 45 °C, followed by washing in 0.2× SSC / 0.1% SDS at about 50-65 °C), under highly stringent conditions (e.g., hybridization in 6× SSC for nucleic acids bound to a filter at about 45 °C, followed by washing in 0.1× SSC / 0.2 % SDS at about 68 °C), or other stringent hybridization conditions known to those skilled in the art, to a nucleotide sequence complementary to the nucleotide sequence encoding any one of the VH and / or VL domains shown in Table 2 and can have the amino acid sequence of the VH domain and / or the amino acid sequence of the VL domain encoded thereby (e.g., Ausubel, F.M. et al., eds., 1989, Current Protocols in Molecular Biology encoded by a nucleotide sequence that hybridizes to the complement of the nucleotide sequence encoding any one of the VH and / or VL domains shown in Table 2 and can have the amino acid sequence of the VH domain and / or the amino acid sequence of the VL domain encoded thereby (e.g., Ausubel, F.M. et al., eds., 1989, Current Protocols in Molecular Biology (Protocols in Molecular Biology), Volume I, Green Publishing Associates and John W iley & Sons, New York, see pages 6.3.1 - 6.3.6 and 2.10.3).

[0150] In another embodiment, the molecules provided herein are under stringent conditions (e.g., for example, hybridization in 6×SSC at about 45°C to DNA bound to a filter and subsequent washing one or more times in 0.2×SSC / 0.1% SDS at about 50 - 65°C), under highly stringent conditions (e.g., hybridization in 6×SSC at about 45°C to nucleic acid bound to a filter and subsequent washing one or more times in 0.1×SSC / 0.2% SDS at about 68°C), or under other stringent hybridization conditions known to those skilled in the art, a nucleotide sequence encoding any one of the VH CDRs and / or VL CDRs shown in Table 2 is hybridized to a complementary nucleotide sequence, and the amino acid sequence of the VH CDR or the amino acid sequence of the VL CDR encoded by the nucleotide sequence can be obtained (e.g., Ausubel, F.M. et al., eds., 1989, Current Protocols in Molecular Biology, Volume I, Green Publi shing Associates and John Wiley & Sons, New York, see pages 6.3.1 - 6.3.6 and 2.10.3). (Protocols in Molecular Biology), Volume I, Green Publishing Associates and John Wiley & Sons, New York, see pages 6.3.1 - 6.3.6 and 2.10.3). shing Associates and John Wiley & Sons, New York, see pages 6.3.1 - 6.3.6 and 2.10.3). pages).

[0151] In some embodiments, provided herein is an isolated nucleic acid encoding the amino acid sequence of the VH CDR or the amino acid sequence of the VL CDR shown in Table 2, or a stringent ​ Under stringent conditions (e.g., hybridization at about 45°C in 6× sodium chloride / sodium citrate (SSC) for DNA bound to a filter and subsequent washing one or more times at about 50 - 65°C in 0.2× SSC / 0.1% SDS), under extremely stringent conditions (e.g., hybridization at about 45°C in 6× SSC for nucleic acid bound to a filter and subsequent washing one or more times at about 68°C in 0.1× SSC / 0.2% SDS), or under other stringent hybridization conditions known to those skilled in the art, there is also an isolated nucleic acid that hybridizes to the complement of a nucleic acid sequence encoding any one of the VH CDRs and / or VL CDRs shown in Table 2.

[0152] In some embodiments, provided herein is an isolated nucleic acid encoding the amino acid sequence of the VH domain and / or the amino acid sequence of the VL domain shown in Table 2, or under stringent conditions (e.g., hybridization at about 45°C in 6× sodium chloride / sodium citrate (SSC) for DNA bound to a filter and subsequent washing one or more times at about 50 - 65°C in 0.2× SSC / 0.1% SDS), under extremely stringent conditions (e.g., hybridization at about 45°C in 6× SSC for nucleic acid bound to a filter and subsequent washing one or more times at about 68°C in 0.1× SSC / 0.2% SDS), or under other stringent hybridization conditions known to those skilled in the art, it is also an isolated nucleic acid that hybridizes to the complement of a nucleotide sequence encoding any one of the VH and / or VL domains shown in Table 2. ​​​​​​​​​​​​​​​

[0153] In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the molecules provided herein can be, for example, conjugated to an antibody. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art.

[0154] In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 4, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 4 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art. In some embodiments, the isolated nucleic acid is the sequence of SEQ ID NO: 6, or a sequence that hybridizes to a complement of the nucleotide sequence of SEQ ID NO: 6 under stringent conditions (e.g., hybridization in 6× sodium chloride / sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC / 0.1% SDS at about 50-65° C.), very stringent conditions (e.g., hybridization in 6× SSC at about 45° C. followed by washes in 0.1× SSC / 0.2% SDS at about 68° C.), or other stringent hybridization conditions known to those of skill in the art.

[0155] In some embodiments, the molecules provided herein can be, for example, conjugated to an antibody. The peptides can be chemically modified by the covalent attachment of molecules of the following types: Although not limited to these, antibody derivatives may include, for example, glycosylation, acetylation, pegylation, phosphorylation, and acetylation. Midification, derivatization with known protecting / blocking groups, proteolytic cleavage, cellular ligands or antibodies that have been chemically modified, such as by linking to other proteins. Any of a number of chemical modifications may be performed, including but not limited to specific chemical cleavage, acetylation, formulation, etc. This can be accomplished by known techniques, including metabolic synthesis of tunicamycin, etc. In addition, the antibody can contain one or more non-classical amino acids.

[0156] The molecules provided herein may comprise any of the framework regions known to those of skill in the art (e.g., human or The framework regions can have, for example, natural or conceptual In a specific embodiment, the amino acid sequence of the present invention may be a consensus framework region. The framework regions of the provided antibodies are human (e.g., human framework For a list of regions, see Chothia et al., 1998, J. Mol. Biol. 278:457-479. (1991), which is incorporated herein by reference in its entirety. Sequences of Proteins of Immunological Interest rest) (US Department of Health and Human Services, Washington, DC), see also 5th ed. I want to be illuminated.

[0157] The BTN1A1 epitope of STC810 was mapped by cross-linking analysis. Table 3 shows the cross-linking activity of BTN1A1-Fc and ST This is a summary of the cross-linked peptides of C810, which represents the BTN1A1 epitope (SEQ ID NO: 31-33) of STC810. Figure 12 shows the synthetic epitope of the BTN1A1(ECD)-Fc antigen for STC810: Figure 12 shows the synthetic epitope of the BTN1A1(ECD)-Fc antigen for STC810: :

Chemical formula

[0158] Table 4 is a summary of the cross-linked peptides of BTN1A1-His and STC810, which represents the BTN1A1 epitope (SEQ ID NO: 36-39) of STC810. Figure 13 shows the synthetic epitope of the BTN1A1(ECD)-His antigen for STC810. Figure 13 shows the synthetic epitope of the BTN1A1(ECD)-His antigen for STC810.

[0159]

Chemical formula

Table 4

Table 5

[0160] Therefore, also provided herein are molecules having antigen-binding fragments that competitively block the BTN1A1 epitopes described herein (e.g., in a dose-dependent manner). In some embodiments, provided herein are molecules having antigen-binding fragments that competitively block the BTN1A1 epitope of STC810 (e.g., in a dose-dependent manner). ope (e.g., in a dose-dependent manner). ​​This is the case. In some embodiments, the molecule provided herein has an antigen-binding fragment that immunospecifically binds to an epitope of BTN1A1 described herein. In some embodiments it has an antigen-binding fragment that immunospecifically binds to the BTN1A1 epitope of STC810. The molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody. In some embodiments, provided herein is an anti-BTN1A1 antibody that competitively blocks the BTN1A1 epitope described herein (e.g., in a dose-dependent manner). In some embodiments, provided herein is an anti-BTN1A1 antibody that competitively blocks the BTN1A1 epitope of STC810 described herein (e.g., in a dose-dependent manner). In some

[0161] embodiments, the anti-BTN1A1 antibody provided herein immunospecifically binds to the BTN1A1 epitope described herein. In some embodiments, the anti-BTN1A1 antibody provided herein immunospecifically binds to the BTN1A1 epitope of STC810. In some embodiments, the molecule has an antigen-binding fragment that competitively blocks the BTN1A1 epitope (e.g., in a dose-dependent manner), where the BTN1A1 epitope has at least 5 contiguous amino acids of the amino acid sequence of SEQ ID NO: 31-41. In some embodiments, the molecule provided herein has an antigen-binding fragment that immunospecifically binds to the BTN1A1 epitope, where the BTN1A1 epitope has the amino acid sequence of SEQ ID NO: 31-41. In some embodiments, the anti-BTN1A1 antibody provided herein immunospecifically binds to the BTN1A1 epitope described herein. In some embodiments, the anti-BTN1A1 antibody provided herein immunospecifically binds to the BTN1A1 epitope of STC810.

[0162] In some embodiments, the molecule has an antigen-binding fragment that competitively blocks the BTN1A1 epitope (e.g., in a dose-dependent manner), where the BTN1A1 epitope has at least 5 contiguous amino acids of the amino acid sequence of SEQ ID NO: 31-41. In some embodiments, the molecule provided herein has an antigen-binding fragment that immunospecifically binds to the BTN1A1 epitope, where the BTN1A1 epitope has the amino acid sequence of SEQ ID NO: 31-41. In some embodiments, the molecule provided herein has an antigen-binding fragment that immunospecifically binds to the BTN1A1 epitope, where the BTN1A1 epitope has the amino acid sequence of SEQ ID NO: 31-41. In some embodiments, the molecule provided herein has an antigen-binding fragment that immunospecifically binds to the BTN1A1 epitope, where the BTN1A1 epitope has the amino acid sequence of SEQ ID NO: 31-41. It has at least 5 consecutive amino acids. The epitope of BTN1A1 is at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or can have at least 15 consecutive amino acids. The epitope of BTN1A1 can have at least 6 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 7 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 8 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 9 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 10 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 11 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 12 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 13 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 14 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 15 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 16 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 17 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 18 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 19 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 20 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. The epitope of BTN1A1 can have at least 21 consecutive amino acids of the amino acid sequence of SEQ ID NO: 31-41. It can be. The molecule can be an antibody. The antibody can be a monoclonal antibody It can be. The antibody can be a humanized antibody.

