Antibodies and molecules that bind immunospecifically to BTN1A1, and their therapeutic use.

Abstract

To provide molecules having an antigen binding fragment that immunospecifically binds to BTN1A1, such as anti-BTN1A1 antibodies.SOLUTION: The present invention provides an antibody that preferentially binds to dimeric BTN1A1 over monomeric BTN1A1 or an antigen binding fragment thereof, wherein (a) the antibody or the antigen binding fragment binds to dimeric BTN1A1 with a KD less than half of the KD exhibited relative to monomeric BTN1A1; or (b) the antibody or the antigen binding fragment binds to glycosylated BTN1A1 with a KD less than half of the KD exhibited relative to unglycosylated BTN1A1, wherein the antibody or the antigen binding fragment is not STC810.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the benefits of U.S. Provisional Application No. 62 / 513,389, filed on 31 May 2017. Therefore; the disclosure is incorporated entirely herein by reference.

[0002] (Reference to the sequence list) This application, filed on May 25, 2018, has a size of 118,784 bytes and is designated as 13532-018-22. The sequence listing was submitted along with a computer-readable format (CRF) copy named 8_ST25.txt. This is incorporated fully herein by reference.

[0003] (1. Field) This invention relates, as a whole, to the fields of cancer immunology and molecular biology. Provided herein This is done by anti-BTN1A1 antibodies or other molecules that have antigen-binding fragments that bind immunospecifically to BTN1A1. and its therapeutic use. [Background technology]

[0004] (2.Background) The immune systems of humans and other mammals protect them from infection and disease. Stimulative and inhibitory ligands and receptors maximize the immune response to infection, It provides a strict regulatory system that limits autoimmunity. Recently, anti-PD1 antibodies or anti-PDL1 antibodies have been used. Therapies that modulate the immune response have been found to be effective in treating some cancers. However, While doing so, new therapies that safely and effectively treat diseases by regulating the immune system Development remains an urgent need, particularly for metastatic cancer. The compositions and methods described satisfy these needs and offer other relevant advantages. ru. [Overview of the project]

[0005] (3. Overview) Provided herein are molecules having an antigen-binding fragment that binds immunospecifically to BTN1A1. In some embodiments, the molecule is an anti-BTN1A1 antibody.

[0006] In some embodiments, the molecule is an antigen-binding fragment that binds immunospecifically to the dimer. The antigen-binding fragment has the following properties: the antigen-binding fragment preferentially binds to the BTN1A1 dimer rather than the BTN1A1 monomer. In some embodiments, the BTN1A1 dimer is one or both of the BTN1A1 dimers. The BTN1A1 monomer is glycosylated at one or more of the positions N55, N215, or N449. It is being done.

[0007] In some embodiments, the molecule binds immunospecifically to glycosylated BTN1A1. It has an antigen-binding fragment. In some embodiments, the antigen-binding fragment is located at positions N55, N21 5, and / or bind immunospecifically to BTN1A1 glycosylated at N449. In one embodiment, the antigen-binding fragment is immunized to BTN1A1 which is glycosylated at position N55. It binds specifically. In some embodiments, the antigen-binding fragment is glycosylated at position N215. It binds immunospecifically to sylated BTN1A1. In some embodiments, the antigen The binding fragment immunospecifically binds to BTN1A1, which is glycosylated at position N449. In one embodiment, the antigen-binding fragment is immunospecific to one or more glycosylated motifs. It binds to the antigen-binding fragment at positions N55 and N215. In some embodiments, the antigen-binding fragment is glycated at positions N55 and N215. It immunospecifically binds to cosylated BTN1A1. In some embodiments, the antibody The protobinding fragment immunospecifically binds to BTN1A1, which is glycosylated at positions N215 and N449. In some embodiments, the antigen-binding fragment is glycosylated at positions N55 and N449. It binds immunospecifically to BTN1A1, which is cleaved of the antigen. In some embodiments, the antigen binding is cleaved. The fragments immunospecifically bind to BTN1A1, which is glycosylated at positions N55, N215, and N449. In some embodiments, the glycosylated BTN1A1 is a dimer.

[0008] In some embodiments, the molecule binds immunospecifically to glycosylated BTN1A1. It has an antigen-binding fragment, and here, the antigen-binding fragment is glycosylated compared to non-glycosylated BTN1A1. It preferentially binds to glycated BTN1A1. In some embodiments, the antigen-binding fragment is non-glycated. BTN1A1 that is glycosylated at positions N55, N215, and / or N449 than lycosylated BTN1A1 It preferentially binds to the antigen-binding fragment. In some embodiments, the antigen-binding fragment is nonglycosylated. It preferentially binds to BTN1A1 that is glycosylated at position N55 rather than to BTN1A1. More specifically, the antigen-binding fragment is glycosylated at position N215 compared to non-glycosylated BTN1A1. It preferentially binds to the ligated BTN1A1. In some embodiments, the antigen binding cleavage occurs. One side preferentially favors BTN1A1 that is glycosylated at position N449 over non-glycosylated BTN1A1. To bind. More specifically, the antigen-binding fragment contains one or more glycosylated molybs. It preferentially binds to the -f. In some embodiments, the antigen-binding fragment is nonglycosy It preferentially binds to BTN1A1 that is glycosylated at positions N55 and N215 rather than to glycosylated BTN1A1. In some embodiments, the antigen-binding fragment is located at position N2 compared to non-glycosylated BTN1A1. It preferentially binds to BTN1A1 glycosylated at 15 and N449. In some embodiments, In this case, the antigen-binding fragment is glycosylated at positions N55 and N449 compared to non-glycosylated BTN1A1. The antigen-binding fragment preferentially binds to the modified BTN1A1. In some embodiments, the antigen-binding fragment This is BTN that is glycosylated at positions N55, N215, and N449 compared to non-glycosylated BTN1A1. It preferentially binds to 1A1.

[0009] In some embodiments, the antigen-binding fragment is a BTN1A1 monomer, for example, glycosyl K shown for the BTN1A1 monomer D K less than half D BTN1A1 dimer, for example, glycosyl It binds to the BTN1A1 dimer. In some embodiments, the antigen-binding fragment binds to the BTN1A1 monodimer. The K shown for a monomer, for example, a glycosylated BTN1A1 monomer. D At least twice as small i, at least 5 times smaller, at least 10 times smaller, at least 15 times smaller, at least 2 0 times smaller, at least 25 times smaller, at least 30 times smaller, at least 40 times smaller, and K is at least 50 times smaller D The BTN1A1 dimer, for example, the glycosylated BTN1A1 dimer, is then bound to it. ru.

[0010] In some embodiments, the antigen-binding fragment is a BTN1A1 monomer, for example, glycosyl The BTN1A1 dimer exhibits a fluorescence intensity (MFI) at least twice as high as that shown for the BTN1A1 monomer. For example, it binds to a glycosylated BTN1A1 dimer. In some embodiments, the antigen The binding fragment is the MFI shown for BTN1A1 monomers, for example, glycosylated BTN1A1 monomers. At least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, BTN1A1 dimers with MFI at least 30 times, at least 40 times, or at least 50 times higher, for example It binds to the glycosylated BTN1A1 dimer.

[0011] In some embodiments, the antigen-binding fragment is shown for non-glycosylated BTN1A1 Reru K D K less than half D It binds to glycosylated BTN1A1. In some embodiments, The antigen-binding fragment is shown for non-glycosylated BTN1A1. D At least twice as small i, at least 5 times smaller, at least 10 times smaller, at least 15 times smaller, at least 2 0 times smaller, at least 25 times smaller, at least 30 times smaller, at least 40 times smaller, and K is at least 50 times smaller D It then binds to glycosylated BTN1A1.

[0012] In some embodiments, the antigen-binding fragment is shown for non-glycosylated BTN1A1 An MFI (Mean Firm Intensity) that is at least twice as high as the average fluorescence intensity (MFI; relative unit of measurement in flow cytometry) It binds to glycosylated BTN1A1. In some embodiments, the antigen-binding fragment is non At least 5 times, at least 10 times, and at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 40 times, or less Both bind to glycosylated BTN1A1 with a 50 times higher MFI.

[0013] In some embodiments, the antigen-binding fragment is located at positions N55, N215, and / or N449. The BTN1A1 glycosylation is immunospecifically masked. In some embodiments, the antibody The original binding fragment immunospecifically masks BTN1A1 glycosylation at position N55. In one embodiment, the antigen-binding fragment immunizes BTN1A1 glycosylation at position N215. To mask specifically. In some embodiments, the antigen-binding fragment is at position N449. The BTN1A1 glycosylation is immunospecifically masked. In some embodiments, the antigen The binding fragment immunospecifically masks one or more glycosylation motifs of BTN1A1. In one embodiment, the antigen-binding fragment is BTN1A1 glycosyl at positions N55 and N215. The antigen-binding fragment is immunospecifically masked. In some embodiments, the antigen-binding fragment is at position N2 Immunospecifically masks BTN1A1 glycosylation at 15 and N449. Several embodiments In this case, the antigen-binding fragment immunospecifically performs BTN1A1 glycosylation at positions N55 and N449. To mask the target. In some embodiments, the antigen-binding fragment is located at positions N55, N215, and This immunospecifically masks BTN1A1 glycosylation in N449.

[0014] In some embodiments, provided herein are immunospecific bindings to BTN1A1. Furthermore, mouse monoclonal antibodies such as STC703, STC810, and STC as shown in Tables 2a to 12b 820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 It is a molecule having an antigen-binding fragment containing the VH or VL domain. In one embodiment, the The offspring are mouse monoclonal antibodies STC703, STC810, and STC82, as shown in Tables 2a-12b. V of 0, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781 It may have an antigen-binding fragment containing both an H domain and a VL domain. Another embodiment In this context, the molecule is the mouse monoclonal antibody STC703 as shown in Tables 2a to 12b. , STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778 Antigens containing one or more VH CDRs having one of the amino acid sequences of either or STC2781 VH CDRs It may have binding fragments. In another embodiment, the molecule is as shown in Tables 2a to 12b. Mouse monoclonal antibodies such as STC703, STC810, STC820, STC1011, STC1012, ST One of the following VL CDRs: C1029, STC2602, STC2714, STC2739, STC2778, or STC2781 It may have an antigen-binding fragment containing one or more VL CDRs having a mino acid sequence. In this embodiment, the molecule is a mouse monoclonal as shown in Tables 2a to 12b. Antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739 Antigen comprising at least one VH CDR and at least one VL CDR of STC2778 or STC2781 It can have binding fragments.

[0015] In some embodiments, the molecule provided herein is (a) (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 10, 1 3, 16, 35, 38, 41, and 44 CDR1; (2) H a V having an amino acid sequence selected from the group consisting of SEQ ID NO: 8, 11, 14, 17, 36, 39, 42, and 45 having V H CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, and 46 selected and having V H CDR3: comprising a heavy chain variable (V H ) region; or (b) (1) a V having an amino acid sequence selected from the group consisting of SEQ ID NO: 19 , 22, 25, 28, 47, 50, 53, and 56 having V L C DR1; (2) a V having an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 23, 26, 29, 48, 51, 54, and 57 having an amino acid sequence and having V L CDR2; and (3) a V having an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 24, 27, 30, 49, 52, 55, and 58 selected and having V L CDR3: comprising a light chain variable (V L ) region: having an antigen binding fragment.

[0016] In some embodiments, the molecule is STC703 or STC810.

[0017] In some embodiments, the molecule does not include an antigen-binding domain comprising the VH domain, VL domain, VH CDR1, VH CDR3, VH CDR3, VL CDR1, VL C DR2, or VL CDR3 of the monoclonal antibody STC810 as shown in Tables 3a and 3b. ​​

[0018] In some embodiments, the molecule is not STC810.

[0019] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 63, 66, V having an amino acid sequence selected from the group consisting of 69 and 72 H CDR1; (2) Sequence IDs 64, 67 V having an amino acid sequence selected from the group consisting of , 70, and 73 H CDR2; and (3) Sequence number V having an amino acid sequence selected from the group consisting of numbers 65, 68, 71, and 74 H CDR3: Includes heavy (b)(1) A selected amine from the group consisting of sequence numbers 75, 78, 81, and 84. V having an ano acid sequence L CDR1; (2) Selected from the group consisting of sequence numbers 76, 79, 82, and 85. V having a mino acid sequence L CDR2; and (3) selected from the group consisting of Sequence IDs 77, 80, 83, and 86. V has the amino acid sequence that is L It contains an antigen-binding fragment that includes a light chain variable (VL) region containing CDR3. do.

[0020] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 91, 94, A net selected from the group consisting of 97, 100, 119, 122, 125, 128, 147, 150, 153, and 156. V having an ano acid sequence H CDR1; (2) Sequence IDs 92, 95, 98, 101, 120, 123, 126, 129, 148, 151 V having an amino acid sequence selected from the group consisting of , 154, and 157 H CDR2; and (3) array Select from the group consisting of numbers 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, and 158. V having the selected amino acid sequence H CDR3: Heavy chain variable (VH) region including; or (b)(1) Sequence ID 103 Selected from the group consisting of 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, and 168. V has an amino acid sequence that L CDR1; (2) Sequence IDs 104, 107, 110, 113, 132, 135, 138, 14 V having an amino acid sequence selected from the group consisting of 1, 160, 163, 166, and 169 L CDR2; average (3) Sequence numbers 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, and 170 V having an amino acid sequence selected from the following group L CDR3: Includes light chain variable (VL) region: It has an antigen-binding fragment.

[0021] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 203, 206 V having an amino acid sequence selected from the group consisting of , 209, and 212 H CDR1; (2) Sequence ID 204 V having an amino acid sequence selected from the group consisting of 207, 210, and 213 H CDR2; and (3) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 205, 208, 211, and 214 H CDR 3: Heavy chain variable (VH) region including; or (b)(1) From the group consisting of Sequence IDs 215, 218, 221, and 224 V having the selected amino acid sequence L CDR1; (2) Consists of Sequence IDs 216, 219, 222, and 225 V having an amino acid sequence selected from the groupL CDR2; and (3) Sequence IDs 217, 220, 223, and V has an amino acid sequence selected from the group consisting of 226. L CDR3: Light chain variable (VL) region: It contains antigen-binding fragments.

[0022] In some embodiments, the molecule is not STC2602.

[0023] In some embodiments, the molecules provided herein include (a)(1)SEQ ID NOs: 231, 234 V having an amino acid sequence selected from the group consisting of , 237, and 240 H CDR1; (2) Sequence ID 232 V having an amino acid sequence selected from the group consisting of 235, 238, and 241 H CDR2; and (3) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 233, 236, 239, and 242 H CDR 3: Heavy chain variable (VH) region including; or (b)(1) From the group consisting of Sequence IDs 243, 246, 249, and 252 V having the selected amino acid sequence L CDR1; (2) Consists of Sequence IDs 244, 247, 250, and 253 V having an amino acid sequence selected from the group L CDR2; and (3) Sequence IDs 245, 248, 251, and V has an amino acid sequence selected from the group consisting of 254. L CDR3: Light chain variable (VL) region: It contains antigen-binding fragments.

[0024] In some embodiments, the molecule is STC2714.

[0025] In some embodiments, the molecules provided herein include (a) (1) Sequence IDs 259, 262 V having an amino acid sequence selected from the group consisting of , 265, and 268 H CDR1; (2) Sequence ID 260 V having an amino acid sequence selected from the group consisting of 263, 266, and 269 H CDR2; and (3) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 261, 264, 267, and 270 H CDR 3: Heavy chain variable (VH) region including; or (b)(1) From the group consisting of Sequence IDs 271, 274, 277, and 280 V having the selected amino acid sequence L CDR1; (2) Consists of Sequence IDs 272, 275, 278, and 281 V having an amino acid sequence selected from the group L CDR2; and (3) Sequence IDs 273, 276, 279, and V has an amino acid sequence selected from a group consisting of 282. L CDR3: Light chain variable (VL) region: It contains antigen-binding fragments.

[0026] In some embodiments, the molecule is STC2739.

[0027] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 287, 290 V having an amino acid sequence selected from the group consisting of , 293, and 296 H CDR1; (2) Sequence ID 288 V having an amino acid sequence selected from the group consisting of 291, 294, and 297 H CDR2; and (3) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 289, 292, 295, and 298 H CDR 3: Heavy chain variable (VH) region including; or (b)(1) From the group consisting of Sequence IDs 299, 302, 305, and 308 V having the selected amino acid sequence LCDR1; (2) Consists of Sequence IDs 300, 303, 306, and 309 V having an amino acid sequence selected from the group L CDR2; and (3) Sequence IDs 301, 304, 307, and V has an amino acid sequence selected from the group consisting of 310. L CDR3: Light chain variable (VL) region: It contains antigen-binding fragments.

[0028] In some embodiments, the molecule is STC2778.

[0029] In some embodiments, the molecules provided herein include (a)(1)SEQ ID NOs: 315, 318 V having an amino acid sequence selected from the group consisting of 321 and 324 H CDR1; (2) Sequence ID 316 V having an amino acid sequence selected from the group consisting of 319, 322, and 325 H CDR2; and (3) V having an amino acid sequence selected from the group consisting of SEQ ID NOs: 317, 320, 323, and 326 H CDR 3: Heavy chain variable (VH) region including; or (b)(1) From the group consisting of SEQ ID NOs: 327, 330, 333, and 336 V having the selected amino acid sequence L CDR1; (2) Consists of sequence numbers 328, 331, 334, and 337 V having an amino acid sequence selected from the group L CDR2; and (3) Sequence IDs 329, 332, 335, and V has an amino acid sequence selected from a group consisting of 338. L CDR3: Light chain variable (VL) region: It contains antigen-binding fragments.

[0030] In some embodiments, the molecule is STC2781.

[0031] Also provided herein are the VH chain, VL chain, and VH chain of the anti-BTN1A1 antibody described herein. Domain, VL Domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL C These are isolated nucleic acid molecules encoding DR3. Further information is provided regarding these nucleic acid molecules. This includes vectors and host cells.

[0032] In some embodiments, the molecules provided herein are BTN1A1 epitopes, e.g. For example, STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739 Competitively blocking the BTN1A1 epitope of STC2778 or STC2781 (e.g., in a dose-dependent manner) It has an antigen-binding fragment that can be defused.

[0033] In some embodiments, the molecule has an antigen-binding fragment that binds immunospecifically to BTN1A1. The product is an anti-BTN1A1 antibody containing an anti-glycosylated BTN1A1 antibody. This antibody is monoclonal It can be a human antibody. The antibody can be a human antibody. It may be an antibody. The antibody may be IgG, IgM, or IgA.

[0034] In some embodiments, the molecule has an antigen-binding fragment that binds immunospecifically to BTN1A1. The offspring are Fab', F(ab')2, F(ab')3, monovalent scFv, bivalent scFv, or single-domain antibodies.