[0163] In some embodiments, the molecule has an antigen-binding fragment that competitively blocks the BTN1A1 epitope (e.g., in a dose-dependent manner), wherein the BTN1A1 epitope has the amino acid sequence of SEQ ID NO: 31-41. In some embodiments, the molecule provided herein has an antigen-binding fragment that immunospecifically binds to an epitope of BTN1A1, wherein the BT N1A1 epitope has the amino acid sequence of SEQ ID NO: 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 31. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 32. The BT N1A1 epitope can have the amino acid sequence of SEQ ID NO: 33. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 34. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 35. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 36. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 37. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 38. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 39. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 40. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 41. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 39. The BTN1A1 epitope can have the amino acid sequence of SEQ ID NO: 40. The BT N1A1 epitope can have the amino acid sequence of SEQ ID NO: 41.

[0164] In certain embodiments, the molecules provided herein are BTN1A1, glycosylated BTN1A1, or have a high affinity for these polypeptides or polypeptide fragments or epitopes. In one embodiment, the molecules provided herein are BTN1A1 antibodies having a higher affinity for BTN1A1 antibodies than known antibodies (e.g., , commercially available monoclonal antibodies discussed elsewhere herein). In a specific embodiment, the molecules provided herein are, when evaluated by techniques described herein or known to those of skill in the art (e.g., BIA core assay), anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay. In certain embodiments, the molecules provided herein are anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay. In certain embodiments, the molecules provided herein are anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay. core assay), anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay. core assay), anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay. core assay), anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay. core assay), anti-BTN1A1 antibodies that can have an affinity for the BTN1A1 antigen that is 2 to 10 times (or more) higher than that of known anti-BTN1A1 antibodies. According to these embodiments, the affinity of the antibody is, in one embodiment, evaluated by BIAcore assay.

[0165] In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments In certain embodiments, the molecules provided herein are antigen-binding fragments that can bind to BTN1A1, glycosylated BTN1A1, or polypeptides or polypeptide fragments or epitopes thereof with a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the molecules provided herein can be anti-BTN1A1 antibodies having a Kd of 500 nM or less. In some embodiments can be an anti-BTN1A1 antibody. In some embodiments, having a Kd of 50 nM or less can be an anti-BTN1A1 antibody. In some embodiments, provided herein The molecule can be an anti-BTN1A1 antibody having a Kd of 20 nM or less. In some embodiments The molecule provided herein can be an anti-BTN1A1 antibody having a Kd of 10 nM or less can be. In some embodiments, the molecule provided herein has a Kd of 5 nM or less can be an anti-BTN1A1 antibody. In some embodiments, provided herein The molecule can be an anti-BTN1A1 antibody having a Kd of 2 nM or less. In some embodiments The molecule provided herein can be an anti-BTN1A1 antibody having a Kd of 1 nM or less can be. In some embodiments, the molecule provided herein has a Kd of 0.5 nM or less can be an anti-BTN1A1 antibody. In some embodiments, herein The molecule provided can be an anti-BTN1A1 antibody having a Kd of 0.1 nM or less.

[0166] In one embodiment, the molecule provided herein can block or neutralize the activity of BTN1A1 The molecule can be a neutralizing antibody. The neutralizing antibody can block the binding of BTN1A1 to its natural ligand and inhibit the signal transduction pathway mediated by BTN1A1 and / or other physiological activities. The IC50 of the neutralizing antibody can be in the range of 0.01 - 10 μg / ml in a neutralization assay. The IC50 of the neutralizing antibody can be 10 μg / ml or less The IC50 of the neutralizing antibody can be 8 μg / ml or less. The IC50 of the neutralizing antibody can be 6 μg / ml or less The IC50 of the neutralizing antibody can be 6 μg / ml or less. It can be. The IC50 of the neutralizing antibody can be 4 μg / ml or less. The I C50 can be 2 μg / ml or less. The IC50 of the neutralizing antibody can be 1 μg / ml or less. It can be. The IC50 of the neutralizing antibody can be 0.8 μg / ml or less. The IC50 of the neutralizing antibody is 0.6 μg / ml or less. The IC50 of the neutralizing antibody can be 0.4 μg / ml or less. The IC50 of the neutralizing antibody can be 0.2 μg / ml or less. The IC50 of the neutralizing antibody is 0.1 μg / ml or less. The IC50 of the neutralizing antibody can be 0.08 μg / ml or less. Neutralizing The IC50 of the antibody can be 0.06 μg / ml or less. The IC50 of the neutralizing antibody can be 0.04 μg / ml or less. It can be. The IC50 of the neutralizing antibody can be 0.02 μg / ml or less. Neutralizing antibody The IC50 of can be 0.01 μg / ml or less.

[0167] The molecule provided herein having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 can be an anti-BTN1A1 antibody. The antibodies provided herein include synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, anti-idiotype (anti-Id) antibodies, and functional fragments of any of the above, but are not limited thereto. Non-limiting examples of functional fragments include single-chain Fv (scFv) (e.g., including single-specificity, bispecificity, etc.), Fab fragments, F(ab') fragments, F(ab)2 fragments, F(ab')2 fragments, disulfide linked Fv (sdFv), Fd fragments, Fv fragments, diabodies, triabodies, tetra-bodies, and mini- Examples include nibody.

[0168] In particular, the molecules provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, such as antigens that bind immunospecifically to BTN1A1 or glycosylated BTN1A1 and molecules containing antigen-binding fragments. 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. It can be of the subclass. It can be possible.

[0169] The molecules provided herein can be monospecific, bispecific, trispecific antibodies, or higher order multispecific antibodies. Multispecific antibodies can be specific for different epitopes of BTN1 A1 described herein, or can be specific for both BTN1A1 polypeptide and heterologous epitopes, e.g., both heterologous polypeptides or solid support materials. In a specific embodiment, the antibodies provided herein are monospecific for a given epitope of the BTN1A1 polypeptide and do not bind to other epitopes. It does not bind to other epitopes.

[0170] (5.2.3. Modifications and Derivatives) The binding properties of any of the above molecules having an antigen-binding fragment that binds immunospecifically to BTN1A1 or glycosylated BTN1A1 can be further improved by screening for mutants that exhibit desired properties. For example, such improvement can be achieved using various phage display methods known in the art. In phage display methods, functional antibodies can be used. can be used. Domains are presented on the surface of phage particles that carry the polynucleotide sequences encoding them. In certain embodiments, such phage are used to display antigen-binding fragments, such as Fab and F v or disulfide bond-stabilized Fv, expressed from a repertoire or combinatorial antibody library (e.g., human or mouse). Phage expressing antigen-binding fragments that bind to a target antigen can be selected or identified using the antigen, e.g., a labeled antigen or an antigen bound or captured on a solid surface or bead. The phage used in these methods are typically filamentous phage, including fd and M13. Antigen-binding fragments are expressed as recombinant fusion proteins with either phage gene III or gene VIII protein. Examples of phage display methods that can be used to generate antibodies or other molecules having the antigen-binding fragments described herein include Brinkman et al., J Immunol Methods, 182:41-50 (1995); Ames et al., J. Immunol. Methods, 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol ., 24:952-958 (1994); Persic et al., Gene, 187:9-18 (1997); Burton et al., Adv. Immunol. 57:191-280 (1994); PCT Publication WO 92 / 001047; WO 90 / 02809; WO 91 / 10737; WO 92 / 01047; WO 92 / 18619; WO 93 / 11236; WO 95 / 15982; WO 95 / 20401; and US Patent Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743; and 5,969,108. Patent Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743; and 5,969,108. Patent Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743; and 5,969,108. U.S. Patent Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5, 750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; the methods disclosed in U.S. Patent Nos. 5,658,727; 5,733,743; and 5,969,108; all of these documents are hereby incorporated by reference in their entirety into this specification. As described in the above references, after phage selection, the antibody - encoding region derived from the phage is isolated and used to generate whole antibodies, including humanized antibodies, or any other desired fragment, and can be expressed in any desired host, including, for example, mammalian cells, insect cells, plant cells,

[0171] yeast, and bacteria, as detailed below. For example, techniques known in the art, such as those disclosed in PCT Publication WO 92 / 22324; Mullinax, R. L. et al., BioTechniques, 12(6):864 - 869(1992); and Sawai et al., Am. J. Reprod. Immunol. 34:26 - 34(1995); and Better, M. et al., Science 240:1041 - 1043(1988), can be used to utilize techniques for recombinantly producing Fab, Fab', and F(ab')2 fragments; all of these documents are hereby incorporated by reference in their entirety into this specification. Examples of techniques that can be used to produce single - chain Fv and antibodies include U.S. Patent Nos. 4,946,778 and 5, 258,498; Huston, J. S. et al., Methods in Enzymology 203:46 - 88(1991); Shu, L et al., Proc. Natl. Acad. Sci. USA 90:7995 - 7999(1993); Skerra, A. et al., Science 240:1038 - 1041(1988); and Bird, R. E. et al., Science 242:423 - 426(1988). et al., Proc. Natl. Acad. Sci. USA 90:7995 - 7999(1993); Skerra, A. et al., Science 240:1038 - 1041(1988); and Bird, R. E. et al., Science 242:423 - 426(1988). For example, techniques known in the art, such as those disclosed in PCT Publication WO 92 / 22324; Mullinax, R. L. et al., BioTechniques, 12(6):864 - 869(1992); and Sawai et al., Am. J. Reprod. Immunol. 34:26 - 34(1995); and Better, M. et al., Science 240:1041 - 1043(1988), can be used to utilize techniques for recombinantly producing Fab, Fab', and F(ab')2 fragments; all of these documents are hereby incorporated by reference in their entirety into this specification. Examples of techniques that can be used to produce single - chain Fv and antibodies include U.S. Patent Nos. 4,946,778 and 5, 258,498; Huston, J. S. et al., Methods in Enzymology 203:46 - 88(1991); Shu, L et al., Proc. Natl. Acad. Sci. USA 90:7995 - 7999(1993); Skerra, A. et al., Science 240:1038 - 1041(1988); and Bird, R. E. et al., Science 242:423 - 426(1988). used to produce single - chain Fv and antibodies include U.S. Patent Nos. 4,946,778 and 5,258,498; Huston, J. S. et al., Methods in Enzymology 203:46 - 88(1991); Shu, L. et al., Proc. Natl. Acad. Sci. USA 90:7995 - 7999(1993); Skerra, A. et al., Science 240:1038 - 1041(1988); and Bird, R. E. et al., Science 242:423 - 426(1988). These documents are all incorporated by reference in their entirety into this specification. These documents are all incorporated by reference in their entirety into this specification. Examples of techniques that can be used to produce single - chain Fv and antibodies include U.S. Patent Nos. 4,946,778 and 5, 258,498; Huston, J. S. et al., Methods in Enzymology 203:46 - 88(1991); Shu, L. et al., Proc. Natl. Acad. Sci. USA 90:7995 - 7999(1993); Skerra, A. et al., Science 240:1038 - 1041(1988); and Bird, R. E. et al., Science 242:423 - 426(1988). ,258,498; Huston, J. S. et al., Methods in Enzymology 203:46 - 88(1991); Shu, L . The techniques described in the literature of Proc. Natl. Acad. Sci. (USA) 90:7995-7999; and the literature of Skerra, A. et al., Science 240:1038-1040 (1988) are mentioned; all of these literatures are incorporated herein by reference in their entirety. The phage display technique can be used to increase the affinity of an anti-BTN1A1 antibody or an anti-glycosylated BTN1A1 antibody, or another molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1 described herein.

[0172] This technique can be used to obtain high-affinity antibodies that can be used in the combinatorial methods described herein. This technique, called affinity maturation, utilizes mutagenesis or CDR walking and reselection using such receptors or ligands (or extracellular domains thereof) or antigenic fragments thereof to identify antibodies that bind to an antigen with a higher affinity when compared to an initial or parental antibody (see, for example, the literature of Glaser, S.M. et al., J. Immunol. 149:3903-3913 (1992)). Mutagenizing entire codons rather than single nucleotides results in a semi-random repertoire of amino acid mutations. Each of which differs by only one amino acid change within a single CDR and contains variants representing each possible amino acid substitution for each CDR residue, a library consisting of a pool of mutant clones can be constructed. By contacting the immobilized mutants with the labeled antigen, mutants with increased binding affinity for the antigen can be screened. Any screening method known in the art can be used. Thus, mutant antibodies with increased binding affinity to an antigen can be identified (e.g., ELI SA) (see, e.g., Wu, H. et al., Proc. Natl. Acad. Sci. (USA) 95(11):6037-6042 (1998); Yelton, D. E. et al., J. Immunol. 155:1994-2004 (1995)). CDR walking with randomization of the light chain can also be used (see Schier et al., J. Mol. Biol. 263:551- 567 (1996)).

[0173] Random mutagenesis can be used in conjunction with phage display methods to identify improved CDRs and / or variable regions. Alternatively, phage display technology can be used to increase (or decrease) CDR affinity by site-directed mutagenesis (e.g., affinity maturation or "CDR-walking"). This technique uses a target antigen or an antigenic fragment to identify antibodies having CDRs that bind the antigen with higher (or lower) affinity compared to an initial or parental antibody (see, e.g., Glaser, S. M. et al., J. Immunol. 149 :3903-3913 (1992)). Methods for achieving such affinity maturation include, for example: Krause, J. C. et al., MBio. 2(1

[0174] ) pii: e00345-10. doi: 10.1128 / mBio.00345-10 (2011); Kuan, C. T. et al., Int. J. Cancer 10.1002 / ijc.25645; Hackel, B. J. et al., J. Mol. Biol. 401(1):84-96 (201 ​​0); Montgomery, D. L. et al., MAbs 1(5):462-474(2009); Gustchina, E. et al., Virology 393(1):112-119(2009); Finlay, W. J. et al., J. Mol. Biol. 388(3):541-5 58(2009); Bostrom, J. et al., Methods Mol. Biol. 525:353-376(2009); Steidl, S. et al., Mol. Immunol. 46(1):135-144(2008); and Barderas, R. et al., Proc. Natl . Acad. Sci.(USA) 105(26):9029-9034(2008); all of these references are hereby incorporated by reference in their entirety herein.

[0175] Provided herein is any derivative of the above molecules having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BTN1A1, which may be an anti-BTN1A1 antibody or an anti-glycosylated BTN1A1 antibody, but has one, two, three, four, five, or more amino acid substitutions, additions, deletions, or modifications compared to the "parent" (or wild-type) molecule. Such amino acid substitutions or additions can introduce natural (i.e., encoded by DNA) or non-natural amino acid residues. Such amino acids can be glycosylated (e.g., with altered content of mannose, 2-N-acetylglucosamine, galactose, fucose, It can be amidated, derivatized with known protecting / blocking groups, subjected to proteolytic cleavage, or linked to a cellular ligand or other protein, etc. In some embodiments, modification of the carbohydrate modification is as follows: solubilization of the antibody, smoothing of intracellular transport and secretion of the antibody, promotion of antibody association, conformational integrity, and regulation of one or more of the antibody-mediated effector functions. In some embodiments, modification of the carbohydrate modification enhances the antibody-mediated effector function compared to an antibody lacking the carbohydrate modification. Carbohydrate modifications that result in modification of the antibody-mediated effector function are well known in the art (see, for example, the literature of Shields, R. L. et al., J. Biol. Chem. 277(30): 26733-26740(2002) ; the literature of Davies J. et al., Biotechnology & Bioengineering 74(4): 288-294(2001); all of these literatures are hereby incorporated by reference in their entirety into this specification). Methods for modifying the carbohydrate content are known to those skilled in the art, for example, see the literature of Wallick, S. C. et al., J. Exp. Med. 168(3): 1099-1109(1988); the literature of Tao, M. H. et al., J. Immunol. 143(8): 2595-2601( 1989); the literature of Routledge, E. G. et al., Transplantation 60(8):847-53(1995); Elliott, S. et al., Nature Biotechnol. 21:414-21(2003); the literature of Shields, R. L. et al., J. Biol. C hem. 277(30): 26733-26740(2002); all of these literatures are hereby incorporated by reference in their entirety into this specification. ​

[0176] In some embodiments, the humanized antibody is an inducible antibody. Such a humanized antibody includes substitutions, deletions, or additions of amino acid residues in one or more non-human CDRs. The humanized antibody inducer can have substantially the same binding, better binding, or worse binding compared to the non-inducible humanized antibody. In some embodiments, one, two, three, four, or five amino acid residues of the CDRs are mutated, for example, substituted, deleted, or added.

[0177] The molecules and antibodies described herein can be modified by chemical modifications known to those of skill in the art, including but not limited to specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicaamycin, etc. In one embodiment, the inducible molecule or inducible antibody possesses the same or identical function as the parent molecule or parent antibody. In another embodiment, the inducible molecule or inducible antibody exhibits modified activity compared to the parent molecule or parent antibody. For example, the inducible antibody (or fragment thereof) can bind more tightly to its epitope than the parent antibody or can be more resistant to proteolysis than the parent antibody.

[0178] The substitutions, additions, or deletions in the derivatized antibody can be in the Fc region of the antibody, thereby serving to modify the binding affinity of the antibody for one or more FcγRs. Methods for modifying antibodies with modified binding to one or more FcγRs are known in the art, for example, PCT publications WO 04 / 029207, WO 04 / 029092, WO 04 / 028564, WO 04 / 028564, WO Nos. 99 / 58572, WO 99 / 51642, WO 98 / 23289, WO 89 / 07142, WO 88 / 07089, and U.S. Pat. Nos. 5,843,597 and 5,642,821 are hereby incorporated by reference in their entirety; these documents are all incorporated herein by reference in their entirety. In some embodiments, the antibody or other molecule can have an altered affinity for activating FcγRs, e.g., FcγRIIIA. Preferably, such modifications also have an altered Fc-mediated effector function. Modifications that affect Fc-mediated effector function are well known in the art (see U.S. Pat. No. 6,1 94,551, and WO 00 / 42072). In some embodiments, the modification of the Fc region results in an antibody having an altered antibody-mediated effector function, an altered binding to other Fc receptors (e.g., Fc activating receptors), an altered antibody-dependent cell-mediated cytotoxicity (ADCC) activity, an altered C1q binding activity, an altered complement-dependent cytotoxicity activity (CDC), phagocytic activity, or any combination thereof.

[0179] ADCC is a cell-mediated reaction in which antigen-nonspecific cytotoxic cells that express FcR (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize an antibody bound to the surface of a target cell and then cause lysis of the target cell (i.e., "kill" the target cell). The major mediator cells are NK cells. NK cells express only FcγRIII, and FcγRIIIA is an activating receptor and FcγRIIIB is an inhibitory receptor; monocytes express FcγRI, FcγRII, and and FcγRIII (Ravetch et al. (1991) Annu. Rev. Immunol., 9:457-92). ADC C activity is expressed as the concentration of antibody or Fc fusion protein that results in half-maximal lysis of target cells. Thus, in some embodiments, the lysis level can be compared to the wild type control. The concentration of the antibody or Fc fusion protein of the present invention that results in half-maximal lysis is At least 2, 3, 5, 10, 20, 50, or 100 times lower than the concentration of the light itself. In embodiments, the antibodies or Fc fusion proteins of the invention have a higher affinity for IgG compared to a wild-type control. For example, maximum target cell lysis of an antibody or Fc fusion protein can be achieved. Cell lysis was 10%, 15%, 20%, 25%, or greater than maximum target cell lysis of the wild-type control. It can be larger than the

[0180] The molecules and antibodies described herein can be modified to have enhanced potency. In some embodiments, the molecules and antibodies are For example, the antibody may be modified to enhance ADCC and / or complement dependent cytotoxicity (CDC). In some embodiments, these therapeutic molecules or antibodies target killer cells that possess Fc receptors. Enhanced effector functions such as ADCC are due to the Fc region. This can be achieved by a variety of means, including introducing the above amino acid substitutions. In addition, cysteine residues were introduced into the Fc region to inhibit interchain disulfide bond formation in this region. Homodimeric antibodies may provide improved internalization capabilities and / or increased It can also have CDC and ADCC. Caron et al., J. Exp Med., 176:1191-95(1992) and Shops, B, J. Immunol., 148:2918-22(1992). Antibodies or molecules with enhanced anti-cancer activity Homodimeric antibodies can also be prepared using heterofunctional cross-linkers. Wolff et al., Cancer Research, 53:2560-65(1993). Furthermore, antibodies or molecules with a double Fc region and thus having enhanced CDC and ADCC capabilities can be artificially produced. Stevenson et al., Anti-Cancer Drug Design 3:219-30(1989).