[0035] In some embodiments, the molecule has an antigen-binding fragment that binds immunospecifically to BTN1A1. The offspring are produced by recombinant DNA. In some embodiments, the molecule is used for imaging. It is conjugated with agents, chemotherapeutic agents, toxins, or radionuclides.

[0036] Also provided herein are antigen-binding fragments that bind immunospecifically to BTN1A1. The composition comprises molecules and a pharmaceutically acceptable carrier. In some embodiments, The composition is formulated for parenteral administration. Furthermore, BTN1 is provided herein. This kit includes molecules and adjuvants that have antigen-binding fragments that bind immunologically to A1.

[0037] Also provided herein are those that bind immunospecifically to BTN1A1 as described herein. This is an antibody-drug conjugate (ADC) containing a molecule having an antigen-binding fragment. What is provided is a method for conjugating cells with a compound using the molecules provided herein. By contacting the molecule provided herein, the compound can be introduced into cells expressing BTN1A1. This is a method of delivery. The compound is an imaging agent, therapeutic agent, poison as described herein. It may be an element or a radionuclide. The compound is conjugated with an anti-BTN1A1 antibody. The conjugate can be any conjugate described herein, such as an ADC. It can be a jugate. The cell can be a cancer cell. The cell is a cancer cell. It can also be a population of cells that includes both cysts and normal cells.

[0038] Also provided herein are anti-BTN1A1 antibodies, which bind immunospecifically to BTN1A1. By administering an effective amount of the molecule described herein having an antigen-binding fragment, the target This is a method of regulating the immune response. Regulating the immune response involves (a) increasing T cell activation. (b) to increase T cell proliferation; and / or (c) to increase cytokine production. This may include modulating the immune response. This includes the activation of CD8+ T cells. In some embodiments, CD8 + T-cell activation is IFNγ This includes induction of secretion or induction of T cell cluster formation.

[0039] Also provided herein is a method for controlling cells expressing BTN1A1, including an anti-BTN1A1 antibody. An effective amount of the molecule described herein having an antigen-binding fragment that binds immunospecifically to A1 and contact This method enhances T cell-dependent apoptosis in the cells by exposing them to contact. The specification provides for immunizing cells expressing BTN1A1 with BTN1A1, including an anti-BTN1A1 antibody. Contact with an effective amount of the molecule described herein having an antigen-binding fragment that specifically binds. This method inhibits the proliferation of the cells. The cells can be cancer cells. .

[0040] Furthermore, provided herein are immunospecific bindings to BTN1A1 as described herein. By administering an effective amount of a molecule having an antigen-binding fragment to the target, the cancer of the target can be treated. This is the method. In some embodiments, the molecule is an anti-BTN1A1 antibody. In one embodiment, the molecule is an antiglycosylated BTN1A1 antibody. In this context, the treatment activates the immune response or activates T cells in the target and It can promote proliferation. In some embodiments, the molecule binds to cancer cells, It induces an immune response that leads to the destruction of cancer cells. In some embodiments, the destruction of cancer cells Destruction is mediated by the ADCC activity of the molecule. In some embodiments, the destruction of cancer cells Destruction is mediated by the CDC activity of the molecule. In some embodiments, the molecule It is administered in combination with high-dose radiation.

[0041] In some embodiments, the subject has metastatic cancer. The cancer is hematological or solid cancer. It can be a tumor. In some embodiments, the cancer is leukemia, lymphoma, and It is a blood cancer selected from the group consisting of myeloma. In some embodiments, the cancer is Breast cancer, lung cancer, thymic cancer, thyroid cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, brain tumor, liver cancer Cancer, bladder cancer, kidney cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectum A solid tumor selected from the group consisting of cancer and skin cancer. The skin cancer is melanoma. It could be either a non-melanoma skin cancer or a non-melanoma skin cancer.

[0042] In some embodiments, the method is immunospecific to BTN1A1 as described herein. This includes systemic administration to a target of a molecule having an antigen-binding fragment to which it binds. In some embodiments, The molecule is administered intravenously, intradermally, intratumorally, intramuscularly, intraperitoneally, subcutaneously, or topically. In some embodiments, the method includes administering a second anti-cancer therapy as the target. This includes surgical therapy, chemotherapy, biological targeted therapy, small molecule targeted therapy, radiotherapy, and cryotherapy. This can be nephropathy, hormone therapy, immunotherapy, or cytokine therapy. In this embodiment, the molecule is administered parenterally.

[0043] Furthermore, the material provided herein preferentially binds to dimer BTN1A1 rather than monomer BTN1A1. A method for producing a molecule containing an antigen-binding fragment, wherein BTN1A1 antigen is provided, and BTN1A1 To produce molecules containing antigen-binding fragments that bind immunologically, and to produce molecules that bind immunologically to BTN1A1 The molecule containing the antigen-binding fragment that binds to the target is preferentially bound to the dimer BTN1A1 rather than the monomer BTN1A1. This method involves screening molecules containing antigen-binding fragments that match. In some embodiments, the BTN1A1 antigen is a BTN1A1 monomer. In this specification, the BTN1A1 antigen is a BTN1A1 dimer. These are molecules produced using the method provided in the detailed document. [Brief explanation of the drawing]

[0044] (4. Brief explanation of the drawing) The following drawings form part of this specification and further illustrate specific embodiments of the invention. This invention includes one or more of these drawings as specific examples presented herein. By referring to this in conjunction with a detailed description of the typical implementation, a better understanding can be achieved. can.

[0045] [Figure 1] Figure 1 - Linear structure of human BTN1A1. Figure 1 shows the linear structure of human BTN1A1, which includes two immunoglobulin domains (V-set, C2-set_2) and two protein interaction domains (PRY, SPRY).

[0046] [Figure 2]Figure 2 - Subcloning of human BTN1A1. The complete coding sequence (CD) of human BTN1A1 with a C-terminal flag tag was subcloned into pcDNA3 using a standard cloning method. As shown in Figure 2, the upper band corresponds to the vector skeleton, and the lower band corresponds to the CD of human BTN1A1 with a flag tag.

[0047] [Figure 3] Figure 3-293 shows the expression of glycosylation-specific mutants and wild-type BTN1A1 in T cells. Site-directed mutagenesis was used to induce specific mutations in the glycosylation sites (N55Q, N215Q, and a combination of N55Q and N215Q) in the extracellular domain of human BTN1A1. The expression of both wild-type BTN1A1 and its mutant forms is shown in Figure 3. As shown, the combined mutant of BTN1A1 (N55Q and N215Q) was not expressed, demonstrating that glycosylation of BTN1A1 is extremely important for its expression.

[0048] [Figure 4] Figures 4A and 4B - BTN1A1 as an immunotherapy target. Figures 4A and 4B show graphs plotting shRNA sequences read from non-irradiated tumors versus non-irradiated spleens (Figure 4A) and irradiated tumors versus non-irradiated spleens (Figure 4B) together with negative controls.

[0049] [Figure 5] Figure 5 - BTN1A1 induction in activated CD8+ T cells. Figure 5 shows a graph illustrating the results of flow cytometry (FACS) analysis. BTN1A1 cell surface expression was analyzed in mouse CD8+ T cells activated with concanavalin A (ConA) or anti-CD3 / anti-CD28.

[0050] [Figure 6]Figures 6A and 6B-BTN1A1 can selectively inhibit CD8+ T cell activation. Figures 6A and 6B show the results of mass cytometry analysis (CyTOF; Fluidigim, South San Francisco, CA) of T cell activation. Figure 6A shows the CyTOF results obtained using activated T killer cells. Figure 6B shows the CyTOF results obtained using naive T killer cells and effector T killer cells.

[0051] [Figure 7] Figure 7 shows cell-based assay formats useful for characterizing the biological activity of BTN1A1. Figure 7 shows graphs illustrating bead-based assays (left panel), co-culture assays (middle panel), and BTN1A1-coated assays (right panel).

[0052] [Figure 8] Beads coated with BTN1A1 can inhibit the proliferation of human total T cells. Figures 8A and 8B show the results of a bead-based T cell proliferation assay according to Figure 7 (left panel). Figure 8A shows flow cytometry readings. Figure 8B shows relative T cell proliferation in a bar graph.

[0053] [Figure 9] Figures 9A and 9B show that 4T1 cells overexpressing mBTN1A1 can inhibit mouse T cell proliferation. Figures 9A and 9B show the results of a co-culture assay according to Figure 7 (middle panel) using 4T1 cells overexpressing BTN1A1 and CFSE-stained mouse splenocytes. Figure 9A shows flow cytometry readings. Figure 9B shows relative T cell proliferation as a bar graph.

[0054] [Figure 10]Figure 10 shows that mBTN1A1 can suppress mouse T cell proliferation. Figure 10 shows the results of a heterogeneous assay according to Figure 7 (right panel) using coated BTN1A1 and CFSE-stained mouse splenocytes.

[0055] [Figure 11] Figure 11 shows that mBTN1A1 can be induced in the tumor microenvironment by high-dose radiation. Figure 11 shows the results of flow cytometry analysis of BTN1A1 expression levels in CD8+ cells isolated from mouse tumors after radiotherapy.

[0056] [Figure 12] Figure 12 shows that mBTN1A1 can be induced in the tumor microenvironment by high-dose radiation. Figure 12 shows images from immunohistochemical analysis of formalin-fixed paraffin-embedded (FFPE) LLC syngeneic tumors from non-irradiated control mice (top row) and mice irradiated with a radiation dose of 2 Gy × 5 (middle row) or 12 Gy × 3 (bottom row).

[0057] [Figure 13] Figure 13 - BTN1A1 is N-linked glycosylated. Recombinant human BTN1A1 protein expressing the extracellular domain was treated with either a simulated (-) or PNGase F for 1 hour, subjected to polyacrylamide gel electrophoresis (PAGE), and stained with Coomassie. As shown in Figure 13, a clear shift is observed in the PNGase F-treated lane, indicating N-linked glycosylation of BTN1A1. The band corresponding to the arrow is the PNGase F protein.

[0058] [Figure 14]Figure 14 - Presumed glycosylation sites in the full-length human BTN1A1 protein. The full-length sequence of human BTN1A1 (SEQ ID NO: 1) was input into the N-linked glycosylation site (Nx[ST] pattern prediction software (http: / / www.hiv.lanl.gov / content / sequence / GLYCOSITE / glycosite.html)). The three candidate glycosylation sites identified by this software are highlighted in red in the sequence shown in Figure 14.

[0059] [Figure 15] Figure 15 shows a high degree of homology in the glycosylation sites of the extracellular domain of BTN1A1. Verified BTN1A1 sequences from three species (human (Homo sapiens), mouse (Mus musculus), and bovine (Bos taurus)) were collected from uniprot (www.uniprot.org), subjected to glycosylation site prediction software (http: / / www.hiv.lanl.gov / content / sequence / GLYCOSITE / glycosite.html), and aligned using clustal W2 (http: / / www.ebi.ac.uk / Tools / msa / clustalw2 / ). As shown in Figure 15, the glycosylation sites (sequence numbers 189-194, in order of appearance) are evolutionarily conserved across species.

[0060] [Figure 16] Figure 16A - High induction of cell surface BTN1A1 in mouse T cells activated by anti-CD3 / CD28 stimulation. Unsensitized mouse T cells were stimulated for 2 days either with simulated stimulation (left) or with anti-CD3 (5 μg / ml) and anti-CD28 (5 μg / ml), and subjected to flow cytometry analysis. Figure 16A shows the high induction of cell surface BTN1A1 in CD3 / CD28-stimulated cells compared to simulated-treated cells.

[0061] Figure 16B - High cell surface BTN1A1 levels in mouse T cells after activation by anti-CD3 / CD28 stimulation. Induction. Unsensitized mouse T cells are stimulated for 2 days (red) or treated with anti-CD3 (5 μg / ml) and anti- The cells were stimulated with CD28 (5 μg / ml) (orange) and subjected to flow cytometry analysis. The current cells were compared to a control group using only the secondary antibody. Figure 16B shows the CD3 / CD28 stimulated cells compared to simulated treated cells. This shows high induction of cell surface BTN1A1 in cells. The blue curve represents isotype control. be.

[0062] [Figure 17] Figure 17 - Bone marrow cells induce BTN1A1 expression in B16-Ova melanoma cells. Extracellular BTN1A1 in B16-Ova cells was detected by staining with an antibody-only control or FITC-BTN1A1 antibody, and BTN1A1 expression levels were examined using flow cytometry. The term "BM" stands for bone marrow.

[0063] [Figure 18] Figures 18A and 18B show that BTN1A1 forms dimers within cells. Figures 18A and 18B show Western blot analysis of lysates from BTN1A1-flag expressing HEK293T cells treated with EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) or Glu (glutaraldehyde) crosslinking agents. Figure 18A shows the Western blot run under reductive denaturation conditions. Figure 18B shows the Western blot run under undenatured conditions.

[0064] [Figure 19]Figures 19A and 19B show dot blot analysis of mouse anti-human BTN1A1 antibody. Figure 19A shows the results of the dot blot analysis, which was used to analyze the sugar specificity of the mouse anti-human BTN1A1 monoclonal antibody. The 6×His-tagged antigen BTN1A1-ECD was treated with PNGase F to remove N-glycosylation. Polyclonal antibodies were used as positive controls. To test the species specificity of BTN1A1, human and mouse BTN1A1 tagged with the human IgG1 Fc region were used (lanes 1-4 for human BTN1A1-Fc and lanes 5-8 for mouse BTN1A1-Fc). The term "ECD" represents the extracellular domain. Figure 19B provides a layout diagram of the dot blot shown in Figure 9A.

[0065] [Figure 20] Figure 20 - BTN1A1-ECD-His6 and BTN1A1-ECD-Fc are N-linked glycosylated. Recombinant human BTN1A1-ECD-His6 and BTN1A1-ECD-Fc protein constructs expressing the extracellular domain were treated with either simulated (-) or PNGase F for 1 hour, subjected to polyacrylamide gel electrophoresis (PAGE), and stained with Coomassie. As shown in Figure 20, a clear shift was observed in lanes 2 and 4 treated with PNGase F, indicating N-linked glycosylation of BTN1A1-ECD-His6 and BTN1A1-ECD-Fc. The band corresponding to the asterisk is the PNGase F protein.

[0066] [Figure 21] Figures 21A-C - FACS analysis of mouse anti-human BTN1A1 monoclonal antibodies. Human BTN1A1-2NQ (i.e., N55Q and N215Q) and human BTN1A1 WT were expressed in HEK293T cells by transient transfection. Surface expression of hBTN1A1 was measured by FACS analysis using anti-BTN1A1 monoclonal antibodies represented as STC703 (Figure 21A), STC810 ​​(Figure 21B), or STC820 (Figure 21C). Anti-BTN1A1 polyclonal antibodies were used as positive controls.

[0067] [Figure 22] Figures 22A-F - Surface plasmon resonance analysis of BTN1A1-Fc and BTN1A1-His binding to immobilized STC703, STC810, or STC820 MAb. Figures 22A, 22C, and 22E: Sensorgrams showing real-time binding of soluble BTN1A1-Fc protein (2-64 nM at 2-fold dilution) to STC703 (Figure 22A), STC810 ​​(Figure 22C), or STC820 (Figure 22E) immobilized on a mouse IgG capture-CM5 chip (BIAcore). Figures 22B, 22D, and 22F: Sensorgrams showing real-time binding of soluble BTN1A1-His protein (2-64 nM at 2-fold dilution) to STC703 (Figure 22B), STC810 ​​(Figure 22D), or STC820 (Figure 22F) immobilized on mouse IgG capture-CM5 chips (BIAcore). Flow cells without immobilized protein were used as controls for nonspecific binding and subtracted from the test flow cells.

[0068] [Figure 23] Figures 23A-C show Western blot analysis of BTN1A1 WT, N55Q, N215Q, and 2NQ mutants. Figure 23A shows schematic diagrams of BTN1A1 WT and its mutants N55Q, N215Q, and 2NQ (i.e., N55Q and N215Q). Figure 23B shows Western blots of BTN1A1 WT and its mutant morphologies probed with antibodies STC810, STC812, STC819, STC820, STC821, STC838, STC848, or STC859. Figure 23C shows gel-loaded controls.

[0069] [Figure 24]Figure 24 - Western blot analysis of BTN1A1 WT, N55Q, N215Q, and 2NQ mutants. Figure 24 shows Western blots of BTN1A1 WT or its mutant morphology using antibodies STC703 (left panel), STC810 ​​(middle panel), or STC820 (right panel).

[0070] [Figure 25] Figure 25 - Immunofluorescence analysis of STC703 and STC810 ​​antibodies by confocal microscopy. HEK293T cells were transiently transfected with expression vectors of wild-type BTN1A1 (BTN1A1 WT) and mutant BTN1A1 (BTN1A1-2NQ (i.e., N55Q and N215Q)). Cells were plated on coverslips and probed with primary antibodies against BTN1A1 (STC703 or STC810) and secondary antibodies against mouse IgG. Blue staining is DAPI, which stains the nucleus.

[0071] [Figure 26] Figures 26A and 26B show that fluorescently labeled STC810 ​​is internalized by cells overexpressing glycosylated BTN1A1 WT. Figure 26A shows a representative image from IncuCyte ZOOM® live cell analysis. The red fluorescence indicating internalized phRodo®-labeled STC810 ​​is visible in the upper right panel but not in the other three panels. Figure 26B shows a graph plotting internalized STC810-phRodo® fluorescence over time. The increase in internalized STC810-phRodo® fluorescence is observed in cells expressing glycosylated BTN1A1 WT but not in cells expressing non-glycosylated BTN1A1 2NQ.

[0072] [Figure 27]Figures 27A and 27B-STC810 ​​synergistically induce IL-2 and IFNγ secretion in mixed lymphocyte reactions with anti-PD-1 antibodies. Figures 27A and 27B show bar graphs illustrating the effect of the indicated antibody treatment on mixed lymphocyte cultures on IL-2 (Figure 27A) or IFNγ (Figure 27B) secretion.

[0073] [Figure 28] Figures 28A and 28B show that STC810 ​​promotes IFNγ secretion and clustering of activated CD8+ T cells. Figure 28A shows images of unactivated (top left panel) or anti-CD3 activated T cell cultures after treatment with IgG control antibody (top right panel), BTN1A1-Fc (bottom left panel), or a combination of BTN1A1-Fc and STC810 ​​(bottom right panel). Figure 28B shows a graph plotting IFNγ levels detected in the supernatant of ConA and IL-2 activated T cells after treatment with STC810 ​​at the indicated concentrations, as determined by ELISA.

[0074] [Figure 29] Figures 29A-C - Surface plasmon resonance analysis of BTN1A1-Fc binding to immobilized STC1011, STC1012, or STC1029 MAb. Figures 29A, 29B, and 29C: Sensorgrams showing real-time binding of soluble BTN1A1-Fc protein (2-64 nM at 2-fold dilution) to STC1011 (Figure 29A), STC1012 (Figure 29B), or STC1029 (Figure 29C) immobilized on a protein A-CM5 chip (BIAcore). Flow cells without immobilized proteins were used as controls for nonspecific binding and subtracted from the test flow cells.

[0075] [Figure 30]Figures 30A-C - Fluorescently labeled STC1012 is internalized by cells overexpressing glycosylated mouse BTN1A1 WT or non-glycosylated mouse BTN1A1 2NQ. Figure 30A shows a representative image from IncuCyte ZOOM® live cell analysis. The red fluorescence indicating internalized phRodo®-labeled STC1012 is visible in the middle panel of the top row (293T mBTN1A1(WT)) and the upper right panel (293T mBTN1A1(2NQ)), but not in the control panel. Figure 30B shows a graph plotting internalized STC1012-phRodo® fluorescence over time. An increase in internalized STC810-phRodo® fluorescence is observed in cells expressing glycosylated BTN1A1 WT and cells expressing non-glycosylated BTN1A1 2NQ. Figure 30C shows the results of a control experiment using pHRodo®-labeled control mIgG1.

[0076] [Figure 31] Figures 31A and 31B show that anti-mBTN1A1 antibodies promote the proliferation of T cells co-cultured with mBTN1A1-overexpressing 4T1 cells. Figures 31A and 31B show the results of the co-culture experiment (middle panel) according to Figure 7. 4T1 cells overexpressing BTN1A1 were co-cultured with mouse spleen cells and the indicated anti-mouse BTN1A1 antibody. Figure 31A shows the results of flow cytometry analysis of proliferating T cells in the co-culture. Figure 31B shows bar graphs illustrating the effects of STC1011, STC1012, and STC1029 on T cell proliferation in the co-culture.

[0077] [Figure 32] Figure 32A shows the epitope mapping of BTN1A1-Fc. STC810 ​​and BTN1A1(ECD)-Fc were subjected to Ag-Ab crosslinking and analyzed by high-mass MALDI. Figure 11 shows the amino acid residues of BTN1A1(ECD)-Fc crosslinked to STC810, including R41, K42, K43, T185, and K188.

[0078] Figure 32 shows the epitope mapping of BTN1A1-His. STC810 ​​and BTN1A1(ECD)-His are mounted on an Ag-Ab frame. The samples were subjected to high-mass MALDI analysis. Figure 32B includes R68, K78, T175, S179, and T185. Hmm, this shows the amino acid residues of BTN1A1(ECD)-His crosslinked to STC810.

[0079] [Figure 33] Figure 33 - T cell killing effect of BTN1A1 antibody. Figure 33 shows a graph plotting T cell-mediated apoptosis in PC3 human prostate cancer cells in the presence of STC810, STC2602, STC2714, or STC2781 BTN1A1 antibody, along with a negative control.

[0080] [Figure 34] Figure 34 - Dimer-specific binding of BTN1A1 antibody. The leftmost panel of Figure 34 is an image of a Coomassie blue-stained SDS-PAGE gel showing the positions of monomeric and dimeric forms of BTN1A1 protein under both undenatured and reduced conditions, along with a size standard. Panels 2 through 5 show Western blots visualizing monomeric and dimeric forms of BTN1A1 protein under both undenatured and reduced conditions using STC810, STC2602, STC2714, and STC2781 antibodies, respectively.

[0081] [Figure 35] Figures 35A-B - Binding affinity (KD) of STC2714 to monomeric and dimeric forms of BTN1A1. Figure 35A: Sensorgram showing real-time binding of soluble BTN1A1-Fc protein (Figure 35A) (2-fold dilution, 2-64 nm) to STC2714 immobilized on a Protein A-CM5 chip (Biacore). Figure 35B: Sensorgram showing real-time binding of soluble BTN1A1-His protein (2-fold dilution, 2-64 nm) to STC2714 immobilized on a Protein A-CM5 chip (Biacore). [Modes for carrying out the invention]

[0082] (5. Detailed explanation) Co-stimulatory molecules of the B7 family can promote the activation and inhibition of immune cells. The molecule buryrophilin, a member of the B7 family, is similar to the B7 family members. It has immunomodulatory functions. Butyrophylline, subfamily 1, member A1 ("BTN1A1") It is a type I membrane glycoprotein and a major component of the milk fat globule membrane, and is structurally similar to the B7 family. They have similarities. BTN1A1 is known as a major protein that regulates the formation of lipid droplets in milk. (Ogg et al., PNAS, 101(27):10084-10089(2004)). BTN1A1 is an immune cell including T cells. It is expressed in [location]. Treatment with recombinant BTN1A1 inhibits T cell activation and prevents EAE in animal models. It was found that it could be controlled (Stefferl et al., J. Immunol. 165(5):2859-65(2000)).

[0083] BTN1A1 is specifically and highly expressed in cancer cells. BTN1A1 in cancer cells is glycosylated. It is also being used to not only aid in cancer diagnosis but also to evaluate the effectiveness of cancer treatments by using BTN1A1 expression. It is also possible.

[0084] Provided herein are an anti-BTN1A1 antibody and a substance that can bind immunospecifically to BTN1A1. Other molecules that can perform cancer diagnosis, evaluate cancer treatment, or modulate the activity of immune cells. These are the methods of use when treating cancer.

[0085] (5.1.Definition) As used herein, and unless otherwise specified, "a," "an," and "the" The article "antibody" refers to one or more grammatical objects of that article. For example, "antibody" (an antibody). This refers to one or more antibodies.

[0086] As used herein, and unless otherwise specified, "butyrophylline, subfalse The terms "Millie 1, Member A1" or "BTN1A1" refer to mammals, for example, primates (e.g., This includes humans, cynomolgus macaques, dogs, and rodents (e.g., mice and rats). , refers to BTN1A1 of any vertebrate source. Unless otherwise specified, BTN1A1 refers to various BTN1 A1 isoforms, related BTN1A1 polypeptides including their SNP variants, and, as well as, but not limited to, BTN1A1 polypeptides. However, the BTN1A1 is such that it includes phosphorylated BTN1A1, glycosylated BTN1A1, and ubiquitinated BTN1A1. Various modification forms are also included. As used herein, glycosylated BTN1A1 is N55, N21 5, and / or BTN1A1 having N449 glycosylation.

[0087] The exemplary amino acid sequence of human BTN1A1 (BC096314.1 GI: 64654887) is shown as a latent glycosylation. The parts that have been modified are shown in bold and underlined, and are provided below:

[0088] [ka]

[0089] An exemplary coding nucleic acid sequence for human BTN1A1 (BC096314.1 GI: 64654887) is provided below:

[0090] [ka]

[0091] The exemplary amino acid sequence of mouse BTN1A1 (GenBank: AAH11497.1) is latently glycosylated. The parts are shown in bold and underlined, and are provided below:

[0092] [ka]

[0093] The following is an example coding nucleic acid sequence for mouse BTN1A1 (GenBank: BC011497.1):

[0094] [ka]

[0095] As used herein, and unless otherwise specified, the term “antibody” means specific It can bind to a specific molecular antigen, and two identical polypeptide chain pairs (where each Each pair has one heavy chain (approximately 50-70 kDa) and one light chain (approximately 25 kDa), and each amino acid in each chain The terminal portion contains a variable region of approximately 100 to 130 or more amino acids, and each chain Each carboxyl terminus of a polypeptide is composed of a constant region (including a constant region), and the polypeptide immunoglobulin This refers to the polypeptide products of B cells within the robulin (or "Ig") class (Borrebaeck (ed.) (1995)). Antibody Engineering, 2nd edition, Oxford University Press.; K Uby's literature (1997), Immunology, 3rd edition, WH Freeman and Company, New York. (See reference). Here, the specific molecular antigen includes the target BTN1A1, which is the BTN1A1 polypeptide. This may be a cydone, a BTN1A1 fragment, or a BTN1A1 epitope. The antibodies provided herein In terms of type, monoclonal antibodies, synthetic antibodies, recombinant antibodies, bispecific antibodies, and multispecific antibodies are all types of antibodies. Heterosexual antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, anti-idiolytic antibodies Examples include, but are not limited to, iotype (anti-Id) antibodies.

[0096] As used herein, and unless otherwise specified, "monoclonal antibody" The term refers to a single cell clone or hybridoma or a cell derived from a single cell. This refers to antibodies that are the product of a population. Monoclonal antibodies produce a single-molecule immunoglobulin species. To achieve this, immunoglobulins are produced by recombinant methods from the heavy and light chains that encode the immunoglobulin gene. It is also intended to refer to the antibody that has been prepared. The amino acid sequence of the antibody in the monoclonal antibody preparation. The antigen-binding activity is substantially the same as that of the antibodies in such preparations, and the antigen-binding activity is substantially the same as that of the antibodies in such preparations. It exhibits sexuality. In contrast, polyclonal antibodies are obtained from various B cells within a population, and this is Each of the polyclonal antibodies is a combination of immunoglobulin molecules that bind to a specific antigen. The immunoglobulin can bind to different epitopes of the same antigen. Methods for producing both clonal and polyclonal antibodies are well known in the art (Harlow and Lane's literature, Antibodies: A Laboratory Manual, Cold Sprin g Harbor Laboratory Press (1989) and Borrebaeck (ed.), Antibody Engineering: Practical Guide Antibody Engineering: A Practical Guide, WH Freeman and Co., Publishers, N New York, pp. 103-120(1991)).

[0097] As used herein, and unless otherwise specified, the term "human antibody" means Corresponding to the human variable region and / or the human constant region or human germline immunoglobulin sequence. This refers to antibodies that have these parts. Such human germline immunoglobulin sequences are Ka Bat et al. (1991), Immunologically interesting protein sequences (Sequences of Proteins of I (Mumunological Interest), 5th edition, US Department of Health and Human Services, NIH This is described in Publication No. 91-3242. Here, the human antibody binds to BTN1A1, This is a natural somatic variant of the human germline immunoglobulin nucleic acid sequence. It can contain antibodies that are used for testing.

[0098] As used herein, and unless otherwise specified, the term “chimeric antibody” is used herein. The heavy chain and / or part of the light chain originate from a specific species or a specific antibody class or subclass. The sequence is identical or homologous to the corresponding sequence in antibodies belonging to the rat, while the remainder of the chain belongs to a different species. The sequence is identical to the corresponding sequence in an antibody of which it originates or belongs to another antibody class or subclass. This refers to homologous antibodies, as well as fragments of such antibodies, insofar as they exhibit the desired biological activity. U.S. Patent No. 4,816,567; and the literature of Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851- See 6855 (1984).

[0099] As used herein, and unless otherwise specified, the term “humanized antibody” is used herein. Native complementarity-determining region ("CDR") residues possess the desired specificity, affinity, and ability. to do the corresponding CDR of a non-human species such as a mouse, rat, rabbit, or non-human primate (for example) Human immunoglobulins (e.g., donor antibodies) whose residues are replaced with those derived from the donor antibody. This refers to a chimeric antibody containing (a) antibodies. In some cases, it may include one or more FR regions of human immunoglobulin. The residue is replaced with the corresponding non-human residue. Furthermore, the humanized antibody is the recipient antibody. It can have residues not found in either the antibody or the donor antibody. These modifications improve antibody performance. This is done to further refine the antibody. The heavy or light chain of the humanized antibody is at least one or multiple. It may include substantially all of the variable region of the number, and in the variable region, all or substantial of the CDR All of these correspond to non-human immunoglobulin CDRs, and all or substantially all of the FRs correspond to human immunoglobulins. It is the FR of the immunoglobulin sequence. Humanized antibodies are at least a portion of the constant region (Fc) of immunoglobulins. Typically, it may contain at least a portion of the constant region of human immunoglobulin. For further details... For reference, see Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332 :323-329(1988); and Presta's literature, Curr. Op. Struct. Biol., 2:593-596(1992); Carte r et al., Proc. Natl. Acd. Sci. USA 89:4285-4289 (1992); and U.S. 6,800,73 See also issues 8, 6,719,971, 6,639,055, 6,407,213, and 6,054,297. stomach.

[0100] As used herein, and unless otherwise specified, the term “recombinant antibody” is used in this specification. This refers to antibodies prepared, expressed, produced, or isolated by recombinant means. Recombinant antibodies are antibodies that are genetically modified. Antibodies expressed using recombinant expression vectors transfected into principal cells, recombinant Antibodies isolated from combinatorial antibody libraries, human immunoglobulin genes Animals that are transgenic and / or transchromosomal (e.g., mau Antibodies isolated from (or from) cattle (e.g., Taylor, LD et al., Nucleo Acids Res) See 20:6287-6295 (1992), or sprayer of immunoglobulin gene sequences to other DNA sequences. Antibodies prepared, expressed, produced, or isolated by any other means involving issing. Such recombinant antibodies can be derived from human germline immunoglobulin sequences. It can have variable and steady-state regions, including (Kabat, EA et al. (1991), Sequences of Proteins of Immunological Interest ), 5th edition, US Department of Health and Human Services, NIH Publication No. 91-3 See 242). Recombinant antibodies are transmutatogenic (or transmutatogenic to human Ig sequences). If a genetically modified animal is used, it may also undergo in vivo somatic mutagenesis. Therefore, the amino acid sequences of the VH and VL regions of the recombinant antibody are the same as those of the VH and VL regions of the human germline. Derived from and related to the germline, but naturally present in the in vivo human antibody germline repertoire. It may be a non-existent array.

[0101] As used herein, and unless otherwise specified, “neutralizing antibody” refers to BTN1A1 and It blocks the binding of the natural ligand and the BTN1A1-mediated signaling pathway and / Or it refers to antibodies that inhibit other physiological activities. The IC50 of a neutralizing antibody is used in a neutralization assay with BTN1 This refers to the concentration of antibody required to neutralize 50% of A1. The IC50 of a neutralizing antibody is the concentration required to neutralize 50% of A1. The concentration can range from 0.01 to 10 μg / ml.

[0102] As used herein, and unless otherwise specified, the term “antigen-binding fragment” And similar terms refer to immune-specific binding to an antigen, and its specificity and affinity for the antigen. This refers to the portion of the antibody that contains the amino acid residue that is attached to the antibody. The antigen-binding fragment is the functional part of the antibody. These can be called fragments. Antigen-binding fragments can be monovalent, divalent, or polyvalent.

[0103] Examples of molecules containing antigen-binding fragments include Fd, Fv, Fab, F(ab'), F(ab)2, and F(ab')2. , single-chain Fv (scFv), diabody, triabody, tetrabody, minibody, or single-chain The main antibody is listed. The scFv can be monovalent or bivalent. Antigen binding... Other molecules that have fragments include, for example, molecules in which such antigen-binding fragments retain binding activity. As far as is concerned, heavy chain or light chain polypeptide, variable region polypeptide, or CDR polypeptide Examples of such antigen-binding fragments include, for example, Harl References from ow and Lane, Antibodies: A Laboratory Manual, Cold Spr ing Harbor Laboratory, New York (1989); Myers (ed.), Molecular Biology and Biotechnology: Comprehensive Desk Reference Book (Molec. Biology and Biotechnology: A Comprehensive Desk Reference), Ne w York: VCH Publishers; Huston et al., Cell Biophysics, 22:189-224(1993); Plu References by ckthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, ED. Advanced Immunochemistry, 2nd edition, Wiley-Liss, New York, NY (1990) It can be found described in ). The antigen-binding fragment consists of at least 5 consecutive amino acid residues, at least 10 consecutive amino acid residues, at least 15 consecutive amino acid residues 0 acid residues, at least 20 consecutive amino acid residues, at least 25 consecutive amino acids residues, at least 40 consecutive amino acid residues, at least 50 consecutive amino acid residues , at least 60 consecutive amino acid residues, at least 70 consecutive amino acid residues, at least At least 80 consecutive amino acid residues, at least 90 consecutive amino acid residues, and at least 100 consecutive amino acid residues, at least 125 consecutive amino acid residues, at least 150 consecutive amino acid residues, at least 175 consecutive amino acid residues, at least 20 An amino acid sequence of 0 consecutive amino acid residues, or at least 250 consecutive amino acid residues. It can be a polypeptide having columns.

[0104] The heavy chain of an antibody has a variable region at its amino terminus with approximately 120-130 or more amino acids. This refers to a polypeptide chain of approximately 50-70 kDa that contains a constant region in its carboxyl terminus. The constant region is determined based on the amino acid sequence of the heavy chain constant region, using alpha (α), delta (δ), One of five different types, called epsilon (ε), gamma (γ), and muon (μ) It can be one. Different heavy chains are of different sizes: α, δ, and γ have about 450 ami. It contains ano acids, while μ and ε contain approximately 550 amino acids. Combined with the light chain... These different types of heavy chains are the four subclasses of IgG, namely IgG1, IgG2, The five types of antibodies, IgA, IgD, IgE, IgG, and IgM, include IgG3 and IgG4, respectively. A class of knowledge is generated. A heavy chain can be a human heavy chain.

[0105] The light chain of an antibody has a variable region with approximately 100 to 110 or more amino acids in its amino-terminus. This refers to a polypeptide chain of approximately 25 kDa that includes a constant region and whose carboxyl terminus contains a constant region. The approximate length of the light chain is 211-217 amino acids. Based on the amino acid sequence of the constant domain. Subsequently, there are two different types called kappa (κ) or lambda (λ). Light chain amino acids The acid sequence is well known in this art. The light chain can be a human light chain.

[0106] The variable domain or variable region of an antibody is usually located at the amino terminus of the light chain or heavy chain. The amino acids have a length of approximately 120-130 amino acids, while the light chain has a length of approximately 100-110 amino acids, and each specific The light or heavy chain of the antibody used in relation to the binding and specificity of the antibody to its particular antigen. This refers to the part. The variable domain has a significantly different sequence among different antibodies. The sequence variation is It is concentrated in CDR, while the less variable parts within the variable domain are in the framework domain. This is called the FR region. The CDRs of the light and heavy chains are primarily involved in the interaction between antibodies and antigens. The amino acid position numbering used herein is based on the literature by Kabat et al. (1991), which is of immunological interest. Protein sequences (Sequences of proteins of immunological interest) (US Department) (Ent of Health and Human Services, Washington, DC), as seen in the 5th edition, EU This is due to the index. The variable region can be the human variable region.