[0181] The glycosylation pattern of the Fc region can also be modified. Some antibody glycosylation forms have been reported to have a positive effect on effector functions including ADCC. Therefore, modification of the carbohydrate component of the Fc region, particularly a decrease in core fucosylation, can also have enhanced therapeutic efficacy. Shinkawa T, et al., J Biol. Chem., 278:3466-73(20 03); Niwa R, et al., Cancer Res., 64:2127-33(2004); Okazaki A, et al., J Mol. Biol. 336:1239^19(2004); and Shields RL, et al., J Biol. Chem.277:26733-40(2002) . The antibodies or molecules described herein having selected glycoforms are treated with glycosylation pathway inhibitors, mutant cell lines lacking or having reduced activity of specific enzymes within the glycosylation pathway or gene expression within the glycosylation pathway is enhanced or knocked out ​​either modified cells, and the use of in vitro remodeling by glycosidase and glycosyltransferase It can be produced by several means, including the use of in vitro remodeling by glycosidase and glycosyltransferase. Methods for modifying the glycosylation of the Fc region and enhancing the therapeutic efficacy of antibodies or other molecules having antigen-binding fragments are known in the art. The literature of Rothman et al., Molecular Immunolog y 26: 1113-1123(1989); the literature of Umana et al., Nature Biotechnology 17: 176-180(1999); Sh ields et al., JBC 277:26733-26740(2002); the literature of Shinkawa et al., JBC 278: 3466-3473(2 003); the literature of Bischoff et al., J. Biol. Chem. 265(26):15599-15605(1990); U.S. Patent Nos. 6,861 ,242 and 7,138,262, and U.S. Publication No. 2003 / 0124652; all of these literatures are hereby incorporated by reference in their entirety into this specification. Those skilled in the art will understand that the antibodies and molecules provided herein can be modified by any method known in the art to have enhanced therapeutic efficacy.

[0182] An inducible molecule or antibody can also have a modified half-life (e.g., serum half-life) of the parent molecule or antibody in a mammal, preferably a human. In some embodiments such a modification results in a half-life of greater than 15 days, preferably greater than 20 days, greater than 25 days, greater than 30 days, greater than 35 days, greater than 40 days, greater than 45 days, greater than 2 months, greater than 3 months, greater than 4 months, or greater than 5 months. The increased half-life of a humanized antibody or other molecule in a mammal, preferably a human result in a higher serum titer of the antibody or other molecule, such that the frequency of administration of the antibody or other molecule is reduced and / or the concentration of the antibody or other molecule to be administered is reduced. Molecules or antibodies having an increased in vivo half-life can be made by techniques known to those of skill in the art. For example, molecules or antibodies having an increased in vivo half-life can be made by modifying amino acid residues that have been identified as being involved in the interaction of the Fc domain with the FcRn receptor (e.g., substituting, deleting, or adding). The humanized antibodies described herein can be modified to increase their in vivo half-life (see, e.g., U.S. Patent No. 6,277,375). For example, the humanized antibodies described herein can be modified with an Fc-hinge domain so as to have an increased in vivo or serum half-life. For example, the humanized antibodies described herein can be modified with an Fc-hinge domain so as to have an increased in vivo or serum half-life. Molecules or antibodies having an increased in vivo half-life can be made by techniques known to those of skill in the art. For example, molecules or antibodies having an increased in vivo half-life can be made by modifying amino acid residues that have been identified as being involved in the interaction of the Fc domain with the FcRn receptor (e.g., substituting, deleting, or adding). Molecules or antibodies having an increased in vivo half-life can be made by techniques known to those of skill in the art. For example, molecules or antibodies having an increased in vivo half-life can be made by modifying amino acid residues that have been identified as being involved in the interaction of the Fc domain with the FcRn receptor (e.g., substituting, deleting, or adding). The humanized antibodies described herein can be modified to increase their in vivo half-life (see, e.g., U.S. Patent No. 6,277,375). For example, the humanized antibodies described herein can be modified with an Fc-hinge domain so as to have an increased in vivo or serum half-life. The humanized antibodies described herein can be modified to increase their in vivo half-life (see, e.g., U.S. Patent No. 6,277,375). For example, the humanized antibodies described herein can be modified with an Fc-hinge domain so as to have an increased in vivo or serum half-life.

[0183] The molecules or antibodies described herein having an increased in vivo half-life can be made by attaching a polymeric molecule such as high molecular weight polyethylene glycol (PEG) to the antibody or antibody fragment. PEG can be attached to the molecule or antibody either by site-specific conjugation of the PEG to the N- or C-terminus of the molecule or antibody, with or without a multifunctional linker, or via the ε-amino groups present on lysine residues. Derivatization with linear or branched polymers that result in minimal loss of biological activity can be used. The degree of conjugation is closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of the PEG molecule to the antibody. Unreacted PEG can be Derivatization with linear or branched polymers that result in minimal loss of biological activity can be used. The degree of conjugation is closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of the PEG molecule to the antibody. Unreacted PEG can be For example, it can be separated from the antibody-PEG conjugate by size exclusion or ion exchange chromatography.

[0184] The molecules or antibodies described herein provide a composition that can be injected into the mammalian circulation substantially without an immunogenic response, and can also be modified by the methods and coupling agents described in Davis et al. (see US Patent No. 4,179,337). Removal of the Fc portion reduces the potential for the antibody fragment to induce unwanted immunological responses, and thus antibodies without Fc can be used for prophylactic or therapeutic treatment. As described above, antibodies can be constructed to be chimeric, partially or fully human, to reduce or eliminate the adverse immunological consequences resulting from administering to an animal antibodies produced in other species or having sequences from other species.

[0185] (5.2.3. Fusions and Conjugates) Provided herein are molecules having antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1, including anti-BTN1A1 antibodies and anti-glycosylated BTN1A1 antibodies. In some embodiments, such molecules are expressed as fusion proteins with other proteins or are chemically conjugated to another moiety.

[0186] In some embodiments, the molecule is a fusion protein having an Fc portion, where the Fc portion can vary by isotype or subclass, can be chimeric or hybrid, and / or, for example, effector function, half-life ​​​​​​​​​​​​It can be modified to improve control and accessibility to tissues, enhance biophysical properties such as stability, and improve (lower cost) the efficiency of production. Many modifications useful in constructing the disclosed fusion proteins and methods for making them are known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. Another embodiment includes IgG2-4 hybrids and IgG4 mutants with reduced binding to FcR that increase their half-life. Representative IG2-4 hybrids and IgG4 mutants are Ang known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. Another embodiment includes IgG2-4 hybrids and IgG4 mutants with reduced binding to FcR that increase their half-life. Representative IG2-4 hybrids and IgG4 mutants are Ang known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. Another embodiment includes IgG2-4 hybrids and IgG4 mutants with reduced binding to FcR that increase their half-life. Representative IG2-4 hybrids and IgG4 mutants are Ang known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. Another embodiment includes IgG2-4 hybrids and IgG4 mutants with reduced binding to FcR that increase their half-life. Representative IG2-4 hybrids and IgG4 mutants are Ang known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. Another embodiment includes IgG2-4 hybrids and IgG4 mutants with reduced binding to FcR that increase their half-life. Representative IG2-4 hybrids and IgG4 mutants are Ang known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge.

[0187] Another embodiment includes IgG2-4 hybrids and IgG4 mutants with reduced binding to FcR that increase their half-life. Representative IG2-4 hybrids and IgG4 mutants are Ang known in the art, see, for example, the references of Mueller, J. P. et al., Mol. Immun. 34(6):441-452(1997), Swann, P. G., Curr. Opin. Immun. 20:493-499(2008), and Presta, L. G., Curr. Opin. Immun. 20:460-470(2008). In some embodiments, the Fc region is the native IgG1, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is a hybrid, e.g., a chimera having an IgG2 / IgG4 Fc constant region. Modifications to the Fc region include IgG4 modified to prevent binding to Fcγ receptors and complement, IgG1 modified to improve binding to one or more Fcγ receptors, IgG1 modified to minimize effector function (amino acid changes), IgG1 with modified / glycan-free glycan (typically by changing the expression host), and IgG1 with modified pH-dependent binding to FcRn, but are not limited thereto. The Fc region can include the entire hinge region or a region less than the entire hinge. the documents of al et al., Molec. Immunol. 30(1):105-108(1993); the documents of Mueller et al., Mol. Immun. 34 (6):441-452(1997); and are described in U.S. Patent No. 6,982,323; all of these documents are incorporated herein by reference in their entirety. In some embodiments, the IgG1 and / or or IgG2 domains are deleted; for example, the documents of Angal et al. describe IgG1 and IgG2 in which serine 241 is replaced with proline.

[0188] In some embodiments, the molecule is a polypeptide having 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 100 amino acids.

[0189] In some embodiments, provided herein is a molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 or glycosylated BT N1A1, and that is linked to, covalently bound to, or forms a complex with at least one moiety . Such a moiety can be, but is not limited to, a moiety that increases the potency of the molecule as a diagnostic or therapeutic agent. In some embodiments, the moiety is an imaging agent, a toxin, a therapeutic enzyme, an antibiotic, a radiolabeled nucleotide, and the like.