[0107] CDR is a non-framework of immunoglobulin (Ig or antibody) VH β-sheet framework. One of the three hypervariable regions (H1, H2, or H3) within the β-cell region, or antibody VL β-sheet Within the framework's non-framework domain, there are three highly variable domains (L1, L2, or L3). It refers to one of the elements. Therefore, CDR is a variable region array scattered within the framework region array. The CDR region is well known to those skilled in the art, for example, the most hypervariable within the antibody variable (V) domain. This area is defined by Kabat (Kabat et al., J. Biol. Chem. 252:6609). -6616 (1977); Kabat's literature, Adv. Prot. Chem. 32:1-75 (1978). Also, the CDR region sequence is, It is not part of the preserved β-sheet framework, and therefore takes on various three-dimensional structures. These residues are structurally defined by Chothia as being capable of doing so (Chothia and Lesk) References, J. Mol. Biol. 196:901-917(1987)). Both terminology are well recognized in the art. The location of the CDR within the standard antibody variable domain is determined by comparing numerous structures. (Al-Lazikani et al., J. Mol. Biol. 273:927-948(1997); Morea et al., Methods 20:267-279(2000)). The number of residues in the hypervariable region varies considerably between different antibodies. In standard variable domain numbering schemes, additional residues at standard positions are conventionally assigned to residues. The numbers are followed by a, b, c, etc. (Al-Lazikani et al., see above (1997)). Such a system of terminology is also well known to those skilled in the art.

[0108] For example, Table 1 below shows a CDR defined according to standard notation. Table 1: CDR definition [Table 1]

[0109] Furthermore, one or more CDRs are incorporated into a molecule covalently or noncovalently, and then immunotherapy is performed. It can be made into an adhesin. Immunoadhesins are CDRs that make larger polypeptide chains It can be incorporated as part of a larger molecule, or the CDR can be covalently linked to another polypeptide chain. It is possible to incorporate the CDR non-covalently. The CDR is an immunoad This allows hesin to bind to a specific antigen.

[0110] The "framework" or "FR" residue refers to a variable domain residue adjacent to the CDR. The bases include, for example, chimeric, humanized, human, domain antibodies, diabolic, linear antibodies, and two. It is present in the hemispecific antibodies. FR residues are variable residues other than the hypervariable region residues as defined herein. This is a domain residue.

[0111] As used herein, and unless otherwise specified, used in connection with antibodies. The term "isolated" in this context refers to antibodies that originate from cellular material or cells or tissue sources. It is substantially free of other contaminating proteins and / or other contaminating components derived from antibodies, or When chemically synthesized, this means that it substantially does not contain chemical precursors or other chemical substances. The phrase "substantially free of cellular material" means that the antibody is isolated or It includes antibody preparations isolated from cellular components of cells produced by recombination. Antibodies that substantially contain no cellular material contain approximately 30%, 20%, 10%, or 5% (by dry weight). Antibody containing less than % heterogeneous proteins (also referred to herein as "contaminating proteins") The body preparation is included. In one embodiment, when the antibody is produced by recombinant, This is substantially free of culture medium; for example, the culture medium is approximately 20% of the volume of the protein preparation. This corresponds to %, 10%, or less than 5%. In one embodiment, the antibody is produced by chemical synthesis. If produced, it will substantially contain no chemical precursors or other chemical substances, for example, It is isolated from chemical precursors or other chemical substances involved in protein synthesis. Therefore, such antibody preparations have a concentration of approximately 30%, 20%, 10%, and less than 5% (by dry weight). It contains compounds other than pre-antibody precursors or the target antibody. The interfering components are not limited to, Substances that interfere with the therapeutic use of antibodies can also be listed, as well as enzymes, hormones, and other Examples include proteinaceous or non-proteinaceous solutes. In one embodiment, an anti The body is determined by (1) the Lowry method (Lowry et al., J. Bio. Chem. 193: 265-275, 1951). When the antibody exceeds 95% by weight, for example, up to 99% by weight, (2) spinning cup sequencer Using this method, obtain to a sufficient extent to obtain at least 15 residues of the N-terminal or internal amino acid sequence. (3) Reduction or non-reduction using Coomassie blue staining or preferably silver staining. The antibody is purified to homogeneity by SDS-PAGE under the original conditions. Since one component is missing, the isolated antibody contains antibodies from the in situ of the recombinant cell. It includes. However, typically, isolated antibodies undergo at least one purification step. It is prepared by... In a specific embodiment, the antibody provided herein is isolated. .

[0112] As used herein, and unless otherwise specified, "polynucleotide" and "nucleonucleotide" are used in this specification. The terms "creotide," "nucleic acid," "nucleic acid molecule," and other similar terms are used interchangeably. It contains DNA, RNA, mRNA, etc.

[0113] When used herein, and unless otherwise specified, when used in connection with nucleic acid molecules The term "isolated" as used means that the nucleic acid molecule is not present in the natural source of the nucleic acid molecule. This means that it is a nucleic acid molecule that has been isolated from the nucleic acid molecule. Furthermore, "isolated" Nucleic acid molecules, such as cDNA molecules, are produced by other cellular materials or by recombinant techniques. This is either substantially free of culture medium, or, if chemically synthesized, contains a chemical precursor. It may be substantially free of certain chemical substances or other chemical substances. Specific embodiments In this specification, the nucleic acid molecules encoding the antibodies provided herein have been isolated or purified.

[0114] As used herein, and unless otherwise specified, “to combine” or “to combine” The term "interaction" refers to intermolecular interactions. Examples of such interactions include hydrogen bonding and ions. Non-covalent phases including bonding, hydrophobic interactions, and / or van der Waals interactions This can be an interaction between an antibody and a target molecule, for example, a single epitope of BTN1A1. The overall strength of the non-covalent interaction is the affinity of the antibody to that epitope. "Binding affinity" usually refers to the single binding of a molecule (e.g., a binding protein, e.g., an antibody). The sum of the strengths of non-covalent interactions between a site and its binding partner (e.g., antigen) To point.

[0115] A binding molecule X, for example, an antibody, and its binding partner Y, for example, the antibody's parent antigen. The harmonizing property is usually determined by the dissociation constant (K D ) can be represented by. Low affinity antibodies are usually found in antigens While antibodies tend to bind slowly and dissociate quickly, high-affinity antibodies typically bind slowly to antigens. It tends to bind faster and remain bound for a longer period. Various methods are known in the art, and using any of them for the purposes of this disclosure is not permitted. It is possible. "K D " or "K D The value is determined by assays known in the art, for example, It can be measured by a binding assay. K D For example, the target Fab-type antibody and It can be measured using a radiolabeled antigen-binding assay (RIA) performed with the antigen. (See Chen et al. (1999) J. Mol Biol 293:865-881). K D or K D The value is, for example, BIAcore( Biacore using trademark)-2000 or BIAcore(trademark)-3000 (BIAcore Inc., Piscataway, NJ) This can be done by using a surface plasmon resonance assay, or, for example, Octet QK384 systolic Measurements can also be taken using biolayer interferometry with TEM (ForteBio, Menlo Park, CA). can.

[0116] As used herein, and unless otherwise specified, a molecule is defined as having such a bond resisting When the body shows specificity and affinity for its congener antigen, the second molecule is "immunologically bound". It is said that antibodies can "bind" to antigens. Such binding involves the antigen recognition site of the antibody. In this case, it binds immunospecifically to the target region or three-dimensional structure ("epitope") of the antigen. Antibodies that bind immune-specifically to the source are used in immunoassays, for example, BIACORE (registered trademark). When determined by the standard assay or other assays known in the art, the antigen recognition portion If there is a certain degree of sequence or three-dimensional structure similarity that can be recognized by a specific position, then other antigens may be used. It can bind with low affinity. Antibodies in general do not bind to completely unrelated antigens. The antibody (and its antigen-binding fragment) does not cross-react with other antigens. The antibody does not cross-react with other molecules. In a non-epidemic-specific manner, for example, other regions of an antibody that do not contain the antigen recognition site on the FcR receptor / They can also be joined thanks to domains, for example, the joining domains within the Fc region.

[0117] Antibodies or anti-antibodies that bind immunospecifically to antigens containing glycosylated sites or to the epitopes of antigens. The primordial binding fragment can be attached to antigens or epitopes in both glycosylated and non-glycosylated forms. It can bind. In some embodiments, the antibody or antigen-binding fragment is non-g It preferentially binds to glycosylated antigens or epitopes rather than lycosylated antigens or epitopes. The preferred bond can be determined by its binding affinity. For example, nonglycosylation. Antibodies or antigen-binding fragments that preferentially bind to glycosylated BTN1A1 rather than BTN1A1 are non-glycosylated. K shown for silated BTN1A1 D K less than D It can bind to glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment is opposed to non-glycosylated BTN1A1. K shown by D K less than half D It binds to glycosylated BTN1A1. In some embodiments In this case, the antibody or antigen-binding fragment is shown to have a K for non-glycosylated BTN1A1 D Less than At least 10 times smaller K D It binds to glycosylated BTN1A1. In some embodiments, The antibody or antigen-binding fragment is shown to represent K for non-glycosylated BTN1A1. D Approximately 75% of, approximately 50% K is approximately 25%, 10%, 5%, 2.5%, or 1%. D It binds to glycosylated BTN1A1. ru.

[0118] Antibodies or antigen-binding fragments that bind immunospecifically to BTN1A1 are either BTN1A1 monomers or BTN1A1 dimers. It can bind to the body. In some embodiments, the antibody or antigen-binding fragment is It preferentially binds to BTN1A1 dimers rather than BTN1A1 monomers. BTN1A1 binding occurs, for example, on the cell surface. For BTN1A1 expressed in or a soluble BTN1A1 domain construct, for example, BTN1 A1 extracellular domain (ECD) construct (e.g., flag-tagged BTN1A1-ECD or BTN1A1-C) This can occur in relation to the ED-Fc fusion construct. In some embodiments, The BTN1A1 monomer or dimer is glycosylated at one or more positions. Several embodiments In this case, the antibody or antigen-binding fragment is expressed with respect to the BTN1A1 monomer. D Less than half K D It binds to the BTN1A1 dimer. In some embodiments, the antibody or antigen-binding fragment is , K shown for BTN1A1 monomer D K is at least 10 times smaller than D It binds to the BTN1A1 dimer. In some embodiments, the antibody or antigen-binding fragment is used against the BTN1A1 monomer. The K shown D Approximately 75%, 50%, 25%, 10%, 5%, 2.5%, or 1% of K D BTN1A It binds to a dimer.

[0119] In some embodiments, BTN1A1 (for example, BTN1A dimer or glycosylated BTN1A1) K of antibodies or antigen-binding fragments that bind immunospecifically to it D This is an enzyme-linked immunosorbent assay (ELISA). ), fluorescent immunoadsorption assay (FIA), chemiluminescent immunoadsorption assay (CLIA), radioimmunoassay (R IA), Enzyme Multiplexed Immunoassay (EMI), Solid-Phase Radioimmunoassay (SPROA), Fluorescence Polarization (FP) Fluorescence resonance energy transfer (FRET) assay, time-resolved fluorescence resonance energy transfer (TR-FRET) assay. This is determined using an ET assay or a surface plasmon resonance (SPR) assay.

[0120] In some embodiments, BTN1A1 (for example, BTN1A dimer or glycosylated BTN1A1) K of antibodies or antigen-binding fragments that bind immunospecifically to it D This is determined using an SPR assay. In some embodiments, the SPR assay is performed using an SPR instrument manufactured by Biacore, for example, BIAcore This is implemented using (trademark)-2000 or BIAcore(trademark)-3000 (BIAcore, Inc., Piscataway, NJ).

[0121] Preferred binding is determined by a binding assay, and, for example, by mean fluorescence intensity ("MFI"). This can also be demonstrated by, for example, an antibody or antigen that preferentially binds to glycosylated BTN1A1. The binding fragment exhibits a higher MFI than that shown for non-glycosylated BTN1A1, compared to glycosylated BTN1A1. It can bind to N1A1. In some embodiments, the antibody or antigen-binding fragment is Glycosylated BTN with an MFI at least twice as high as that shown for non-glycosylated BTN1A1 It binds to 1A1. In some embodiments, the antibody or antigen-binding fragment is nonglycosyl Binding to glycosylated BTN1A1 with an MFI at least three times higher than that shown for glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment is used against non-glycosylated BTN1A1. At least 5 times, at least 10 times, at least 15 times, or at least 20 times the MFI shown It binds to glycosylated BTN1A1 with high MFI.

[0122] As used herein, and unless otherwise specified, a molecule is an antigen or epithelium. This means "immunologically masking" the glycosylation of a specific glycosylation site, or a particular glycosylation site. It is said that (1) the antigen or epitope cannot be glycosylated, non-glyco (2) Block the glycosylation site of the sylated antigen or epitope, or (2) Glycosylated antigen Alternatively, the epitope or the glycosylated antigen or a specific glycosylated portion of the epitope. They bind at the position and exert physiological effects of glycosylation, such as downstream effects mediated by glycosylation. This refers to the ability to interfere with any of the signal transduction. For example, BTN1A1 glycosylation. The antibody or antigen-binding fragment that provides immune-specific masking is (1) the glycosylation of non-glycosylated BTN1A1 (2) Block the glycosylation site and prevent its glycosylation, or bind to glycosylated BTN1A1. , the physiological effects of glycosylation, for example, the immunosuppressive effect mediated by glycosylation This refers to any antibody or antigen-binding fragment that interferes with the process. Another example is in N55 and N215. Antibodies or antigen-binding fragments that immunospecifically mask BTN1A1 glycosylation are (1) non-glycosylated (2)N It binds to BTN1A1, which is glycosylated at 55 and N215, and the physiological effects of glycosylation, for example If either antibody or antigen interferes with the immunosuppressive effect mediated by glycosylation It refers to a binding fragment.

[0123] As used herein, and unless otherwise specified, the term “carrier” means “carrier.” Diluents and adjuvants (for example, Freund's adjuvant) are administered along with the therapeutic agent. This refers to a complete or incomplete excipient, stabilizer, or vehicle. The "carrier" is used to protect cells or mammals exposed to it at the dosage and concentration used. It is a non-toxic carrier, which can be a sterilizing solution such as water and oil, and oil contains... Petroleum, animal, plant, or synthetic origin oils, such as peanut oil, soybean oil, mineral oil, and sesame oil. This includes things like:

[0124] As used herein, and unless otherwise specified, the term "vector" means This refers to a substance used to introduce nucleic acid molecules into host cells. Examples of vectors include expression vectors, plasmids, phage vectors, and viral vectors. Examples include chromosomes, episomes, and artificial chromosomes, which are stable to host cell chromosomes. It may include a selectable sequence or marker that can be operated for embedding. Furthermore, a vector It may include one or more selectable marker genes and appropriate expression regulatory sequences. Selectable marker genes that can be used include, for example, resistance to antibiotics or toxins. It provides, compensates for autotrophic deficiencies, or supplies essential nutrients that are not present in the culture medium. Expression regulation The sequence consists of constitutive and inducible promoters, transcription enhancers, and transmutations, which are well known in the art. It may include a phototerminator, etc. Two or more nucleic acid molecules (e.g., the heavy chain and light chain of an antibody) If both nucleic acid molecules are to be co-expressed, then both nucleic acid molecules can be expressed in, for example, a single expression vector. - Or it can be inserted into separate expression vectors. For single-vector expression, encoding Nucleic acids are functionally linked to one common regulatory expression sequence, or to different regulatory expression sequences, e.g. For example, it can be linked to one inductive promoter and one constitutive promoter. The introduction of nucleic acid molecules into host cells can be confirmed using methods well known in this field. Such methods include, for example, nucleic acid analysis, for example, mRNA Northern blotting or This refers to immunoblotting for polymerase chain reaction (PCR) amplification or gene product expression. Other suitable methods for testing the expression of the introduced nucleic acid sequence or its corresponding gene product. Examples of analytical methods include: nucleic acid molecules, the desired product (e.g., anti-BTN provided herein). It is understood by those skilled in the art that it is expressed in an amount sufficient to produce 1A1 antibody, and also, The current level can be optimized using methods well known in this field to obtain sufficient expression. This will be further understood.

[0125] As used herein, and unless otherwise specified, the term “host cell” means Specific target cells transfected with nucleic acid molecules and their offspring or potential This refers to offspring of such cells. Offspring of such cells may undergo mutations or environmental changes in subsequent generations. Transfecting nucleic acid molecules is caused by the influence or integration of nucleic acid molecules into the host cell genome. The parent cell does not have to be identical to the one that was used to create the new cell.

[0126] As used herein, and unless otherwise specified, the term “Target” means treatment "Animals" refers to animals that are the subject of observation and / or experimentation. "Animals" include vertebrates and invertebrates. This includes things such as fish, crustaceans, reptiles, birds, and especially mammals. This includes mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, and spirits. This includes, but is not limited to, mates such as monkeys, chimpanzees, apes, and humans. do not have.

[0127] As used herein, and unless otherwise specified, the terms "cancer" or "cancerous" are used in this specification. The term typically refers to a physiological condition in mammals characterized by unregulated cell proliferation. Examples of cancer include, but are not limited to, blood cancers and solid tumors.

[0128] When used herein, and unless otherwise specified, when used in relation to cancer patients The terms "to treat," "to treat," and "treatment" refer to reducing the severity of cancer. or refers to any action that prevents or slows the progression of cancer, which includes (a) inhibiting the growth of cancer cells. (b) to cause or halt the development of cancer, and (b) to cause regression of cancer or the persistence of cancer This includes delaying or minimizing one or more symptoms associated with the condition.

[0129] As used herein, and unless otherwise specified, the term “therapeutic dose” is used in this specification. , the severity of a given disease, disability, or illness and / or symptoms associated therewith and / or A drug that is sufficient to reduce and / or improve the duration (for example, as described herein) This refers to the amount of antibodies (or any other drugs described herein) that are used as therapeutic agents. The therapeutic dose is (i) a reduction or improvement in the progression or progression of a given disease, disability, or illness. (ii) improvement, (ii) reduction or improvement of recurrence, onset, or occurrence of a given disease, disability, or illness. (iii) therapies other than the administration of antibodies provided herein The amount may be necessary to improve or enhance the preventive or therapeutic effect. The substance / The therapeutically effective dose of a molecule / drug (e.g., anti-BTN1A1 antibody) depends on the individual's condition, age, sex, and weight. , as well as factors such as the ability of the substance / molecule / drug to induce a desired response in an individual. It may vary. The therapeutically effective dose is the amount that is therapeutically beneficial while minimizing any toxic or adverse effects of the substance / molecule / drug. It includes an amount that outweighs the effect.

[0130] As used herein, and unless otherwise specified, “administer” or “administer” The term refers to a substance that exists outside the body, and is then introduced to the patient, for example, through the mucous membrane, intradermally, intravenously, Intramuscular delivery, and / or any other substance described herein or known in the art. This refers to the act of delivering a substance by injection or by other physical means. (Disease, disability) When treating harm, disease, or symptoms thereof, administration of the substance is usually for the disease, It is performed after the onset of a disability, illness, or symptoms thereof. In the event of administering the substance to prevent these symptoms, the administration of the substance is usually not intended to treat the disease, disorder, or illness. It is performed before the onset of the illness or its symptoms.

[0131] (5.2 Molecules having antigen-binding fragments that bind immunospecifically to BTN1A1) Provided herein are antigens that bind immunologically to BTN1A1, including anti-BTN1A1 antibodies. It is a molecule having a binding fragment. In some embodiments, it binds immunospecifically to BTN1A1. The antigen-binding fragment binds to a fragment or epitope of BTN1A1. In some embodiments, In this configuration, the antigen-binding fragment binds immunospecifically to the BTN1A1 dimer. Several embodiments In this case, the antigen-binding fragment is not the antigen-binding fragment of STC810. In some embodiments The BTN1A1 epitope can be a linear epitope. Several embodiments In this context, the BTN1A1 epitope can be a three-dimensional epitope. In this embodiment, the BTN1A1 epitope is found in the BTN1A1 dimer and in the BTN1A1 monomer. It is not possible. In some embodiments, the antigen-binding fragment has an immunospecific binding to BTN1A1. The molecule provided herein inhibits the immunosuppressive function of BTN1A1.

[0132] N-glycosylation is initiated in the endoplasmic reticulum (ER) and subsequently processed in the Golgi apparatus. It is a post-modification (Schwarz and Aebi, Curr. Opin. Struc. Bio., 21(5): 576-582 (2011) This type of modification involves modifying a pre-formed glycan composed of oligosaccharides with NXT Moth. The membrane transitions to the asparagine (Asn) side chain acceptor located inside the f(-Asn-X-Ser / Thr-) molecule. It is first catalyzed by the related oligosaccharide transferase (OST) complex. (and Reithmeier's work, Methods, 41: 451-459 2007); Helenius and Aebi's work, Science e, 291(5512):2364-9(2001). Addition or removal of saccharides from pre-formed glycans. Each of these precisely regulates the N-glycosylation cascade in a cell- and position-dependent manner. It is mediated by glycosyltransferases and glycosidases of the group.

[0133] In some embodiments, the molecule is selected from one or more glycosylated motifs of BTN1A1. It has an antigen-binding fragment that selectively binds. In some embodiments, the antigen-binding fragment is It binds immunospecifically to glycopeptides having a glycosylated motif and to adjacent peptides. In some embodiments, the antigen-binding fragment has a glycosylated motif in three dimensions. It binds immunospecifically to one or more of the nearby peptide sequences. In this embodiment, the antigen-binding fragment is one or more glycosylated motifs of the BTN1A1 monomer. It selectively binds to one or more glycosylated motifs of the BTN1A1 dimer.

[0134] In some embodiments, the antigen-binding fragment is shown for non-glycosylated BTN1A1 Reru K D K is at least 30%, 40%, 50%, 60%, 70%, 80%, or less than 90% of the total. D Glico It binds to glycosylated BTN1A1 (for example, glycosylated BTN1A1 dimer). In one embodiment, The antigen-binding fragment is shown for non-glycosylated BTN1A1. D Less than 50% of K D Glycosil It binds to BTN1A1. In some embodiments, the antigen-binding fragment is nonglycosylated. K shown for BTN1A1 D 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% K is less than %, 20%, 30%, 40%, and 50%. D It binds to glycosylated BTN1A1. In this embodiment, the antigen-binding fragment is represented by K for non-glycosylated BTN1A1. D Rather K is at least 10 times smaller D It then binds to glycosylated BTN1A1.

[0135] The specific glycosylation site of a particular BTN1A1 isoform or variant is that specific BTN1 The A1 isoform or variant may vary, with amino acids at positions 55, 215, or 449. In these circumstances, a person skilled in the art would know that sequence alignment and other common techniques in the art are possible. Based on general knowledge, the N55, N215, and N449 of human BTN1A1 exemplified above correspond to The glycosylation site of any specific BTN1A1 isoform or mutant can be determined. Therefore, the non-glycosylated BTN1A1 isophore is provided herein. Compared to the BTN1A1 isoform or mutant, the glycosylated form of the BTN1A1 isoform is immunospecific. It is also a molecule that has an antigen-binding fragment that binds to a target. The lycosylation sites correspond to N55, N215, and N449 of the human BTN1A1 sequence provided above. It can be a part of the body.

[0136] In some embodiments, the molecule is glycosylated BTN1A1 (e.g., glycosylated B It has an antigen-binding fragment that binds immunospecifically to the TN1A1 dimer. The antigen-binding fragment is glycosylated at positions N55, N215, and / or N449 in BTN1A1 It binds immunospecifically to the antigen. In some embodiments, the antigen-binding fragment is at position N55. It binds immunospecifically to glycosylated BTN1A1. In some embodiments, The antigen-binding fragment binds immunospecifically to BTN1A1, which is glycosylated at position N215. In some embodiments, the antigen-binding fragment is glycosylated at position N449 in BT It binds immunospecifically to N1A1. In some embodiments, the antigen-binding fragment is one or more. It binds immunospecifically to the glycosylated motif of the antigen. In some embodiments, the antigen The binding fragment immunospecifically binds to BTN1A1, which is glycosylated at positions N55 and N215. In some embodiments, the antigen-binding fragment is glycosylated at positions N215 and N449. It binds immunospecifically to BTN1A1. In some embodiments, the antigen-binding fragment It immunospecifically binds to BTN1A1, which is glycosylated at positions N55 and N449. In one embodiment, the antigen-binding fragment is glycosylated at positions N55, N215, and N449. It binds immunospecifically to BTN1A1.

[0137] In some embodiments, the molecule is glycosylated BTN1A1 (e.g., glycosylated B It has an antigen-binding fragment that binds immunospecifically to the TN1A1 dimer, where the antigen-binding fragment is It preferentially binds to glycosylated BTN1A1 over non-glycosylated BTN1A1. Several implementations In this case, the antigen-binding fragment is located at positions N55, N215, and / or higher than non-glycosylated BTN1A1. It preferentially binds to BTN1A1 that is glycosylated at N449. In some embodiments, The antigen-binding fragment is glycosylated at position N55 compared to non-glycosylated BTN1A1. It preferentially binds to 1A1. In some embodiments, the antigen-binding fragment is nonglycosy It preferentially binds to BTN1A1 that is glycosylated at position N215 rather than to BTN1A1 that is otherwise glycosylated. In one embodiment, the antigen-binding fragment is glycosylated at position N449 compared to non-glycosylated BTN1A1. It preferentially binds to cosylated BTN1A1. In some embodiments, the antigen binds The composite fragment preferentially binds to one or more glycosylated motifs. In some embodiments... Furthermore, the antigen-binding fragment is glycosylated at positions N55 and N215 compared to non-glycosylated BTN1A1. Preferentially binds to BTN1A1 that is present. In some embodiments, the antigen-binding fragment is Preferentially binds to BTN1A1 that is glycosylated at positions N215 and N449 rather than non-glycosylated BTN1A1 . In some embodiments, the antigen-binding fragment preferentially binds to BTN1A1 that is glycosylated at positions N55 and N449 rather than 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 non-glycosylated BTN1A1.

[0138] Preferential binding can be determined by binding affinity. For example, an antibody or antigen-binding fragment that preferentially binds to glycosylated BTN1 A1 (e.g., glycosylated BTN1A1 dimer) can bind to glycosylated BTN1A1 with a K less than the K D shown for non-glycosylated BTN1A1. D In some embodiments, the antibody or antigen-binding fragment can bind to glycosylated BTN1A1 with a K less than half of the K shown for non-glycosylated BTN1A1. D In some D embodiments, the antibody or antigen-binding fragment can bind to glycosylated BTN1A1 with a K at least 10-fold less than the K D shown for non-glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment can bind to glycosylated BTN1A1 with a K D about 75% of the K shown for non-glycosylated BTN1A1. D At a K D In some embodiments, the antibody or antigen The binding fragment is shown for non-glycosylated BTN1A1. D K is approximately 50% of D Glycosylation It binds to BTN1A1. In some embodiments, the antibody or antigen-binding fragment is nonglycated. K shown for silated BTN1A1 D K is approximately 25% of D It then binds to glycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment is used against non-glycosylated BTN1A1. The K shown D K is about 10% of D It binds to glycosylated BTN1A1. In some embodiments The antibody or antigen-binding fragment is shown to have a K for non-glycosylated BTN1A1. D Approximately 5% of Aru K D It binds to glycosylated BTN1A1. In some embodiments, the antibody or antigen The binding fragment is shown for non-glycosylated BTN1A1. D K is approximately 2.5% of D Glycosil It binds to BTN1A1. In some embodiments, the antibody or antigen-binding fragment is non-glycosylglyceride. K shown for cosylated BTN1A1 D K is about 1% of D It then binds to glycosylated BTN1A1.

[0139] Preferential binding is determined, for example, by a binding assay indicated by fluorescence intensity ("MFI"). It is also possible to prioritize glycosylated BTN1A1 (e.g., glycosylated BTN1A1 dimer). The antibody or antigen-binding fragment that binds to the target is more effective than the MFI shown for non-glycosylated BTN1A1. It can also bind to glycosylated BTN1A1 with a high MFI. In some embodiments The antibody or antigen-binding fragment has at least two MFIs shown against non-glycosylated BTN1A1. It binds to glycosylated BTN1A1 with twice the MFI. In some embodiments, an antibody or anti The original binding fragment exhibits an MFI at least three times higher than that shown for non-glycosylated BTN1A1. It binds to lycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment is Glycosylated BTN1A exhibits an MFI at least 5 times higher than that shown for non-glycosylated BTN1A1. It binds to 1. In some embodiments, the antibody or antigen-binding fragment is nonglycosylated B It binds to glycosylated BTN1A1 with an MFI at least 10 times higher than the MFI shown for TN1A1. In some embodiments, the antibody or antigen-binding fragment is used against non-glycosylated BTN1A1. The glycosylated BTN1A1 binds at an MFI at least 15 times higher than the indicated MFI. Several implementations In this embodiment, the antibody or antigen-binding fragment is the MFI shown for nonglycosylated BTN1A1 It binds to glycosylated BTN1A1 with at least a 20-fold higher MFI.

[0140] In some embodiments, the antigen-binding fragment is (for example, glycosylated BTN1A1 dimer). Immunospecifically masses BTN1A1 glycosylation at locations N55, N215, and / or N449 (in the body). In some embodiments, the antigen-binding fragment is located at position N55, where BTN1A1 is present. Cosylation is immunospecifically masked. In some embodiments, the antigen-binding fragment is Immunospecifically masks BTN1A1 glycosylation at position N215. In several embodiments, In this context, the antigen-binding fragment immunospecifically masks the BTN1A1 glycosylation at position N449. In some embodiments, the antigen-binding fragment is one or more glycosylation of BTN1A1. The motif is immunospecifically masked. In some embodiments, the antigen-binding fragment is Immunospecifically masks BTN1A1 glycosylation at positions N55 and N215. In one embodiment, the antigen-binding fragment is exempt from BTN1A1 glycosylation at positions N215 and N449. To mask disease-specifically. In some embodiments, the antigen-binding fragment is located at positions N55 and N Immunospecifically masks BTN1A1 glycosylation at 449. In some embodiments, The antigen-binding fragment then immunohistochemically performs BTN1A1 glycosylation at positions N55, N215, and N449. Wear a mask in an unusual way.

[0141] In some embodiments, the molecule is selectively formed into a BTN1A1 dimer rather than a BTN1A1 monomer. It has an antigen-binding fragment to bind to. In some embodiments, the BTN1A1 dimer is a cell It is expressed on the surface. In some embodiments, the BTN1A1 dimer is a soluble form of BTN1A1. Protein fragments, e.g., extracellular domain construct of BTN1A1, e.g., Fc-fusion tannins This is a protein construct (e.g., BTN1A1-ECD-Fc). In some embodiments, The BTN1A1 monomer is a BTN1A1 extracellular domain construct, for example, Flag tagging or Hi This is an s6-tagged BTN1A1-ECD construct. In some embodiments, the BTN1A1 dimer The molecule that selectively binds to glycosylated BTN1A1 is provided herein. It is a molecule. In some embodiments, the BTN1A1 monomer is compared to the BTN1A1 dimer. The preferred binding is, for example, determined using a surface plasmon resonance assay (e.g., BIAcore) to determine BTN BTN1A1-ECD-Fc construct compared to 1A1-ECD-His6 or BTN1A1-ECD-Flag construct This is determined by determining the preferred combination to the. In some embodiments, the The molecule is STC703 or STC810. In some embodiments, the molecule is STC810. No. In some embodiments, the molecule is as described in Tables 3a and 3b. Clonal antibody STC810: VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1 It does not contain antigen-binding domains including VL CDR2 and / or VL CDR3.

[0142] In some embodiments, the antigen-binding fragment is a BTN1A1 monomer (e.g., glycosyl K shown for the BTN1A1 monomer D at least 30%, 40%, 50%, 60%, 70%, 80% , or less than 90% K D It then binds to the BTN1A1 dimer (for example, the glycosylated BTN1A1 dimer). In this embodiment, the antigen-binding fragment is a BTN1A1 monomer (for example, glycosylated BTN1A1 monomer) K shown for the mass D Less than 50% of K D BTN1A1 dimer (for example, glycosylated BTN1A1 dimer) It binds to the BTN1A1 monomer (for example). In some embodiments, the antigen-binding fragment binds to the BTN1A1 monomer (for example) For example, the K shown for glycosylated BTN1A1 monomer. D 1%, 2%, 3%, 4%, 5%, 6%, 7% K is less than %, 8%, 9%, 10%, 15%, 20%, 30%, 40%, and 50%. D BTN1A1 dimer (for example) In some embodiments, the antigen binds to the glycosylated BTN1A1 dimer. The fragment is shown for the BTN1A1 monomer (e.g., glycosylated BTN1A1 monomer). D Less than At least 10 times smaller K D It then binds to the BTN1A1 dimer (for example, the glycosylated BTN1A1 dimer). In some embodiments, the molecule is STC703 or STC810. In this case, the molecule is not STC810. In some embodiments, the molecule is as shown in Table 3a and The VH domain, VL domain, and VH C of the monoclonal antibody STC810 ​​as described in 3b. Antigen-binding domains including DR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 It does not include.

[0143] Preferred bonding can be determined by bonding affinity. For example, BTN1A1 dimer ( For example, an antibody or antigen-binding fragment that preferentially binds to the glycosylated BTN1A1 dimer is BTN1A1 K shown for monomers (e.g., glycosylated BTN1A1 monomers) D K less than D BTN1A1 dimer It can be bonded to (for example, a glycosylated BTN1A1 dimer). In some embodiments... The antibody or antigen-binding fragment is then attached to the BTN1A1 monomer (for example, glycosylated BTN1A1 monomer). In contrast, K is shown D K less than half D This results in a BTN1A1 dimer (for example, a glycosylated BTN1A1 dimer). To bind. In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g. For example, the K shown for glycosylated BTN1A1 monomer.D K is at least 10 times smaller than D B It binds to the TN1A1 dimer (for example, the glycosylated BTN1A1 dimer). In some embodiments... The antibody or antigen-binding fragment is then attached to the BTN1A1 monomer (for example, glycosylated BTN1A1 monomer). In contrast, K is shown D K is approximately 75% of D BTN1A1 dimer (for example, glycosylated BTN1A1 dimer) It binds to the antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer ( For example, the K shown for glycosylated BTN1A1 monomer D K is approximately 50% of D BTN1A1 diquantity It binds to the form (e.g., glycosylated BTN1A1 dimer). In some embodiments, the antibody The body or antigen-binding fragment is shown against the BTN1A1 monomer (e.g., glycosylated BTN1A1 monomer). Reru K D K is approximately 25% of D It binds to the BTN1A1 dimer (for example, the glycosylated BTN1A1 dimer). In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (for example, G K shown for lycosylated BTN1A1 monomer D K is about 10% of D BTN1A1 dimer (for example, It binds to a glycosylated BTN1A1 dimer. In some embodiments, the antibody or antigen The binding fragment is shown for the BTN1A1 monomer (e.g., glycosylated BTN1A1 monomer) and K D Approximately K is 5% D It then binds to the BTN1A1 dimer (for example, the glycosylated BTN1A1 dimer). In this embodiment, the antibody or antigen-binding fragment is a BTN1A1 monomer (for example, glycosylated B K shown for TN1A1 monomer D K is approximately 2.5% of D BTN1A1 dimer (for example, glycosyl It binds to the BTN1A1 dimer. In some embodiments, the antibody or antigen-binding fragment is , the K shown for BTN1A1 monomers (e.g., glycosylated BTN1A1 monomers) D K is about 1% of D It then binds to the BTN1A1 dimer. In some embodiments, the molecule is STC703 or STC81 It is 0. In some embodiments, the molecule is not STC810. In this case, the molecule is a monoclonal antibody STC810 ​​as described in Tables 3a and 3b. VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL It does not contain the antigen-binding domain, including CDR3.

[0144] Preferential binding is determined, for example, by a binding assay indicated by fluorescence intensity ("MFI"). It is also possible to preferentially bind to BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers). The antibody or antigen-binding fragment that binds to the BTN1A1 monomer (e.g., glycosylated BTN1A1 monomer) BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers) are formed at an MFI higher than the MFI shown. It can be combined. In some embodiments, the antibody or antigen-binding fragment is BTN1A1 The MF is at least twice as high as the MFI shown for monomers (e.g., glycosylated BTN1A1 monomers). I binds to the BTN1A1 dimer (e.g., glycosylated BTN1A1 dimer). Several embodiments In this case, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). BTN1A1 dimer (e.g., glycosylated BTN1) has an MFI at least three times higher than the MFI shown for BTN1A1. It binds to the A1 dimer. In some embodiments, the antibody or antigen-binding fragment is BTN1A1 The MF is at least 5 times higher than the MFI shown for monomers (e.g., glycosylated BTN1A1 monomers). I binds to the BTN1A1 dimer (e.g., glycosylated BTN1A1 dimer). Several embodiments In this case, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). BTN1A1 dimer (e.g., glycosylated BTN) has an MFI at least 10 times higher than the MFI shown for BTN1A1. It binds to the 1A1 dimer. In some embodiments, the antibody or antigen-binding fragment binds to BTN1A1. The MFI shown for monomers (e.g., glycosylated BTN1A1 monomers) is at least 15 times higher. FI binds to the BTN1A1 dimer (e.g., glycosylated BTN1A1 dimer). Several embodiments In this case, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). BTN1A1 dimer (e.g., glycosylated BTN) has an MFI at least 20 times higher than the MFI shown for BTN1A1. It binds to the 1A1 dimer. In some embodiments, the molecule is STC703 or STC810. In some embodiments, the molecule is not STC810. Furthermore, the molecule is a VH-dominant of the monoclonal antibody STC810 ​​as described in Tables 3a and 3b. In, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 It does not contain antigen-binding domains.