[0190] The molecules provided herein can include a therapeutic moiety (or one or more therapeutic moieties). The molecules provided herein can be cytotoxins, such as cytostatic agents or cytocidal agents An agent, therapeutic agent, or radioactive metal ion, such as an α-emitter, etc., can be conjugated to a therapeutic moiety or a recombinant fusion antibody. Cytotoxins or cytotoxic agents include any agent that is harmful to cells. As therapeutic moieties, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5- fluorouracil, decarbazine); alkylating agents (e.g., mechlorethamine , thioepa, chlorambucil, melphalan, carmustine (BCNU), and lom ustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiammine platinum(II) (DD P), and cisplatin); anthracyclines (e.g., daunorubicin (former name, daunoma ycin) and doxorubicin); antibiotics (e.g., dactinomycin (former name, actinomai cin), bleomycin, mitomycin, and anthramycin (AMC)); auristatin molecules (e.g., auristatin PHE, auristatin F, monomethyl auristatin E, bre ostatins 1, and solastatin 10; Woyke et al., Antimicrob. Agents Chemother. 46 :3802-8(2002), Woyke et al., Antimicrob. Agents Chemother. 45:3580-4(2001), Moh ammad et al., Anticancer Drugs 12:735-40(2001), Wall et al., Biochem. Biophys. [citations]; and Wall et al., Biochem. Biophys. [citations]); Res. Commun. 266:76-80(1999), the literature of Mohammad et al., Int. J. Oncol. 15:367-72(1999) are hereby incorporated by reference in their entirety); hormones (e.g., glucocorticoids, progestins, androgens, and estrogens), DNA repair enzyme inhibitors (e.g., etoposide or topotecan), kinase inhibitors (e.g., compound ST1571 , imatinib mesylate (Kantarjian et al., Clin Cancer Res. 8(7):2167-76(2002)); cytotoxic agents (e.g., paclitaxel, cytochalasin B, gramicidin D, ethidium bromide , emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine , colchicin, doxorubicin, daunorubicin, dihydroxyanthra quinone, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotest osterone, glucorticoid, procaine, tetracaine, lidocaine , propranolol, and puromycin and their analogs or homologs, and U.S. Patent Nos. 6,245,759, 6,399,633, 6,383,790, 6,335,156, 6,271,242 , 6,242,196, 6,218,410, 6,218,372, 6,057,300, 6,034,053, , 5,985,877, 5,958,769, 5,925,376, 5,922,844, 5,911,995, 5,8 , 72,223, 5,863,904, 5,840,745, 5,728,868, 5,648,239, 5,587,45 , 8, 5,648,239, 5,587,45 the compound disclosed on the 9th); farnesyl transferase inhibitors (e.g., R115777 , BMS-214662, and, for example, U.S. Patent Nos. 6,458,935, 6,451,812, 6,440,974 , 6,436,960, 6,432,959, 6,420,387, 6,414,145, 6,410,541, 6 ,410,539, 6,403,581, 6,399,615, 6,387,905, 6,372,747, 6,369, 034, 6,362,188, 6,342,765, 6,342,487, 6,300,501, 6,268,363 , 6,265,422, 6,248,756, 6,239,140, 6,232,338, 6,228,865, 6 ,228,856, 6,225,322, 6,218,406, 6,211,193, 6,187,786, 6,169, 096, 6,159,984, 6,143,766, 6,133,303, 6,127,366, 6,124,465 , 6,124,295, 6,103,723, 6,093,737, 6,090,948, 6,080,870, 6 ,077,853, 6,071,935, 6,066,738, 6,063,930, 6,054,466, 6,051, 582, 6,051,574, and those disclosed by U.S. Patent No. 6,040,305); topoisomer ase inhibitors (e.g., camptothecin; irinotecan; SN-38; topotecan; 9-aminocampt othecin; GG-211 (GI 147211); DX-8951f; IST-622; rubitecan; pyrazoloacridine; XR -5000; Saintpin; UCE6; UCE1022; TAN-1518A; TAN 1518B; KT6006; KT6528; ED-110; NB-506; ED-110; NB-506; and rebeccamycin); burgarein; DNA minor groove Binders, such as Hoescht dye 33342 and Hoechst dye 33258; niddicin; fagaronine; epi berberine; coralin; β-lapachone; BC-4-1; bisphosphonates (e.g., alendro trone, cimadronte, clodronate, tiludronate, etidronate, i bandronate, neridronate, olpadronate, risedronate, pyridronate trone, pamidronate, zoledronate), HMG-CoA reductase inhibitors (e.g., lovastatin n, simvastatin, atorvastatin, pravastatin, fluvastatin, statin, cerivastatin, rescol, lupitor, rosuvastatin, and atorvastatin); a ntisense oligonucleotides (e.g., those disclosed in U.S. Patent Nos. 6,277,832, 5,998,596, 5,8 85,834, 5,734,033, and 5,618,709); adenosine deami nase inhibitors (e.g., fludarabine phosphate and 2-chlorodeoxyadenosine); ibrit umomab tiuxetan (Zevalin (registered trademark)); tositumomab (Bexxar (registered trademark))), and pharmaceutically acceptable salts, solvates, inclusion compounds, and prodrugs thereof are included but are not limited thereto.

[0191] Furthermore, the molecules provided herein are antibodies that can be conjugated or recombinantly fused to a therapeutic moiety or drug moiety that modifies a given biological response. Therapeutic The moiety or drug moiety should not be considered limited to classical chemotherapeutic agents. For example, the drug moiety can be a protein, peptide, or polypeptide having the desired biological activity. Such proteins include, for example, toxins such as abrin, ricin A, Pseudomonas aeruginosa exotoxin, cholera toxin, or diphtheria toxin; proteins such as tumor necrosis factor, γ-interferon, α-interferon, nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, apoptosis substances such as TNF-γ, TNF-γ, AIM I (see International Publication WO 97 / 33899), AIM II (see International Publication WO 97 / 34911) Fas ligand (Takahashi et al., 1994, J. Immunol., 6:1567 - 1574), and VEGF (see International Publication WO 99 / 23105), anti-angiogenic substances such as angiostatin, endostatin, or components of the coagulation pathway (e.g., tissue factor); or biological response modifiers such as lymphokines (e.g., interferon γ, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-5 (“IL-5”), interleukin-6 (“IL-6”) , interleukin-7 (“IL-7”), interleukin 9 (“IL-9”), interleukin-10 (“IL-10”), interleukin-12 (“IL-12”), interleukin-15 (“IL-15”), interleukin-23 (“IL-23”), granulocyte macrophage colony-stimulating factor (“GM-CSF”), and granulocyte colony-stimulating factor (“G-CSF”), etc.), or growth factors (e.g., growth hormone ), etc.), or growth factors (e.g., growth hormone ), interleukin-23 (“IL-23”), granulocyte macrophage colony-stimulating factor (“GM-CSF”), and granulocyte colony-stimulating factor (“G-CSF”), etc.), or growth factors (e.g., growth hormone ), interleukin-23 (“IL-23”), granulocyte macrophage colony-stimulating factor (“GM-CSF”), and granulocyte colony-stimulating factor (“G-CSF”), etc.), or growth factors (e.g., growth hormone ), or growth factors (e.g., growth hormone or a coagulation agent (e.g., calcium, vitamin K, tissue factor, e.g., but not limited to, Hageman factor (factor XII), high molecular weight kininogen (HMWK), prekallikrein (PK), coagulation protein - factor II (prothrombin), factor V, factor XIIa, factor V III, factor XIIIa, factor XI, factor XIa, factor IX, factor IXa, factor X, phospholipid protein, and fibrin monomer).

[0192] Furthermore, the antibodies provided herein can be conjugated to a polypeptide a therapeutic moiety, e.g., a radioactive metal ion, e.g., an α - emitter, e.g., 213 Bi, or but not limited to 131 In, 131 LU, 131 Y, 131 Ho, 131 Sm, useful macrocyclic chelating agents for conjugating radioactive metal ions to the polypeptide. In certain embodiments, the macrocyclic chelating agent is 1,4,7,10 - tetraazacyclododecane - N,N',N'',N'''-tetraacetic acid (DOTA) which can be attached to the antibody via a linker molecule. Such linker molecules are generally known in the art and are incorporated herein by reference in their entirety from the literature of Denardo et al., 1998, Clin Cancer Res. 4(10):2483 - 90; Peterson et al., 1999, Bioconjug. Chem. 10(4): 553 - 7; and Zimmerman et al., 1999, Nucl. Med. Biol. 26(8):943 - 50. Clin Cancer Res. 4(10):2483 - 90; Peterson et al., 1999, Bioconjug. Chem. 10(4): 553 - 7; and Zimmerman et al., 1999, Nucl. Med. Biol. 26(8):943 - 50.

[0193] Conjugated to or recombinantly fused with a therapeutic moiety or drug that binds immunospecifically to BTN1A1 should be selected to achieve the desired prophylactic or therapeutic effect. In certain embodiments, the antibody is a modified antibody. A clinician or other healthcare provider should consider the following when determining which therapeutic moiety or drug to conjugate or recombinantly fuse to the antibodies provided herein: the nature of the disease, the severity of the disease, and the condition of the subject. In some embodiments, the moiety is an enzyme, a hormone, a cell surface receptor, a toxin (e.g., abrin, ricin A, Pseudomonas aeruginosa exotoxin (i.e., PE-40), diphtheria toxin, ricin,

[0194] gelonin, or pokeweed antiviral protein), a protein (e.g., tumor necrosis factor, interferon (e.g., α-interferon, β-interferon), nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, or an apoptosis agent (e.g., tumor necrosis factor-α, tumor necrosis factor-β)), a biological response modifier (e.g., e.g., lymphokine (e.g., interleukin-1 (“IL-1”), interleukin-2 (“IL-2”) , interleukin-6 (“IL-6”)), granulocyte macrophage colony-stimulating factor (“GM-CSF” ), granulocyte colony-stimulating factor (“G-CSF”), or macrophage colony-stimulating factor (“M -CSF”)), or a growth factor (e.g., growth hormone (“GH”))), a cytotoxin (e.g., a cell proliferation inhibitor or cell-destroying agent, e.g., paclitaxol, cytochalasin B, g ramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, or other cytotoxic agents), or a radioactive agent. ​​ Vincristine, vinblastine, colchicin, doxorubicin, daunor bicin, dihydroxyanthracindione, mitoxantrone, mitomycin, actin omycin D, 1-dehydrotestosterone, glucocorticoid, procaine, tetraca ine, lidocaine, propranolol, monomethyl auristatin F (MMAF), monomethyl auristatin E (MMAE; e.g., vedotin), and puromycin, and their similar forms or homologs), antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thio guanine, cytarabine, 5-fluorouracil, decarbazine), alkylating agents (e.g., mechlorethamine, thioepa, chlorambucil, melphalan, BiCN U (registered trademark) (carmustine; BCNU), and lomustine (CCNU), cyclophosphamide (cyclot hosphamide), busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP), cisplatin), anthracycli nes (e.g., daunorubicin (former name, daunomycin) and doxorubicin), antibiotics (e.g actinomycin (former name, actinomycin), bleomycin, mitomycin, and anthramycin (AMC)), or antimitotic agents (e.g., vincristine and vinb lastine).

[0195] Techniques for conjugating such therapeutic moieties to antibodies are well known; e.g., the literature of Amon et al "Monoclonal Antibodies for Immunotargeting of Drugs in Cancer Therapy (Monoclonal An "Antibodies For Immunotargeting Of Drugs In Cancer Therapy)", monoclonal antibodies and cancer therapy (MONOCLONAL ANTIBODIES AND CANCER THERAPY), Reisfeld et al. (eds.), 1985, pp. 24 3 - 56, published by Alan R. Liss; the literature of Hellstrom et al., "Antibodies For Drug Delivery" in Controlled Drug Delivery (2nd Edition), Robinson et al. (eds.), 1987, pp. 623 - 53, published by Marcel Dekker; the literature of Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therap y: A Review" in Monoclonal Antibodies, 84: Biological And Clinical Applications (MONOCLONAL ANTIBOD IES '84: BIOLOGICAL AND CLINICAL APPLICATIONS), Pinchera et al. (eds.), 1985, pp. 475 - 50 6, published therein); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", Monoclonal Antibodies For Cancer Detection And Therapy Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", Monoclonal Antibodies For Cancer Detection And Therapy (MONOCL ONAL ANTIBODIES FOR CANCER DETECTION AND THERAPY), Baldwin et al. (eds.), 1985, pp. 303 - 16, published by Academic Press; Thorpe et al., Immunol. Rev. 62:119-158 (1982); Carter et al., Cancer J. 14(3):154-169 (2008); Alley et al., Curr. Opin. Chem. Biol. 14(4):529-537 (2010); Carter et al., Amer. Assoc. Cancer Res. Educ. Book. 2005(1 ):147-154 (2005); Carter et al., Cancer J. 14(3):154-169 (2008); Chari, Acc . Chem Res. 41(1):98-107 (2008); Doronina et al., Nat. Biotechnol. 21(7):778-784 (2003); Ducry et al., Bioconjug Chem. 21(1):5-13 (2010); Senter, Curr. Opi n. Chem. Biol. 13(3):235-244 (2009); and Teicher, Curr Cancer Drug Target. 9 (8):982-1004 (2009). See also

[0196] In some embodiments, the molecules described herein can be conjugated to a marker such as a peptide to facilitate purification. In some embodiments, the marker is a hexa-histidine peptide (SEQ ID NO: 55), a hemagglutinin "HA" tag corresponding to an epitope derived from the influenza hemagglutinin protein (Wilson, I. A. et al., Cell, 37:767-778 (1984)), or a "flag" tag (Knappik, A. et al., Biotechniques 17( 4):754-761 (1994)). ​​

[0197] In some embodiments, the moiety can be an imaging agent detectable in an assay. Such imaging agents can be enzymes, cofactor families, radiolabels, non-radio active paramagnetic metal ions, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, luminescent molecules, bioluminescent molecules, photoaffinity molecules, colored particles, or ligands such as biotin.

[0198] In some embodiments, enzymes include, but are not limited to, horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase. Cofactor family complexes include, but are not limited to, streptavidin / biotin and avidin / biotin. Fluorescent substances include, but are not limited to, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin. Luminescent substances such as, but not limited to, luminol. Bioluminescent substances include, but are not limited to, luciferase, luciferin, and aequorin. Radioactive substances include, but are not limited to, bismuth ( 21 3 Bi), carbon ( 14 C), chromium ( 51 Cr), cobalt ( 57 Co), fluorine ( 18 F), gadolinium ( 153 Gd, 159 Gd), gallium ( 68 Ga, 67 Ga), germanium ( 68 Ge), holmium ( 166 Ho), indium ( 115 In, 113In, 112 In, 111 In), iodine( 131 I, 125 I, 123 I, 121 I), lanthanum( 140 La) , lutetium( 177 Lu), manganese( 54 Mn), molybdenum( 99 Mo), palladium( 103 Pd), phosphorus( 3 2 P), praseodymium( 142 Pr), promethium( 149 Pm), rhenium( 186 Re, 188 Re), rhodium( 105 Rh), ruthenium( 97 Ru), samarium( 153 Sm), scandium( 47 Sc), selenium( 75 Se), strontium( 85 Sr), sulfur( 35 S), technetium( 99 Tc), thallium( 201 Ti), tin( 113 Sn , 117 Sn), tritium( 3 H), xenon( 133 Xe), ytterbium( 169 Yb, 175 Yb), ytt rium( 90 Y), zinc( 65 Zn); Positron-emitting metals using various positron emission tomography methods, and non-radioactive paramagnetic metal ions are included.

[0199] The imaging agent is directly or indirectly via an intermediate (e.g., a linker known in the art) to a molecule having an antigen-binding fragment using techniques known in the art. For example, for example, a linker known in the art), It can be conjugated. For metal ions that can be conjugated to the antibodies and other molecules described herein for use as diagnostic agents, see, for example, U.S. Patent No. 4,741,900. Some conjugation methods include, for example, diethylenetriamine pentaacetic anhydride (DTPA) attached to the antibody; ethylenetriamine tetraacetic acid; N-chloro- p-toluenesulfonamide; and / or the use of metal chelate complexes utilizing any organic chelating agent such as tetrachloro-3-6α-diphenylglycouril-3. Monoclonal antibodies can also be reacted with an enzyme in the presence of a coupling agent such as glutaraldehyde or periodate. Conjugates with fluorescein markers can be prepared in the presence of these coupling agents or by reaction with isothiocyanates.

[0200] The molecules described herein can be conjugated to a second antibody to form an antibody heteroconjugate as described in U.S. Patent No. 4,676,980 by Segal. Such heteroconjugate antibodies can further bind to a hapten (e.g., fluorescein), or to a cell marker (e.g., 4-1-BB, B7-H4, CD4, CD8, CD14, CD25, CD27, CD40, CD68, CD16 3, CTLA4, GITR, LAG-3, OX40, TIM3, TIM4, TLR2, LIGHT, ICOS, B7-H3, B7-H7, B7-H7C R, CD70, CD47), or to a cytokine (e.g., IL-7, IL-15, IL-12, IL-4, TGF-β, IL- 10, IL-17, IFNγ, Flt3, BLys) or a chemokine (e.g., CCL21).

[0201] The molecules described herein can be attached to a solid support, which is useful for the purification of an immunoassay or a target antigen or other molecules that can bind to a target antigen immobilized on the support via binding to the antibodies or antigen-binding fragments described herein. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.

[0202] Also provided herein are any such antibodies, antigen-binding fragments, and nucleic acid molecules (DNA or RNA) encoding molecules having such antigen-binding fragments that immunospecifically bind to BTN1A1 or glycosylated BTN1A1. Also provided herein are vector molecules (e.g., plasmids) capable of transferring or replicating such nucleic acid molecules. The nucleic acid can be single-stranded, double-stranded, and can contain both single-stranded and double-stranded portions.

[0203] (Antibody-drug conjugate (ADC)) The molecules provided herein can effect the internalization of BTN1A1 into cells. Also provided herein are antibody-drug conjugates (ADCs) comprising any of the anti-BTN1A1 antibodies described herein. In a specific embodiment, provided herein is an ADC having STC810 or a humanized variant thereof as the antibody.

[0204] In some embodiments, provided herein are antibody-drug conjugates comprising antibody-drug conjugates of the following formulas (Ia) and (Ib): ​

Chemical

Chemical formula

[0205] In certain embodiments of the antibody-drug conjugate (ADC) of formula (Ib), R is as defined herein W, (L 1 ) a , (L 2 ) b , (L 3 ) c , Z, W-(L 1 ) a -(L 2 )b -(L 3 ) c 、(L 1 ) a -(L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z and is selected from the group consisting of. In certain embodiments, R is W , (L 1 ) a , (L 2 ) b , (L 3 ) c , and W-(L 1 ) a -(L 2 ) b -(L 3 ) c and is selected from the group consisting of. In certain embodiments, R is Z, (L 1 ) a -(L 2 ) b -(L 3 ) c -Z, and W-(L 1 ) a -(L 2 ) b -(L 3 ) c -Z and is selected from the group of selected.

[0206] In certain embodiments of the antibody-drug conjugate (ADC) of formula (Ib), R is a detectable pro be. In certain embodiments, R is a fluorophore, chromophore, radiolabel, enzyme, ligand and, antibody, or antibody fragment. In certain embodiments, R is a ligand (e.g., prostate specific membrane antigen, etc. tumor cells, or virus-infected cells such as HIV-infected cells specific ligand).

[0207] In certain embodiments of an antibody-drug conjugate (ADC) of formula (Ib), R is an amide, N-(C1 -6 alkyl)amide, carbamate, N-(C 1-6 alkyl)carbamate, amine, N-(C 1-6 a lkyl)amine, ether, thioether, urea, N-(C 1-6 alkyl)urea, or N,N- di(C 1-6 alkyl)urea bond and is attached to the remainder of the linker molecule.