[0145] In some embodiments, the antibody or antigen-binding fragment is a glycosylated monomer BTN1A1 It preferentially binds to the glycosylated dimer BTN1A1 rather than to the glycosylated dimer BTN1A1. Each BTN1A1 monomer may be independently glycosylated at the same or different positions. i. In some embodiments, one of the monomers in the BTN1A1 dimer is glycosyl It is not converted. The glycosylated BTN1A1 monomer in the glycosylated BTN1A1 dimer is at position N55 It may be glycosylated with N215 and / or N449. In some embodiments The glycosylated BTN1A1 monomer is glycosylated at position N55. Several embodiments In this case, the glycosylated BTN1A1 monomer is glycosylated at position N215. In that embodiment, the glycosylated BTN1A1 monomer is glycosylated at position N449. In some embodiments, the glycosylated BTN1A1 monomer is glycated at positions N55 and N215. It is lycosylated. In some embodiments, the glycosylated BTN1A1 monomer is located at It is glycosylated with N55 and N449. In some embodiments, glycosylated B The TN1A1 monomer is glycosylated at positions N215 and N449. In some embodiments... Furthermore, the glycosylated BTN1A1 monomer is glycosylated at positions N55, N215, and N449. ru.

[0146] (5.2.1. Other molecules containing antibodies and antigen-binding fragments) In some embodiments, an anti-BTN1A1 antibody, an anti-glycosylated BTN1A1 antibody, or an anti-BTN1 A1 dimer antibody can be IgG, IgM, IgA, IgD, or IgE. Anti-BTN1A1 antibody or Antiglycosylated BTN1A1 antibodies or anti-BTN1A1 dimer antibodies are chimeric antibodies, affinity matured antibodies, and These can be glycosylated antibodies or human antibodies. Examples include anti-BTN1A1 antibodies and anti-glycosylated BTN1A1 antibodies. , or anti-BTN1A1 dimer antibody, camelized antibody, intrabody, anti-idiotype (anti-Id) It can also be an antibody. In some embodiments, it is an anti-BTN1A1 antibody, anti-glycosylated BTN1A1 antibodies, or anti-BTN1A1 dimer antibodies, are either polyclonal or monoclonal antibodies. It is possible. In some embodiments, the molecule is STC703 or STC810. In some embodiments, the molecule is not STC810. The molecule is the VH domain of the monoclonal antibody STC810 ​​as described in Tables 3a and 3b. , including VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 It does not contain an antigen-binding domain.

[0147] Antibodies can be produced from any animal source, including birds and mammals. In this embodiment, the antibody is derived from sheep, mice (e.g., rats and rat), rabbits, and y It is of a ghi, guinea pig, camel, horse, or chicken. Furthermore, newer technologies Development and screening of human antibodies derived from human combinatorial antibody libraries. This makes it possible. For example, bacteriophage antibody expression technology is fully described herein by reference. As described in U.S. Patent No. 6,946,546, the specific antibody incorporated within is an animal antibody These techniques enable production in the absence of disease. (Marks, 1992; Stemm) See the literature by er (1994); Gram et al. (1992); Barbas et al. (1994); and Schier et al. (1996) ) is further described therein; these references are fully incorporated herein by reference. .

[0148] Methods for producing polyclonal antibodies in various animal species, as well as humanized, chimeric, and complete Methods for producing various types of monoclonal antibodies, including human antibodies, are well known in this field. For example, the following U.S. patent provides a feasible description of such a method, and is cited. Incorporated herein by: U.S. Patent Nos. 3,817,837; 3,850,752; 3,939,350 ;No. 3,996,345;No. 4,196,265;No. 4,275,149;No. 4,277,437;No. 4,366,241;No. 4,469,7 No. 97; No. 4,472,509; No. 4,606,855; No. 4,703,003; No. 4,742,159; No. 4,767,720; No. 4,8 No. 16,567; No. 4,867,973; No. 4,938,948; No. 4,946,778; No. 5,021,236; No. 5,164,296; No. 5,196,066; No. 5,223,409; No. 5,403,484; No. 5,420,253; No. 5,565,332; No. 5,571,69 No. 8; No. 5,627,052; No. 5,656,434; No. 5,770,376; No. 5,789,208; No. 5,821,337; No. 5,84 No. 4,091; No. 5,858,657; No. 5,861,155; No. 5,871,907; No. 5,969,108; No. 6,054,297; No. No. 6,165,464; No. 6,365,157; ​​No. 6,406,867; No. 6,709,659; No. 6,709,873; No. 6,753,407 No. 6,814,965; No. 6,849,259; No. 6,861,572; No. 6,875,434; No. 6,891,024; No. 7,407 No. 659; and No. 8,178,098 (These documents are fully incorporated herein by reference) (ru).

[0149] Anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody or anti-BTN1A1 dimer antibody (e.g., STC703) Alternatively, it may contain STC810, which binds immunospecifically to BTN1A1 or glycosylated BTN1A1. Molecules having antigen-binding fragments that bind heteromorphically or specifically to the BTN1A1 dimer are, Any method known in the art that is useful for the production of lipeptides, for example, in vitro synthesis, compounding Humanized antibodies can also be produced by methods such as recombinant DNA production. Antibodies described herein can be produced using recombinant immunoglobulin expression technology. It can also be produced using [a specific method]. Recombinant production of immunoglobulin molecules, including humanized antibodies, is being carried out in the United States. Japanese Patent No. 4,816,397 (Boss et al.), U.S. Patent Nos. 6,331,415 and 4,816,567 (both Cabinet). (against lly et al.), British Patent GB 2,188,638 (Winter et al.), and British Patent GB 2,209,757 These documents are listed in issue number; these documents are fully incorporated herein by reference. Techniques for recombinant expression of immunoglobulins, including tethered immunoglobulins, are described in the text by Goeddel et al. Presentation, Gene Expression Technology, Methods in Enzymology gy), Vol. 185, Academic Press (1991), and Borreback's literature, Antibody Engineering (An This can also be found in tibody engineering, WH Freeman (1992); these documents are cited. This is fully incorporated herein by reference to the production, design, and expression of recombinant antibodies. Further information can be found in Mayforth's literature, *Designing Antibodies*, Academic Press. This can be found in San Diego (1993).

[0150] In one embodiment, an anti-BTN1A1 antibody, an anti-glycosylated BTN1A1 antibody, or an anti-BTN1A1 dimer may be present. Somatic antibodies are human antibodies. Human antibodies are antibody libraries derived from human immunoglobulin sequences. Various methods known in the art, including the phage display method described above using - It can be manufactured by (U.S. Patent Nos. 4,444,887 and 4,716,111; and International Publication No. 9) Issues 8 / 46645, WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 337 (See Issue 35 and WO 91 / 10741). Human antibodies express functional endogenous immunoglobulins. Although it is not possible to express human immunoglobulin genes, transgenic individuals can express human immunoglobulin genes. It can be produced using a mouse. For example, human heavy chain and light chain immunoglobulins Genetic complexes can be introduced into mouse embryonic stem cells randomly or by homologous recombination. Alternatively, in addition to human heavy and light chain genes, human variable regions, constant regions, and diversity regions. The region can be introduced into mouse embryonic stem cells. Mouse heavy chain and light chain immunoglobulin gene The offspring can be individually or simultaneously subjected to the introduction of human immunoglobulin gene loci by homologous recombination. This can be prevented. In particular, homozygous deletions in the JH region can prevent endogenous antibody production. To hinder. To proliferate modified embryonic stem cells and microinject them into blastocysts to produce chimeric mice. Then, the chimeric mice are crossbred to produce homozygous offspring that express human antibodies. To do so, transgenic mice are subjected to a selected antigen using conventional methods, for example, BTN1A1 polypeptide or glycosylated BTN1A1 polypeptide or BTN1A1 polypeptide dimer Immunizing with all or part of the antigen. Monoclonal antibodies against the antigen are conventional hybrids. Using this technology, it can be obtained from immunized transgenic mice (for example, (See U.S. Patent No. 5,916,771). This transgenic mouse possesses human immunoglobulins. Phosphorus transgenes are rearranged during B cell differentiation, followed by class switching and somatic cell differentiation. It undergoes mutation. Therefore, using such techniques, therapeutically useful IgG, IgA, IgM It can produce, and IgE antibodies. This outlines the technology for producing human antibodies. Furthermore, the literature by Lonberg and Huszar (1995, fully incorporated herein by reference) See Int. Rev. Immunol. 13:65-93). Human antibodies and human monoclonal antibodies This will be a detailed discussion of the technology for producing such antibodies and the protocols for producing them. For example, see International Publication WO 98 / 24893, W, which is fully incorporated herein by reference. O 96 / 34096 and WO 96 / 33735; and U.S. Patents 5,413,923, 5,625,126, 5, Nos. 633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,9 See issue 39,598. Furthermore, see Abgenix (Freemont, Calif.) and Medarex (Princeton) Companies such as , NJ) are using technologies similar to the above to develop human antigens for selected antigens. They can be contracted to provide antibodies.

[0151] In some embodiments, an anti-BTN1A1 antibody or an anti-glycosylated BTN1A1 antibody or an anti-BTN1 A1 dimer antibodies are chimeric antibodies, for example, non-human antibodies with heterogeneous antigen-binding sequences derived from non-human donors. , transplanted into human or humanized sequences (e.g., framework and / or constant domain sequences) This is an antibody. In one embodiment, the non-human donor is a rat. In this case, the antigen-binding sequence is synthesized, for example, mutagenesis (for example, human f Obtained by methods such as phage display screening of a phage library. In this embodiment, the chimeric antibody may have a mouse V region and a human C region. In one embodiment, the mouse light chain V region is fused to the human κ light chain. The mouse heavy chain V region is fused to the human IgG1 C region.

[0152] Methods for producing chimeric antibodies are well known in the art. For example, Morrison's literature, 1985. Science 229:1202; Oi et al., 1986; BioTechniques 4:214; Gillies et al., 1989 , J. Immunol. Methods 125:191-202; and U.S. Patent Nos. 6,311,415, 5,807,715, and See issues 4,816,567 and 4,816,397; all of these documents are cited in full. This is incorporated herein by reference. One or more CDRs and human immunoglobulin molecules of non-human species Chimeric antibodies containing the framework region are, for example, CDR-grafted (EP 239,400 International Publication No. WO 91 / 09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,0 (No. 89), veneering or resurfacing (EP Nos. 592, 106; EP Nos. 519, 596; Padlan's references) 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka et al., 1994, Protein E Engineering 7:805; and Roguska et al., 1994, Proc. Natl. Acad. Sci. USA 91:969), and various techniques known in the art, including chain shuffling (US Patent No. 5,565,332). It can be produced using the method; all of these documents are fully incorporated herein by reference. To be absorbed.

[0153] An exemplary process for producing recombinant chimeric anti-BTN1A1 antibody is as follows: a) Conventional By molecular biological methods, mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) The CDR and variable region of the monoclonal antibody are fused to the Fc region derived from human immunoglobulin. We construct an expression vector that encodes an antibody heavy chain and expresses it, thereby creating a chimeric antibody b) producing a vector for expressing the weight chain; b) using conventional molecular biology methods, mouse Antibody light chain of anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTN1A1 dimer) monoclonal antibody We encode a light chain, construct an expression vector that expresses it, and thereby express a chimeric antibody light chain. c) producing vectors for use; and c) expressing these vectors using conventional molecular biology methods. The cells are then transferred to host cells to produce transfected host cells for the expression of chimeric antibodies. d) Transferring to produce chimeric antibodies using conventional cell culture techniques This may include culturing the induced cells.

[0154] An exemplary process for producing recombinant humanized anti-BTN1A1 antibody is as follows: a) Conventional Molecular biological methods are required to maintain CDR and donor antibody binding specificity. The smallest part of the variable region framework is mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-B (TN1A1 dimer) Derived from non-human immunoglobulins such as monoclonal antibodies, the remaining part of the antibody The fraction encodes an antibody heavy chain derived from human immunoglobulin, and the expression vector expresses it. a) Construct and thereby produce a vector for the expression of humanized antibody heavy chains; b) Conventional molecules By biological methods, the variable required to maintain CDR and donor antibody binding specificity The smallest part of the region framework is mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTN1A (1) Derived from non-human immunoglobulins such as monoclonal antibodies, the remaining part of the antibody We encoded antibody light chains derived from human immunoglobulins and constructed expression vectors to express them. c) These expression vectors The actor is transferred to a host cell using conventional molecular biology methods, and then tracers for humanized antibody expression are used. to produce infected host cells; and d) to produce humanized antibodies, Conventional cell culture techniques may include culturing transfected cells. Cut.

[0155] In both exemplary methods, such expression vectors are cotransferred to host cells. These expression vectors can be activated and contain different selectable markers. While it is possible to do so, it is preferable that they be identical except for the sequences encoding the heavy chain and the light chain. This procedure results in equivalent expression of heavy chain polypeptides and light chain polypeptides. Alternatively, You can also use a single vector that encodes both heavy-chain polypeptides and light-chain polypeptides. The coding sequences of the heavy and light chains may include cDNA, genomic DNA, or both. The host cells used to express recombinant antibodies are Escherichia coli. Bacterial cells such as, or more preferably, eukaryotic cells (for example, Chinese hamster ovaries) It can be either CHO cells or HEK-293 cells. The choice of expression vector is important. It depends on the selection of chief cells and has the desired expression and regulatory characteristics in the selected host cells. You can choose from the following. Other cell lines that can be used include CHO-K1, NSO, Examples include, but are not limited to, PER.C6 (Crucell, Leiden, Netherlands). Furthermore, species-specific codon usage biases are accounted for by host cells in order to enhance protein expression. If you choose this option, you can optimize codon usage. For example, in the case of CHO cell expression, The DNA that codes for antibodies is found in the Mongolian golden rat (Cricetulus griseus) (Chinese ham). Star ovarian cells incorporate codons that are preferentially used by (this is the origin of star ovarian cells). This can be achieved. By utilizing codon optimization methods, it is possible to promote improved expression by desired host cells. (For example, the literature of Wohlgemuth, I. et al., Philos. Trans. R. Soc. Lond. B Bi) ol. Sci. 366(1580):2979-2986(2011); Jestin, JL et al., J. Mol. Evol. 69(5):4 52-457 (2009); Literature by Bollenbach, T. et al., Genome Res. 17(4):401-404 (2007); Kurland, CG et al., Prog. Nucleic Acid Res. Mol. Biol. 31:191-219(1984); Grosjean, H. See also Gene 18(3): 199-209(1982).

[0156] In some embodiments, an anti-BTN1A1 antibody, an anti-glycosylated BTN1A1 antibody, or an anti-BTN1 A1 dimer antibody can be a monoclonal antibody. In some embodiments, Anti-BTN1A1 antibodies, anti-glycosylated BTN1A1 antibodies, or anti-BTN1A1 dimer antibodies are polyclonal. It can be an antibody. BTN1A1 polypeptide, glycosylated BTN1A1 polypeptide, or To produce antibodies specific to the BTN1A1 dimer, animals are subjected to an antigen, such as the BTN1A1 polypeptide. Inoculation with ptido, glycosylated BTN1A1 polypeptide, or BTN1A1 dimer polypeptide This can be done. In many cases, the antigen is bound to or conjugated to another molecule, leading to an immune response. It enhances the immune response. The conjugate binds to the antigen used to induce an immune response in animals. It is any peptide, polypeptide, protein, or non-protein substance that is present. This is possible. Antibodies produced in animals in response to antigen inoculation are various individual antibody-producing B phosphorus They possess various non-identical molecules (polyclonal antibodies) produced from Pacocytes. Considering the precise conditions for ronal antibody production, most of the antibodies in animal serum are Animals recognize collective epitopes on antigenic compounds to which they have been immunized.

[0157] This specificity is further enhanced by affinity purification, allowing recognition of the target antigen or epitope. Only the antibodies that are needed can be selected. The method for producing monoclonal antibodies (MAbs) is... It can be started in the same way as the method for preparing a licronal antibody. Several embodiments In this process, rodents such as mice and rats are used in the production of monoclonal antibodies. In some embodiments, rabbit, sheep, or frog cells are subjected to monoclonal antibodies. It is used in the production of [product name]. The use of rats is well known and can offer certain advantages. Mice (e.g., BALB / c mice) are routinely used, and typically a high percentage of stable fusions are produced. This will result in...

[0158] Hybridoma technology is BTN1A1 polypeptide or glycosylated BTN1A1 polypeptide or Single B lymphocytes from mice already immunized with BTN1A1 dimer polypeptide and immortal myeloma This involves fusion with cells (usually mouse myeloma cells). This technique uses the same antigen or epitope specificity. It is possible to produce an unlimited amount of structurally identical antibodies (monoclonal antibodies) that possess the following properties: Thus, it provides a method for growing a single antibody-producing cell over an infinite number of generations.

[0159] In one embodiment, the antibody is derived from a camelid antibody lacking a light chain, preferably This is a single variable domain of immunoglobulin derived from heavy chain camelid animal antibodies, and it is, V H H domain sequence or known as Nanobodies®. Nanobody® (Nb) is a natural The smallest functional fragment or single variable domain (V) of a naturally existing single-chain antibody. H H) is public to those skilled in the art. This is knowledge. These are derived from heavy-chain-only antibodies found in camelids (Hamers-Caster). Man et al., Nature, 363(6428):446-8(1993); Desmyter et al., Nat Struct Biol., 3(9):803-11.(1996)). In the family Camelidae, immunological factors lacking light polypeptide chains Globulins can be seen. "Camellidae" includes Old World camelids (Bactrian camel (Ca (Melus bactrianus) and dromedarius (Camelus dromedarius) and New World camelids Things (for example, alpaca (Lama paccos), llama (Lama glama), guanaco (Lama guanicoe), This includes vicuña (Lama vicugna). Single variable domain heavy chain antibodies are described herein. In this regard, Nanobody (trademark) or V H It is represented as an H antibody. Nb has a small size and unique biophysics. The characteristics include the recognition of uncommon or hidden epitopes and the cavity of protein targets. Alternatively, it surpasses conventional antibody fragments in terms of binding to the active site. Furthermore, Nb exhibits multiple specificity. It can be designed as a sex and multivalent antibody, conjugated to a reporter molecule, or humanized. Nb is stable, remains present in the gastrointestinal system, and can be easily manufactured.

[0160] When two antigen-binding sites with different specificities are combined into a single construct, two Heavily specific antibodies can combine two separate antigens with excellent specificity into one, Therefore, it has great potential as a therapeutic agent. Bispecific antibodies each have different immunological properties. It is created by fusing two hybridomas that can produce robulin. This is possible. A bispecific antibody connects two scFv antibody fragments while simultaneously performing complete immunoassay. It can also be produced by removing the Fc portion present in robulin. Each scFv unit in the construct is linked to one another by a synthetic polypeptide linker. It can be composed of one variable domain derived from each of the heavy (VH) and light (VL) antibody chains. The latter minimizes immunogenicity while maximizing resistance to proteolysis. They are often genetically modified in this way. Each scFv unit, two scFv units This includes the incorporation of short (usually less than 10 amino acids) polypeptide spacers for crosslinking, and several others. This technique allows for the connection of multiple molecules, thereby generating bispecific single-chain antibodies. Therefore, the resulting bispecific single-chain antibody has different specificities on a single polypeptide chain. This species contains two VH / VL pairs, where the VH domain and VL domain in each scFv unit. The main thing is a peptide long enough to allow intramolecular association between these two domains. The scFv units, separated by a drinker and formed in this way, are, for example, one To prevent undesirable associations between the VH domain of one scFv unit and the VL domain of the other scFv unit. They are connected to each other in close proximity by polypeptide spacers that are kept sufficiently short.