[0208] In certain embodiments of an antibody-drug conjugate (ADC) of formula (Ia) or (Ib), each L 1 , L 2 , and L 3 is independently selected from the group consisting of -NHC(O)-, -C(O)NH-, -(CH2CH2O) p , -(CH2CH2O) p CH2CH2-, -CH2CH2-(CH2C H2O) p -, -OCH(CH2O-)2, -(AA) r -, unsubstituted phenylenyl, and phenylenyl substituted with one or two substituents independently selected from the group consisting of halo, CF3-, CF3O-, CH3O ]-, -C(O)OH, -C(O)OC 1-3 alkyl, -C(O)CH3, -CN, -NH-, -NH2, -O-, -OH, -NHCH3, -N( CH3)2, and C 1-3 alkyl; wherein a, b, and c are each independently 0 or 1; and each p and r is independently 1, 2, or 3. In certain embodiments , one or more of L , L 1 , L 2 , and L 3 is -(AA) r- and here, -(AA) r - is ValCit wherein (for example, the first amino acid is valine, the second amino acid is citrulline, and r is 1). In certain embodiments, L 1 , L 2 , and L 3 one or more of are -(AA) r - and here, -(AA) r - is ValAla (for example, the first amino acid is valine, the second amino acid is alanine, and r is 1). In certain embodiments, L 1 , L 2 , and L 3 one or more of are phenylenyl substituted by -C(O)OH and -NH2. In certain embodiments, L 1 , L 2 , and L 3 one or more of are phenylenyl substituted by -C(O)O- and -NH-. In certain embodiments, L one or more of are phenylenyl substituted by -OC(O)- and -NH-. In certain embodiments, L 1 , L 2 , and L 3 one or more of are phenylenyl substituted by -OC(O)- and -NH-. In certain embodiments L 1 , L 2 , and L 3 one or more of are phenyl renyl substituted by -O- and -NH-. In certain embodiments, L 1 , L 2 , and L 3 one or more of are para amino novobenzyl (PAB) which is optionally substituted with -C(O)O-, -OC(O)-, or -O-. In certain embodiments, L 1 is -(CH2) q -, L 2does not exist, L 3 does not exist, CTX is bonded via an amide bond to (L 1 ) a -(L 2 ) b -(L 3 ) c is bonded. In certain embodiments, L 1 is -(CH2 ) q -, L 2 is -(OCH2CH2) p -, L 3 does not exist, CTX is bonded via an amide bond to (L 1 ) a - (L 2 ) b -(L 3 ) c is bonded. In certain embodiments, L 1 is -(CH2CH2O) p -, L 2 is -(C H2) q -, L 3 does not exist, CTX is bonded via an amide bond to (L 1 ) a -(L 2 ) b -(L 3 ) c is bonded to. In certain embodiments, each L 1 is independently selected from the group consisting of -(CH2CH2O) p CH2CH2- and -CH2CH2-(CH2CH2O) p -, L 2 does not exist, L 3 does not exist, CTX is bonded via an amide bond to (L 1 ) a -(L 2 ) b -(L 3 ) c is bonded. In certain embodiments, each L 1 is -(CH2) q - , -(CH2CH2O) p , -(CH2CH2O) p CH2CH2-, -CH2CH2-(CH2CH2O) p -, and -C(O)- from the group consisting of independently selected, L 2 is Val-Cit, L 3 is PAB, CTX is, via an amide bond (L 1 ) a -(L 2 ) b -(L 3 ) c is attached to. In certain embodiments, each L 1 is, -(CH2) q -, -(CH2CH2 O) p , -(CH2CH2O) p CH2CH2-, -CH2CH2-(CH2CH2O) p -, and -C(O)- independently selected from the group consisting of selected, L 2 is Val-Cit, L 3 is PAB, CTX is, via an amide bond (L 1 ) a -(L 2 ) b -(L 3 ) c is attached to. In certain embodiments, each L 1 is, -(CH2) q -, -(CH2CH2O) p , -(CH2 CH2O) p CH2CH2-, -CH2CH2-(CH2CH2O) p -, and -C(O)- independently selected from the group consisting of, L 2 is Val-Ala, L 3 is PAB, CTX is, via an amide bond (L 1 ) a -(L 2 ) b -(L 3 ) c is attached to is present.

[0209] In certain embodiments of an antibody-drug conjugate (ADC) of formula (Ia) or (Ib), CTX is a tubulin stabilizer, a tubulin destabilizer, a DNA alkylating agent, a DNA minor groove binding agent, a DNA intercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor , a gyrase inhibitor, a protein synthesis inhibitor, a proteasome inhibitor, and an antimetabolite selected from the group consisting of.

[0210] In certain embodiments of an antibody-drug conjugate (ADC) of formula (Ia) or (Ib), CTX is a chemical therapeutic agent. Those skilled in the art will recognize appropriate chemotherapeutic agents disclosed, for example, in the literature of Chu, E., DeVite, V. T., 2012, Physicians' Cancer Chemotherapy Drug Manual 2012 (Jones & B artlett Learning Oncology) and similar documents. will be aware.

[0211] In certain embodiments, CTX may be any FDA-approved chemotherapeutic agent. In certain embodiments, CTX may be any FDA-approved chemotherapeutic agent available for cancer treatment.

[0212] In certain embodiments, CTX is an alkylating agent, an anthracycline, a cytoskeletal disrupting agent (taxane), an epothilone, a histone deacetylase inhibitor (HDAC), a topoisomerase I inhibitor, a topoisomerase II inhibitor, a kinase inhibitor, a monoclonal antibody, a nucleic otide analogue, a peptide antibiotic, a platinum-based agent, a retinoid, a vinca alkaloid or a​​ is selected from the group consisting of derivatives and radioisotopes.

[0213] In certain embodiments, CTX is actinomycin, all-trans retinoic acid, aza cytidine, azathioprine, bleomycin, bortezomib, carboplatin, capecita bine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubici n, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, e toposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imati nib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxa ntrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thiogua nin, topotecan, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine, selected from the group consisting of.

[0214] In certain embodiments, CTX is a tubulin stabilizer, a tubulin destabilizer, DNA alkylating agent, DNA minor groove binder, DNA intercalator, topoisomerase I inhibitor, topoisomerase II inhibitor, gyrase inhibitor, protein synthesis inhibitor, p roteasome inhibitor, and antimetabolite, selected from the group consisting of.

[0215] In certain embodiments, CTX is actinomycin D, amonafide, auristatin , benzophenone, benzothiazole, calicheamicin, camptothecin, CC-1065 (NS C 298223), semadotin, colchicine, combretastatin A4, drostatins, doxol Bisin, Elinafide, Emtansine (DM1), Etoposide, KF-12347 (Raynamycin) , maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome -inhibitor 1 (PSI 1), Loridine A, T-2 toxin (trichothecene analog), Paclitaxel, Tub ulin, Velcade (registered trademark), and Vincristine selected from the group consisting of. In one embodiment , CTX is auristatin, calicheamicin, maytansinoid, or tub ulysin.

[0216] In one embodiment, CTX is monomethyl auristatin E (MMAE), monomethyl aur istatin F (MMAF), pyrrolobenzodiazepine (PDB), calicheamicin γ, mertansine, or tubulysin T2. In one embodiment, CTX is MMAE or MMAF. In a certain embodiment, CTX is PDB. In one embodiment, CTX is tubulysin T2 . In one embodiment, CTX is tubulysin T3 or tubulysin T4 and their structures are provided below:

Chemical formula

[0217] Accordingly, the conjugate protein or fusion protein provided herein can include any anti-BTN1A1 antibody or antigen-binding fragment described herein. In one embodiment , the conjugate protein or fusion protein provided herein can include the VH or VL domain of the mouse monoclonal antibody STC810 as shown in Table 2. In one embodiment, the conjugate protein or fusion protein provided herein comprises both the VH domain and the VL domain of the mouse monoclonal antibody STC810 as shown in Table 2. In another embodiment, the conjugate protein or fusion protein provided herein comprises one or more VH CDRs having the amino acid sequence of any one of the VH CDRs of the mouse monoclonal antibody STC810 as shown in Table 2. In another embodiment, the conjugate protein or fusion protein comprises one or more VL CDRs having the amino acid sequence of any one of the VL CDRs of the mouse monoclonal antibody STC810 as shown in Table 2. In yet another embodiment, the conjugate protein or fusion protein provided herein

[0218] comprises at least one VH CDR and at least one VL CDR of the mouse monoclonal antibody STC810 as shown in Table 2. In some embodiments, the conjugate protein or fusion protein provided can comprise an antigen-binding fragment that competitively blocks (e.g., in a dose-dependent manner) the BTN1A1 epitope described herein. The BTN1A1 epitope can be the epitope of STC810 described herein. In some embodiments, the conjugate protein or fusion protein provided can And the BTN1A1 epitope has at least 5 consecutive amino acids of the amino acid sequences of SEQ ID NOs: 31 to 41. It has amino acids.

[0219] (5.3 Compositions) Also provided herein are compositions having a molecule with an antigen-binding fragment that immunospecifically binds to BTN1A1 (including glycosylated BTN1A1). In some embodiments, the composition has an anti-BTN1A1 antibody (including an anti-glycosylated BTN1A1 antibody). In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55, N215, and / or N449. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N55. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N215. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at position N449. In some aspects, the antigen-binding fragment immunospecifically binds to one or more glycosylation motifs. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55 and N215. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N215 and N449. In some aspects, the antigen-binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55 and N449. In some aspects, the antigen -binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55, N215, and N449. ​

[0220] In some embodiments, provided herein is a composition having a molecule with an antigen-binding fragment that immunospecifically binds to BTN1A1, wherein the antigen-binding fragment preferentially binds to glycosylated BTN1A1 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N55, N215, and / or N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N55 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N215 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at position N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to one or more glycosylation motifs. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55 and N215 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N215 and N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 glycosylated at positions N55 and N449 over non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment has ... ... ... ... ... ... ... ... ... ... ... ... ... ... The piece binds preferentially to BTN1A1 that is glycosylated at positions N55, N215, and N449 rather than non-glycosylated BTN1A1.

[0221] In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is less than half of the Kd shown for non-glycosylated BTN1A1. In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with a Kd that is at least 10-fold smaller than the Kd shown for non-glycosylated BTN1A1.

[0222] In some embodiments, the antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 2-fold higher than the MFI shown for non-glycosylated BTN1A1. In some embodiments the antigen-binding fragment binds to glycosylated BTN1A1 with an MFI that is at least 5 times higher than the MFI shown for non-glycosylated BTN1A1.

[0223] In some aspects, provided herein are compositions having a molecule with an antigen-binding fragment that immunospecifically masks BTN1A1 glycosylation at positions N55, N215, and / or N449. In some aspects, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N55. In some aspects, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N215. In some aspects, the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N449. In some aspects, the antigen-binding fragment immunospecifically masks one or more glycosylation motifs of BTN1A1. ​​​​​​​Specifically mask the immunity. In some embodiments, the antigen-binding fragment specifically masks the BTN1A1 glycosylation at positions N55 and N 215. In some embodiments, the antigen-binding fragment specifically masks the BTN1A1 glycosylation at positions N215 and N449 to do. In some embodiments, the antigen-binding fragment specifically masks the BTN1A1 glyco sylation at positions N55 and N449. In some embodiments, the antigen-binding fragment is located Specifically mask the BTN1A1 glycosylation at N55, N215, and N449.