[0161] Antigen-binding fragments that immunospecifically bind to BTN1A1, glycosylated BTN1A1, or BTN1A1 dimers. Examples of molecules having: (i) Fab fragments consisting of VL, VH, CL, and CH1 domains; (ii) VH and (iii) A fragment of "Fd" consisting of the CH1 domain; (iii) A fragment of "Fv" consisting of the VL and VH domains of a single antibody. (iv) A "dAb" fragment consisting of a VH domain; (v) An isolated CDR region; (vi) Two ligated F The F(ab')2 fragment is a bivalent fragment containing the ab fragment; (vii) The VH domain and VL domain are these two A peptide linker enables the association of the domains to form a binding domain. The linked single-chain Fv molecules ("scFv"); (viii) double-specific single-chain Fv dimers (USA See numbers 5,091,513); and (ix) multivalent or multispecific fragments constructed by gene fusion. One example is the diamond body (U.S. Patent Application Publication No. 20050214860), but it is not limited to these. It is not done. Fv, scFv, or diabody molecules have a distension that links the VH domain and the VL domain. It can be stabilized by incorporating a rufid bridge. scFv connects to the CH3 domain. It is also possible to create miniature bodies (Hu et al., Cancer Res., 56(13):3055-61(199) 6)).

[0162] Antibody-like conjugated peptide mimetics are also intended in this embodiment. (See Murali et al.) Cell Mol. Biol., 49(2):209-216(2003) states that it acts as a lightly armored antibody and has a longer blood flow "Anti" peptides have specific advantages such as a long half-life and a relatively simple synthesis method. Body-like conjugated peptide mimetics (ABiPs) are described, and this document is cited by It is fully incorporated herein.

[0163] (5.2.2. Anti-BTN1A1 antibody) Cloning of 68 mouse monoclonal antibodies that immune-specifically bind to human BTN1A1. And it was characterized (Example 8; see Table 10 below). Furthermore, it was immunospecifically bound to mouse BTN1A1. Three types of mouse monoclonal antibodies were cloned and characterized (see Example 14). STC It was found that 703 and STC820 preferentially bind to the BTN1A1 dimer rather than the BTN1A1 monomer. K between STC810 ​​and hBTN1A1-Fc (dimer) D According to Biacore, it was determined to be 0.92 nM, and STC K between 810 and hBTN1A1-His (monomer) D (According to Biacore, this was determined to be 12.4 nM). ST Antibodies designated as C703, STC810, and STC820 exhibit high affinity for glycosylation-specific binding. This was shown (see, for example, Figures 21A-F and Figure 23). Treatment with monoclonal anti-BTN1A1 antibody It enhances T cell-dependent apoptosis in cancer cells, inhibits cancer cell proliferation, and activates CD8+ T cells. This led to pharmacokinetics and glycosylation-dependent internalization of BTN1A1 into lysosomes. However, This means that the anti-BTN1A1 antibody has specific sequence characteristics and binds immunospecifically to a specific epitope. Anti-BTN1A1 antibodies and their use in cancer treatment are also provided herein.

[0164] In some embodiments, the anti-BTN1A1 antibodies provided herein are described herein. The monoclonal antibodies STC703, STC810, STC1011, STC1012, STC1029, STC2602, STC2 714, STC2739, STC2778, or STC2781, or the VH domain of these humanized variants, VL Includes domains, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. In one embodiment, the anti-BTN1A1 antibody is a human germline immunoglobulin amino acid sequence or The variants are VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or V L FR4 may be further included. In some embodiments, the anti-BTN1A1 antibody is shown in Table 3. The VH domain, VL domain, and V of the monoclonal antibody STC810 ​​as described in a and 3b. Does not include H CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3.

[0165] In some embodiments, the anti-BTN1A1 antibody contains fewer than six CDRs. In this embodiment, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL It includes one, two, three, four, or five CDRs selected from the group consisting of CDR3. These consist of. In a specific embodiment, the antibody is a monoclonal antibody as described herein. Naru antibodies STC703, STC810, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, ST C2778, or STC2781, or their humanized variants VH CDR1, VH CDR2, VH CDR3, VL One, two, three, or four selected from the group consisting of CDR1, VL CDR2, and / or VL CDR3, if The antibody contains or consists of five CDRs. In a specific embodiment, the antibody is human Germline immunoglobulin amino acid sequences or their variants VH FR1, VH FR2, VH FR3, VH FR4 , further including VL FR1, VL FR2, VL FR3, and / or VL FR4.

[0166] In some embodiments, the antibody is a humanized antibody, a monoclonal antibody, or a recombinant antibody. The body, antigen-binding fragment, or any combination thereof. In some embodiments, The antibody is a humanized monoclonal antibody or its antigen-binding fragment.

[0167] Some embodiments provided herein include (i) provided herein Anti-BTN1A1 antibodies can help BTN1A1 polypeptides (e.g., BTN expressed on the cell surface or soluble BTN) 1A1), binding to the BTN1A1 fragment, or the BTN1A1 epitope (for example, in a dose-dependent manner) (ii) competitively block and / or (ii) an anti-BTN1A1 antibody provided herein (e.g., humanized A humanized antibody that binds to the BTN1A1 epitope, which is conjugated by an anti-BTN1A1 antibody. It is a body. In some embodiments, the antibody is a monoclonal as described herein. Antibodies STC703, STC810, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2 778, or STC2781, or their humanized variants are BTN1A1 polypeptides (e.g., cells) Binding to surface-expressed or soluble BTN1A1, BTN1A1 fragments, or BTN1A1 epitopes. In other embodiments, the inhibitor The body is the monoclonal antibody BTN1A1 described herein or its humanized variant (e.g., It binds to (e.g., recognizes) the BTN1A1 epitope, which is then conjugated by a humanized anti-BTN1A1 antibody. do. Table 2a: Heavy chain variable (VH) and light chain variable (VL) regions of mouse monoclonal anti-human BTN1A1 antibody STC703 ) array of regions [Table 2] Table 2b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC703 [Table 3] Table 3a: Heavy chain variable (VH) and light chain variable (VL) regions of mouse monoclonal anti-human BTN1A1 antibody STC810 ) array of regions [Table 4] Table 3b: CDR sequence of mouse monoclonal anti-human BTN1A1 antibody STC810 [Table 5] Table 4a: Heavy chain variable (VH) and light chain variable (VL) regions of mouse monoclonal anti-human BTN1A1 antibody STC820 ) array of regions [Table 6] Table 4b: CDR sequence of mouse monoclonal anti-human BTN1A1 antibody STC820 [Table 7] Table 5a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC1011 (VL) region array [Table 8] Table 5b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC1011 [Table 9] Table 6a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC1012 (VL) region array [Table 10] Table 6b: CDR sequence of mouse monoclonal anti-mouse BTN1A1 antibody STC1012 [Table 11] Table 7a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC1029 (VL) region array [Table 12] Table 7b: CDR sequence of mouse monoclonal anti-mouse BTN1A1 antibody STC1029 [Table 13] Table 8a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC2602 (VL) region array [Table 14] Table 8b: CDR sequence of mouse monoclonal anti-mouse BTN1A1 antibody STC2602 [Table 15] Table 9a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC2714 (VL) region array [Table 16] Table 9b: CDR sequence of mouse monoclonal anti-mouse BTN1A1 antibody STC2714 [Table 17] Table 10a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC2739 Array of variable (VL) regions [Table 18] Table 10b: CDR sequence of mouse monoclonal anti-mouse BTN1A1 antibody STC2739 [Table 19] Table 11a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC2778 Array of variable (VL) regions [Table 20] Table 11b: CDR sequence of mouse monoclonal anti-mouse BTN1A1 antibody STC2778 [Table 21] Table 12a: Heavy chain variable (VH) region and light chain variable region of mouse monoclonal anti-mouse BTN1A1 antibody STC2781 Array of variable (VL) regions [Table 22] Table 12b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2781 [Table 23]

[0168] Therefore, the following are provided in this specification: BTN1A1 or glycosylation having the following sequence characteristics It is a molecule having an antigen-binding fragment that binds immunospecifically to methylated BTN1A1. Several implementations In this specification, the molecules provided are (a)(1)SEQ ID NOs: 7, 10, 13, 16, 35, 38, 41 , or VH CDR1 having a 44-amino acid sequence; (2) SEQ ID NOs: 8, 11, 14, 17, 36, 39, 42, Alternatively, VH CDR2 having a 45-amino acid sequence; and (3) Sequence IDs 9, 12, 15, 18, 37, 40, 43 , or a heavy chain variable (VH) region containing VH CDR3 having a sequence of 46 amino acids; and / or (b) 1) VL CDR1 having the amino acid sequence of SEQ ID NOs. 19, 22, 25, 28, 47, 50, 53, or 56; (2 ) VL CDR2 having the amino acid sequence of SEQ ID NOs. 20, 23, 26, 29, 48, 51, 54, or 57; and (3) VL CDR3 having the amino acid sequence of SEQ ID NOs. 21, 24, 27, 30, 49, 52, 55, or 58 It has an antigen-binding fragment that has a light chain variable (VL) region containing :.

[0169] In some embodiments, provided herein are (a) (1) Sequence IDs 7, 10, 13 , VH CDR1 having amino acid sequences of 16, 35, 38, 41, or 44; (2) SEQ ID NOs: 8, 11, 14, 17, VH CDR2 having amino acid sequences of 36, 39, 42, or 45; and (3) SEQ ID NOs: 9, 12, 15, 18, 37 A heavy chain variable (VH) region containing VH CDR3 having an amino acid sequence of 40, 43, or 46; and (b)(1 ) VL CDR1 having the amino acid sequence of sequence numbers 19, 22, 25, 28, 47, 50, 53, or 56; (2) sequence VL CDR2 having amino acid sequences number 20, 23, 26, 29, 48, 51, 54, or 57; and (3) sequence Light chain containing VL CDR3 having amino acid sequences numbered 21, 24, 27, 30, 49, 52, 55, or 58. This antibody has a variable (VL) region. This antibody may be a monoclonal antibody. The antibody can be a humanized antibody.

[0170] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In this embodiment, the molecules provided herein are (a)(1)SEQ ID NOs. 63, 66, 69, or VH CDR1 having a 72-amino acid sequence; (2) Amino acid sequence of sequence numbers 64, 67, 70, or 73 (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 65, 68, 71, or 74; and VH CD R3: Heavy chain variable (VH) region including; and / or (b)(1) Ami of sequence numbers 75, 78, 81, or 84 VL CDR1 having an amino acid sequence; (2) V having the amino acid sequence of sequence numbers 76, 79, 82, or 85 (3) L CDR2; and VL CDR3 having the amino acid sequence of SEQ ID NOs. 77, 80, 83, or 86. It has an antigen-binding fragment that has a light chain variable (VL) region.

[0171] In some embodiments, provided herein are (a)(1) Sequence IDs 63, 66, 69 , or VH CDR1 having an amino acid sequence of 72; (2) amino acid sequence of SEQ ID NOs. 64, 67, 70, or 73 (3) VH CDR2 having a column; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 65, 68, 71, or 74. : Heavy chain variable (VH) region containing; and (b)(1) Having the amino acid sequence of SEQ ID NOs. 75, 78, 81, or 84 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 76, 79, 82, or 85; and (3) It has a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of sequence number 77, 80, 83, or 86. This antibody is a monoclonal antibody. This antibody is humanized. It can be an antibody.

[0172] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In this embodiment, the molecules provided herein are (a)(1)SEQ ID NOs: 91, 94, 97, 100, 119 VH CDR1 having amino acid sequences of 122, 125, 128, 147, 150, 153, or 156; (2) sequence Amino acid combinations numbered 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 VH CDR2 having a column; and (3) Sequence IDs 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, A heavy chain variable (VH) region containing a VH CDR3 having an amino acid sequence of 155 or 158; and / or (b)(1) Sequence numbers 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168 VL CDR1 having the amino acid sequence; (2) SEQ ID NOs: 104, 107, 110, 113, 132, 135, 138, 141 VL CDR2 having amino acid sequences of 160, 163, 166, or 169; and (3) SEQ ID NOs. 105, 10 It has an amino acid sequence of 8, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170. It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3.

[0173] In some embodiments, provided herein are (a) (1) Sequence IDs 91, 94, 97 VH CDR1 having amino acid sequences of 100, 119, 122, 125, 128, 147, 150, 153, or 156; ( 2) Amino acids of sequence numbers 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 VH CDR2 having the sequence; and (3) having the amino acid sequences of sequence numbers 93, 96, 99, 102, 121, and 12 The heavy chain variable (VH) region containing VH CDR3: (1) SEQ ID NOs: 103, 106, 109, 112, 131, 134, 137 VL CDR1 having amino acid sequences of 140, 159, 162, 165, or 168; (2) SEQ ID NOs: 104, 107, VL CDR having amino acid sequences of 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169 2; and (3) Sequence IDs 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 This antibody contains VL CDR3, which has the amino acid sequence of the following: This antibody is monoclonal. It can be an antibody. This antibody can be a humanized antibody.

[0174] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In this embodiment, the molecules provided herein include (a) (1) Sequence IDs 203, 206, 209, if (1) VH CDR1 having a 212-amino acid sequence; (2) SEQ ID NOs. 204, 207, 210, or 213 VH CDR2 having an anoacid sequence; and (3) amino acid sequences of SEQ ID NOs: 205, 208, 211, or 214 VH CDR3 having: heavy chain variable (VH) region; and / or (b)(1) Sequence IDs 215, 218, 221, Or VL CDR1 having an amino acid sequence of 224; (2) Sequence IDs 216, 219, 222, or 225 VL CDR2 having an amino acid sequence; and (3) amino acids of sequence numbers 217, 220, 223, or 226 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3 sequence.

[0175] In some embodiments, provided herein are (a) (1) Sequence IDs 203, 206, VH CDR1 having an amino acid sequence of 209 or 212; (2) SEQ ID NOs. 204, 207, 210, or 213 VH CDR2 having a amino acid sequence; and (3) the amino acid sequence of SEQ ID NOs: 205, 208, 211, or 214 (b)(1) Sequence IDs 215, 218, 221, or 224 VL CDR1 having the amino acid sequence; (2) the amino acid sequence of sequence numbers 216, 219, 222, or 225 (3) VL CDR2 having the amino acid sequence of SEQ ID NOs. 217, 220, 223, or 226; and VL CDR3 having the amino acid sequence of SEQ ID NOs. 217, 220, 223, or 226. This antibody has a light chain variable (VL) region containing :. This antibody is a monoclonal antibody. This is possible. The antibody can be a humanized antibody.

[0176] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 231, 234, 237, if (1) VH CDR1 having a 240-amino acid sequence; (2) SEQ ID NOs. 232, 235, 238, or 241 VH CDR2 having an anoacid sequence; and (3) the amino acid sequence of SEQ ID NOs: 233, 236, 239, or 242 VH CDR3 having: heavy chain variable (VH) region; and / or (b)(1) Sequence IDs 243, 246, 249, or VL CDR1 having a 252-amino acid sequence; (2) Sequence IDs 244, 247, 250, or 253 VL CDR2 having an amino acid sequence; and (3) amino acids of SEQ ID NOs. 245, 248, 251, or 254 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3 sequence.

[0177] In some embodiments, provided herein are (a) (1) Sequence IDs 231, 234, VH CDR1 having an amino acid sequence of 237 or 240; (2) SEQ ID NOs. 232, 235, 238, or 241 VH CDR2 having a amino acid sequence; and (3) the amino acid sequence of SEQ ID NOs: 233, 236, 239, or 242 (b)(1) Sequence IDs 243, 246, 249, or 252 VL CDR1 having the amino acid sequence; (2) the amino acid sequence of sequence numbers 244, 247, 250, or 253 (3) VL CDR2 having the amino acid sequence of SEQ ID NOs. 245, 248, 251, or 254; and VL CDR3 having the amino acid sequence of SEQ ID NOs. 245, 248, 251, or 254. This antibody has a light chain variable (VL) region containing :. This antibody is a monoclonal antibody. This is possible. The antibody can be a humanized antibody.

[0178] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In embodiments, the molecules provided herein include (a) (1) Sequence IDs 259, 262, 265, if (1) VH CDR1 having a 268-amino acid sequence; (2) SEQ ID NOs. 260, 263, 266, or 269 VH CDR2 having an anoacid sequence; and (3) the amino acid sequence of SEQ ID NOs: 261, 264, 267, or 270 VH CDR3 having: heavy chain variable (VH) region; and / or (b)(1) Sequence IDs 271, 274, 277, Or VL CDR1 having a 280-amino acid sequence; (2) Sequence IDs 272, 275, 278, or 281 VH CDR2 having an amino acid sequence; and (3) amino acids of sequence numbers 273, 276, 279, or 282 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3 sequence.

[0179] In some embodiments, provided herein are (a)(1) Sequence IDs 63, 66, 69 , or VH CDR1 having an amino acid sequence of 72; (2) amino acid sequence of SEQ ID NOs. 64, 67, 70, or 73 (3) VH CDR2 having a column; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 65, 68, 71, or 74. : Heavy chain variable (VH) region containing; and (b)(1) Having the amino acid sequence of SEQ ID NOs. 75, 78, 81, or 84 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 76, 79, 82, or 85; and (3) It has a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of sequence number 77, 80, 83, or 86. This antibody is a monoclonal antibody. This antibody is humanized. It can be an antibody.

[0180] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In embodiments, the molecules provided herein include (a) (1) Sequence IDs 287, 290, 293, if (1) VH CDR1 having a 296-amino acid sequence; (2) SEQ ID NOs. 288, 291, 294, or 297 VH CDR2 having an anoacid sequence; and (3) amino acid sequences of SEQ ID NOs: 289, 292, 295, or 298 VH CDR3 having: heavy chain variable (VH) region; and / or (b)(1) Sequence IDs 299, 302, 305, Alternatively, VL CDR1 having a 308-amino acid sequence; (2) Sequence IDs 300, 303, 306, or 309 VL CDR2 having an amino acid sequence; and (3) amino acids of SEQ ID NOs. 301, 304, 307, or 310 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3 sequence.