[0224] In some embodiments, the composition has a molecule having an antigen-binding fragment comprising the VH or VL domain of the mouse monoclonal antibody STC810 as shown in Table 2 It can be. In one embodiment, the composition has a molecule having an antigen-binding fragment comprising both the VH domain and the VL domain of the mouse monoclonal antibody STC810 as shown in Table 2 It can be. In another embodiment, the composition has at least one VH CDR having the amino acid sequence of any one of the VH CDRs of the mouse monoclonal antibody STC810 as shown in Table 2 It can have a molecule having an antigen-binding fragment containing. In another embodiment, the composition Is a mouse mono as shown in Table 2 It can have a molecule having an antigen-binding fragment containing one or more VH CDRs having the amino acid sequence of any one of the VH CDRs of the clonal antibody STC810. In another embodiment, the composition Is a mouse mono as shown in Table 2 It can have a molecule having an antigen-binding fragment containing one or more VL CDRs having the amino acid sequence of any one of the VL CDRs of the clonal antibody STC810. In yet another embodiment, the composition has at least one VH CDR and at least one VL CDR of the mouse monoclonal antibody STC810 as shown in Table 2 It can have an antigen-binding fragment containing. In yet another embodiment, the composition has at least one VH CDR and at least one VL CDR of the mouse monoclonal antibody STC810 as shown in Table 2 It can have a molecule having a fusion fragment.

[0225] In some embodiments, the composition can have a molecule having an antigen-binding fragment that competitively blocks the BTN1A1 epitope described herein (e.g., in a dose-dependent manner). The BTN1A1 epitope can be an epitope of STC810 described herein. In some embodiments, the composition can have a molecule having an antigen-binding fragment that immunospecifically binds to the epitope of BTN1A1 described herein. The BT N1A1 epitope can be an epitope of STC810 described herein. In some embodiments, the BTN1A1 epitope has at least 5 consecutive amino acids of the amino acid sequence of SEQ ID NOs: 31-41. In some embodiments, the composition can have at least 0.1% by weight of an antibody or other molecule described herein. In some embodiments, the composition can have at least 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or more of an anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1. In other embodiments, for example, the anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1

[0226] In some embodiments, the composition can have at least 0.1% by weight of an antibody or other molecule described herein. In some embodiments, the composition can have at least 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or more of an anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1. In other embodiments, for example, the anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 In some embodiments, the composition can have at least 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or more of an anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1. In other embodiments, for example, the anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 In some embodiments, the composition can have at least 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, 90% by weight, or more of an anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1. In other embodiments, for example, the anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 In some embodiments, for example, the anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 Other molecules can occupy from about 2% to about 75%, from about 25% to about 60%, from about 30% to about 50%, or any of these ranges of the weight of the composition.

[0227] The composition is a pharmaceutical composition having, as an active ingredient, an anti-BTN1A1 antibody or another molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 and a pharmaceutically acceptable carrier. The pharmaceutical composition can further include one or more additional active ingredients. A pharmaceutically acceptable carrier can be one that has been approved by a regulatory authority of the federal or state government for use in animals, and more specifically in humans, or one that is described in the United States Pharmacopeia, the European Pharmacopeia, or other generally recognized pharmacopeias.

[0228] The preparation of a pharmaceutical composition having the antibodies or other molecules described herein as active ingredients is known to those skilled in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Edition, 1990, which is incorporated herein by reference. Further, for administration to animals (including humans), it is understood that the preparation should meet the standards of sterility, pyrogenicity, general safety, and purity required by the FDA Office of Biological Standards.

[0229] Pharmaceutically acceptable carriers include liquid, semi-solid, i.e., paste, or solid carriers. Examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, bulking agents, etc., or combinations thereof. A pharmaceutically acceptable carrier can be one that has been approved by a regulatory authority of the federal or state government for use in animals, and more specifically in humans, or one that is described in the United States Pharmacopeia, the European Pharmacopeia, or Possible carriers include those known to those skilled in the art, such as aqueous solvents (e.g., water, alcohol / aqueous solution, ethanol, physiological saline solution, parenteral vehicles, such as sodium chloride, phos phate dextrose, etc.), non-aqueous solvents (e.g., propylene glycol, polyethylene glycol, vegetable oil, and injectable organic esters, such as ethyl oleate), dispersion media, coatings (e.g., lecithin), surfactants, antioxidants, preservatives (e.g., antibacterial agents or antifungal agents, antioxidants, chelating agents, inert gases, parabens (e.g., methyl para ben, propyl paraben), chlorobutanol, phenol, sorbic acid, thimerosal), isotonic agents (e.g., saccharides, sodium chloride), absorption delaying agents (e.g., aluminum monostearate , gelatin), salts, drugs, drug stabilizers (e.g., buffers, amino acids, such as glycine and lysine, carbohydrates, such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc. ), gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, pigments, fluid, and nutritional supplements, similar such materials, and combinations thereof can be mentioned. Any conventional medium, drug, diluent, or carrier is used in an administrable composition for use in practicing the method, unless it is harmful to the recipient or to the therapeutic effectiveness of the composition contained therein. The pH and exact concentration of the various components in the pharmaceutical composition are adjusted according to well-known parameters. According to one aspect of the present disclosure, the composition is prepared in any convenient and practical manner, i.e., dissolved, suspended, emulsified It can be combined with a carrier by methods such as melting, mixing, encapsulation, absorption, milling, etc. Such procedures are routine for those skilled in the art.

[0230] In some embodiments, a pharmaceutically acceptable carrier can be an aqueous pH buffer solution. Examples include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid; low molecular weight (e.g., less than about 10 amino acid residues) polypeptides ; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspartic acid, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; 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™.

[0231] In some embodiments, a pharmaceutically acceptable carrier can be a sterile liquid such as water and oils including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water can be, in particular, the carrier when the pharmaceutical composition is administered intravenously. Physiological saline aqueous solutions as well as aqueous dextrose and glycerol solutions can also be utilized, in particular, as liquid carriers for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, Yoke, silica gel, sodium stearate, glycerol monostearate, talc , sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol , polysorbate-80, and the like. The composition may contain a trace amount of a wetting agent or an emulsifier, or a pH buffering agent. These compositions can take the form of solutions, suspensions, emulsions, tablets , pills, capsules, powders, sustained-release formulations, and the like.

[0232] Certain embodiments of the present disclosure may have different types of carriers depending on whether it is administered in the form of a solid, liquid, or aerosol, and whether it needs to be sterilized for an administration route such as injection. The composition can be administered intravenously, intradermally, transdermally, intramedullary cavity, intraarterially, intraperitoneally, intranasally, intravaginally, rectally, intramuscularly, subcutaneously, mucosally, orally, topically, locally, by inhalation (e.g., aerosol inhalation), by injection, by infusion, by continuous infusion, by direct localized perfusion bathing of target cells , by catheter, by lavage fluid, in a lipid composition (e.g., liposome), or by other methods known to those skilled in the art or by any combination of the above for formulation for administration (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, which is incorporated herein by reference). Usually, such a composition can be prepared as either a liquid solution or a suspension; a solid form suitable for use in preparing a solution or suspension can also be prepared by adding a liquid before injection; and the preparation can also be emulsified. ​​​

[0233] Release an anti-BTN1A1 antibody or other molecule having an antigen-binding fragment that immunospecifically binds to BTN1A1 It can be formulated into a composition in base form, neutral form, or salt form. Pharmaceutically acceptable Salts that can be obtained include acid addition salts, for example, those formed with the free amino groups of proteinaceous compositions, or those formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide; or organic bases derived from isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, or procaine. formed with, or those formed with organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide; or organic bases derived from isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, or procaine. formed with, or those formed with organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide; or organic bases derived from isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, or procaine. formed with, or those formed with organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide; or organic bases derived from isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, or procaine. formed with, or those formed with organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide; or organic bases derived from isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, or procaine. formed with, or those formed with organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups include, for example, inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide; or organic bases derived from isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, or procaine. can also be derived from.

[0234] In a further embodiment, provided herein is a pharmaceutical composition having a lipid The lipid can broadly include a class of substances that are characteristically insoluble in water and extractable with organic solvents. Examples include compounds containing long-chain aliphatic hydrocarbons and their derivatives. The lipid can be natural or synthetic (i.e., designed or produced by humans). The lipid can be a biomolecule. Biomolecules are well known in the art and include, for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, sphingoglycolipids, glycolipids, sulfatides, lipids containing ether and ester-linked fatty acids, polymeric lipids, and combinations thereof. Compounds specifically described herein that are understood by those skilled in the art as lipids and other compounds not specifically described herein The lipid can broadly include a class of substances that are characteristically insoluble in water and extractable with organic solvents. Examples include compounds containing long-chain aliphatic hydrocarbons and their derivatives. The lipid can be natural or synthetic (i.e., designed or produced by humans). The lipid can be a biomolecule. Biomolecules are well known in the art and include, for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, sphingoglycolipids, glycolipids, sulfatides, lipids containing ether and ester-linked fatty acids, polymeric lipids, and combinations thereof. Compounds specifically described herein that are understood by those skilled in the art as lipids and other compounds not specifically described herein The lipid can broadly include a class of substances that are characteristically insoluble in water and extractable with organic solvents. Examples include compounds containing long-chain aliphatic hydrocarbons and their derivatives. The lipid can be natural or synthetic (i.e., designed or produced by humans). The lipid can be a biomolecule. Biomolecules are well known in the art and include, for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, sphingoglycolipids, glycolipids, sulfatides, lipids containing ether and ester-linked fatty acids, polymeric lipids, and combinations thereof. Compounds specifically described herein that are understood by those skilled in the art as lipids and other compounds not specifically described herein The lipid can broadly include a class of substances that are characteristically insoluble in water and extractable with organic solvents. Examples include compounds containing long-chain aliphatic hydrocarbons and their derivatives. The lipid can be natural or synthetic (i.e., designed or produced by humans). The lipid can be a biomolecule. Biomolecules are well known in the art and include, for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, sphingoglycolipids, glycolipids, sulfatides, lipids containing ether and ester-linked fatty acids, polymeric lipids, and combinations ther...

Claims

[Claim 1] The novel products, methods and processes substantially as herein described.

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