[0181] In some embodiments, provided herein are (a) (1) Sequence IDs 287, 290, VH CDR1 having an amino acid sequence of 293 or 296; (2) A sequence of 288, 291, 294, or 297 VH CDR2 having a amino acid sequence; and (3) the amino acid sequence of SEQ ID NOs: 289, 292, 295, or 298 (b)(1)Sequence IDs 299, 302, 305, or 308 VL CDR1 having the amino acid sequence; (2) the amino acid sequence of SEQ ID NOs: 300, 303, 306, or 309 (3) VL CDR2 having the amino acid sequence of SEQ ID NOs. 301, 304, 307, or 310; and VL CDR3 having the amino acid sequence of SEQ ID NOs. 301, 304, 307, or 310. This antibody has a light chain variable (VL) region containing :. This antibody is a monoclonal antibody. This is possible. The antibody can be a humanized antibody.

[0182] In another embodiment, the following are provided herein: BTN1A1 or G It is a molecule that has an antigen-binding fragment that binds immunospecifically to lycosylated BTN1A1. In embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 315, 318, 321, if (1) VH CDR1 having a 324-amino acid sequence; (2) SEQ ID NOs. 316, 319, 322, or 325 VH CDR2 having an anoacid sequence; and (3) the amino acid sequence of SEQ ID NOs: 317, 320, 323, or 326 VH CDR3 having: heavy chain variable (VH) region; and / or (b)(1) Sequence IDs 327, 330, 333, Alternatively, VL CDR1 having a 336-amino acid sequence; (2) SEQ ID NOs. 328, 331, 334, or 337 VL CDR2 having an amino acid sequence; and (3) amino acids of SEQ ID NOs. 329, 332, 335, or 338 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3 sequence.

[0183] Several embodiments are provided herein, (a) (1) Sequence IDs 315, 318, VH CDR1 having amino acid sequence 321 or 324; (2) A sequence number 316, 319, 322, or 325 VH CDR2 having a amino acid sequence; and (3) the amino acid sequence of SEQ ID NOs: 317, 320, 323, or 326 (b)(1)Sequence IDs 327, 330, 333, or 336 VL CDR1 having the amino acid sequence; (2) the amino acid sequence of sequence numbers 328, 331, 334, or 337 (3) VL CDR2 having the amino acid sequence of SEQ ID NOs. 329, 332, 335, or 338; and VL CDR3 having the amino acid sequence of SEQ ID NOs. 329, 332, 335, or 338. This antibody has a light chain variable (VL) region containing :. This antibody is a monoclonal antibody. This is possible. The antibody can be a humanized antibody.

[0184] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 7, 10, 13, VH CDR1 having amino acid sequences of 16, 35, 38, 41, or 44; (2) SEQ ID NOs: 8, 11, 14, 17 VH CDR2 having amino acid sequences of 36, 39, 42, or 45; and / or (3) SEQ ID NOs: 9, 12 Heavy chain variable (VH) CDR3 containing amino acid sequences of 15, 18, 37, 40, 43, or 46 It has an antigen-binding fragment having a region. In some embodiments, the heavy chain variable (VH) region (1) VH CDR1 having the amino acid sequence of SEQ ID NOs. 7, 10, 13, 16, 35, 38, 41, or 44; and (2) VH CDR2 having the amino acid sequence of SEQ ID NOs. 8, 11, 14, 17, 36, 39, 42, or 45 In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 7, 10, 13, 16, VH CDR1 having amino acid sequences of 35, 38, 41, or 44; and (3) SEQ ID NOs: 9, 12, 15, 18, 37 This includes VH CDR3 having an amino acid sequence of 40, 43, or 46. In some embodiments, The molecules provided herein are (2) the amines of SEQ ID NOs: 8, 11, 14, 17, 36, 39, 42, or 45. VH CDR2 having an anoic acid sequence; and (3) amino acids of SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, or 46. It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has an acid sequence.

[0185] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 63, 66, 69 , or VH CDR1 having an amino acid sequence of 72; (2) SEQ ID NOs. 64, 67, 70, or 73 VH CDR2 having a amino acid sequence; and / or (3) amino acid sequence of SEQ ID NOs. 65, 68, 71, or 74 It has an antigen-binding fragment having a heavy chain variable (VH) region containing a VH CDR3: with a column. In this embodiment, the heavy chain variable (VH) region is (1) the amino acid of SEQ ID NO: 63, 66, 69, or 72. (2) VH CDR1 having the sequence; and VH CD having the amino acid sequence of SEQ ID NOs. 64, 67, 70, or 73. Includes R2. In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 63, 66, 6 VH CDR1 having an amino acid sequence of 9 or 72; and (3) amino acids of SEQ ID NOs. 65, 68, 71, or 74 Contains VH CDR3 having an acid sequence. In some embodiments, the portion provided herein The offspring is (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 64, 67, 70, or 73; and (3) SEQ ID NO: Antibody having a heavy chain variable (VH) region containing VH CDR3: having an amino acid sequence of 65, 68, 71, or 74 It contains the original binding fragment.

[0186] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 91, 94, 97 VH CD having amino acid sequences of 100, 119, 122, 125, 128, 147, 150, 153, or 156 R1; (2) Sequence numbers 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 VH CDR2 having an amino acid sequence; and / or (3) SEQ ID NOs: 93, 96, 99, 102, 121, 124, 127, Heavy chain variable (VH) containing VH CDR3: having amino acid sequences of 130, 149, 152, 155, or 158 It has an antigen-binding fragment having a region. In some embodiments, the heavy chain variable (VH) region (1) The ami with sequence numbers 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156. VH CDR1 having an acid sequence; and (2) Sequence IDs 92, 95, 98, 101, 120, 123, 126, 129, 148 The VH CDR2 comprises having an amino acid sequence of 151, 154, or 157. In some embodiments, The heavy chain variable (VH) region is (1) Sequence IDs 91, 94, 97, 100, 119, 122, 125, 128, 147, 1 VH CDR1 having amino acid sequences of 50, 153, or 156; and (3) SEQ ID NOs: 93, 96, 99, 102, 12 It contains VH CDR3 having the amino acid sequence 1, 124, 127, 130, 149, 152, 155, or 158. In some embodiments, the molecules provided herein include (2) SEQ ID NOs: 92, 95, 98, 101 VH CDR2 having amino acid sequences of 120, 123, 126, 129, 148, 151, 154, or 157; and (3 ) Amino acid combination of sequence numbers 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158 It has an antigen-binding fragment having a heavy chain variable (VH) region containing a VH CDR3: column.

[0187] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 203, 206, 2 VH CDR1 having an amino acid sequence of 09 or 212; (2) SEQ ID NOs: 204, 207, 210, or 2 VH CDR2 having a 13-amino acid sequence; and / or (3) SEQ ID NOs. 205, 208, 211, or 214 It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has an amino acid sequence. In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 203, 206, 209, or VH CDR1 having a 212-amino acid sequence; and (2) amino acids of sequence numbers 204, 207, 210, or 213 It includes a VH CDR2 having a sequence. In some embodiments, the heavy chain variable (VH) region is (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 203, 206, 209, or 212; and (3) SEQ ID NO: 205, The VH CDR3 comprises an amino acid sequence of 208, 211, or 214. In some embodiments, The molecules provided herein (2) have the amino acid sequence of SEQ ID NOs. 204, 207, 210, or 213 (3) VH CDR2 having the amino acid sequence of SEQ ID NOs. 205, 208, 211, or 214; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 205, 208, 211, or 214. It has an antigen-binding fragment that has a heavy chain variable (VH) region containing :.

[0188] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 231, 234, 2 VH CDR1 having an amino acid sequence of 37 or 240; (2) SEQ ID NOs. 232, 235, 238, or 2 VH CDR2 having a 41-amino acid sequence; and / or (3) Sequence IDs 233, 236, 239, or 242 It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has an amino acid sequence. In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 231, 234, 237, or VH CDR1 having a 240-amino acid sequence; and (2) amino acids of sequence numbers 232, 235, 238, or 241 It includes a VH CDR2 having a sequence. In some embodiments, the heavy chain variable (VH) region is (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 231, 234, 237, or 240; and (3) SEQ ID NO: 233, The VH CDR3 comprises an amino acid sequence of 236, 239, or 242. In some embodiments, The molecules provided herein (2) have the amino acid sequence of SEQ ID NOs. 232, 235, 238, or 241 (3) VH CDR2 having the amino acid sequence of SEQ ID NOs. 233, 236, 239, or 242; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 233, 236, 239, or 242. It has an antigen-binding fragment that has a heavy chain variable (VH) region containing :.

[0189] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 259, 262, 2 VH CDR1 having an amino acid sequence of 65 or 268; (2) SEQ ID NOs. 260, 263, 266, or 2 VH CDR2 having a 69-amino acid sequence; and / or (3) SEQ ID NOs. 261, 264, 267, or 270 It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has an amino acid sequence. In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 259, 262, 265, or VH CDR1 having a 268-amino acid sequence; and (2) amino acids of sequence numbers 260, 263, 266, or 269 It includes a VH CDR2 having a sequence. In some embodiments, the heavy chain variable (VH) region is (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 259, 262, 265, or 268; and (3) SEQ ID NO: 261, The VH CDR3 comprises an amino acid sequence of 264, 267, or 270. In some embodiments, The molecules provided herein (2) have the amino acid sequence of SEQ ID NOs. 260, 263, 266, or 269 (3) VH CDR2 having the amino acid sequence of SEQ ID NOs. 261, 264, 267, or 270; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 261, 264, 267, or 270. It has an antigen-binding fragment that has a heavy chain variable (VH) region containing :.

[0190] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 287, 290, 2 VH CDR1 having an amino acid sequence of 93 or 296; (2) SEQ ID NOs. 288, 291, 294, or 2 VH CDR2 having a 97-amino acid sequence; and / or (3) Sequence IDs 289, 292, 295, or 298 It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has an amino acid sequence. In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 287, 290, 293, or VH CDR1 having a 296-amino acid sequence; and (2) amino acids of sequence numbers 288, 291, 294, or 297 It includes a VH CDR2 having a sequence. In some embodiments, the heavy chain variable (VH) region is (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 287, 290, 293, or 296; and (3) SEQ ID NO: 289, The present invention includes VH CDR3 having an amino acid sequence of 292, 295, or 298. In some embodiments, The molecules provided herein (2) have the amino acid sequence of SEQ ID NOs. 288, 291, 294, or 297 (3) VH CDR2 having the amino acid sequence of SEQ ID NOs. 289, 292, 295, or 298; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 289, 292, 295, or 298. It has an antigen-binding fragment that has a heavy chain variable (VH) region containing :.

[0191] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 315, 318, 3 VH CDR1 having an amino acid sequence of 21 or 324; (2) SEQ ID NOs: 316, 319, 322, or 3 VH CDR2 having a 25-amino acid sequence; and / or (3) SEQ ID NOs. 317, 320, 323, or 326 It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has an amino acid sequence. In some embodiments, the heavy chain variable (VH) region is (1) Sequence IDs 315, 318, 321, or VH CDR1 having a 324-amino acid sequence; and (2) amino acids of sequence numbers 316, 319, 322, or 325 It includes a VH CDR2 having a sequence. In some embodiments, the heavy chain variable (VH) region is (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 315, 318, 321, or 324; and (3) SEQ ID NO: 317, The present invention includes VH CDR3 having an amino acid sequence of 320, 323, or 326. In some embodiments, The molecules provided herein (2) have the amino acid sequence of SEQ ID NOs. 316, 319, 322, or 325 (3) VH CDR2 having the amino acid sequence of SEQ ID NOs. 317, 320, 323, or 326; and VH CDR3 having the amino acid sequence of SEQ ID NOs. 317, 320, 323, or 326. It has an antigen-binding fragment that has a heavy chain variable (VH) region containing :.

[0192] In some embodiments, the molecules provided herein are SEQ ID NOs: 7, 10, 13, 16 , 35, 38, 41, 44, 63, 66, 69, 72, 91, 94, 97, 100, 119, 122, 125, 128, 147, 150 , 153, 156, 203, 206, 209, 212, 231, 234, 237, 240, 259, 262, 265, 268, 287, 290 Heavy chain variable (VH) containing VH CDR1 having amino acid sequences of 293, 296, 315, 318, 321, or 324 It has an antigen-binding fragment having a region. The VH CDR1 has the amino acid sequence of SEQ ID NO: 7 The VH CDR1 may have the amino acid sequence of SEQ ID NO: 10. R1 may have the amino acid sequence of SEQ ID NO: 13. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 16. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 35. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 38. The VH CDR1 It may have the amino acid sequence of SEQ ID NO: 41. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 44. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 63. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 66. The VH CDR1 is It may have the amino acid sequence of SEQ ID NO: 69. The VH CDR1 has the amino acid sequence of SEQ ID NO: 72. It may have an acid sequence. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 91. Yes, it is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 94. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 94. It may have the amino acid sequence of SEQ ID NO: 97. The VH CDR1 has the amino acid sequence of SEQ ID NO: 100. It may have a sequence. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 119. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 122. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 122. It may have the amino acid sequence of SEQ ID NO: 125. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 128. It may have an acid sequence. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 147. Yes, it is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 150. The VH CDR1 is It may have the amino acid sequence of SEQ ID NO: 153. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 156. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 203. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 206. The VH CDR1 It may have the amino acid sequence of SEQ ID NO: 209. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 212. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 231. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 234. The VH CDR 1 may have the amino acid sequence of SEQ ID NO: 237. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 240. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 259. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 262. The VH CDR 1 may have the amino acid sequence of SEQ ID NO: 265. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 268. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 287. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 290. The VH CDR 1 may have the amino acid sequence of SEQ ID NO: 293. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 296. It may have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO: 315. This is possible. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 318. The VH CDR 1 may have the amino acid sequence of SEQ ID NO: 321. The VH CDR1 may have the amino acid sequence of SEQ ID NO: 324. It may have a mino acid sequence.

[0193] In some embodiments, the molecules provided herein are SEQ ID NOs: 8, 11, 14, 17 , 36, 39, 42, 45, 64, 67, 70, 73, 92, 95, 98, 101, 120, 123, 126, 129, 148, 151 , 154, 157, 204, 207, 210, 213, 232, 235, 238, 241, 260, 263, 266, 269, 288, 291 Heavy chain variable (VH) containing VH CDR2 having amino acid sequences of 294, 297, 316, 319, 322, or 325 It has an antigen-binding fragment having a region. The VH CDR2 has the amino acid sequence of SEQ ID NO: 8 The VH CDR2 may have the amino acid sequence of SEQ ID NO: 11. R2 may have the amino acid sequence of SEQ ID NO: 14. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 17. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 36. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 39. The VH CDR2 It may have the amino acid sequence of SEQ ID NO: 42. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 45. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 64. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 67. The VH CDR2 is It may have the amino acid sequence of SEQ ID NO: 70. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 73. It may have an acid sequence. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 92. Yes, it is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 95. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 95. It may have the amino acid sequence of SEQ ID NO: 98. The VH CDR2 has the amino acid sequence of SEQ ID NO: 101. It may have a sequence. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 120. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 123. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 123. It may have the amino acid sequence of SEQ ID NO: 126. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 129. It may have an acid sequence. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 148. Yes, it is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 151. The VH CDR2 is It may have the amino acid sequence of SEQ ID NO: 154. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 157. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 204. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 207. The VH CDR2 It may have the amino acid sequence of SEQ ID NO: 210. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 213. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 232. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 235. The VH CDR 2 may have the amino acid sequence of SEQ ID NO: 238. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 241. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 260. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 263. The VH CDR 2 may have the amino acid sequence of SEQ ID NO: 266. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 269. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 288. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 291. The VH CDR 2 may have the amino acid sequence of SEQ ID NO: 294. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 297. It may have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 316. This is possible. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 319. The VH CDR 2 may have the amino acid sequence of SEQ ID NO: 322. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 325. It may have a mino acid sequence. In some embodiments, provided herein The molecules are sequence numbers 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, 74, 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, 158, 205, 208, 211, 214, 233, 236, 239, 242, It has an amino acid sequence of 261, 264, 267, 270, 289, 292, 295, 298, 317, 320, 323, or 326. VH CDR3 is included in the heavy-chain variable (V H The VH CDR3 has an antigen-binding fragment having a region. It may have the amino acid sequence of number 9. The VH CDR3 has the amino acid sequence of sequence number 12. It may have. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 15. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 20. The VH CDR3 may have the amino acid sequence of SEQ ID NO: It can have a sequence of 37 amino acids. The VH CDR3 has the amino acid sequence of SEQ ID NO: 40 This is possible. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 43. H CDR3 may have the amino acid sequence of SEQ ID NO: 46. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 65 It may have the amino acid sequence of the VH CDR3. The VH CDR3 has the amino acid sequence of SEQ ID NO: 68. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 71. CDR3 may have the amino acid sequence of SEQ ID NO: 74. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 93. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 96. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 99. R3 may have the amino acid sequence of SEQ ID NO: 102. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 121. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 124. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 127. DR3 may have the amino acid sequence of SEQ ID NO: 130. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 149. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 152. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 155. DR3 may have the amino acid sequence of SEQ ID NO: 158. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 205. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 208. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 211. DR3 may have the amino acid sequence of SEQ ID NO: 214. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 233. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 236. This is possible. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 239. The VH C DR3 may have the amino acid sequence of SEQ ID NO: 242. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 261. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 264. This is possible. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 267. The VH C DR3 may have the amino acid sequence of SEQ ID NO: 270. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 289. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 292. This is possible. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 295. The VH C DR3 may have the amino acid sequence of SEQ ID NO: 298. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 317. It may have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 320. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 323. DR3 may have the amino acid sequence of SEQ ID NO: 326.

[0194] In some embodiments, the molecule provided herein is (1) the amino acid of SEQ ID NO: 7 (2) VH CDR1 having the sequence; (3) VH CDR2 having the amino acid sequence of sequence number 8; and / or (4) sequence number It has an antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: which has the amino acid sequence of No. 9. do.

[0195] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 10. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 11; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence of column number 12. It has.

[0196] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 13. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 14; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence of column number 15. It has.

[0197] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 16. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 18. It has.

[0198] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 35. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 36; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 37. It has.

[0199] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 38. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 39; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 40. It has.

[0200] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 41. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 42; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 43. It has.

[0201] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 44. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 45; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 46. It has.

[0202] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 63. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 64; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 65. It has.

[0203] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 66. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 67; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 68. It has.

[0204] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 69. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 70; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 71. It has.

[0205] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 72. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 73; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 74. It has.

[0206] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 91. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 92; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 93. It has.

[0207] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 94. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 95; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 96. It has.

[0208] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 97. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 98; and / or (4) Antigen-binding fragment having a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 99. It has.

[0209] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 100. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 101; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 102. It has a piece.

[0210] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 119. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 120; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 121. It has a piece.

[0211] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 122. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 123; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 124. It has a piece.

[0212] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 125. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 126; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 127. It has a piece.

[0213] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 128. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 129; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 130. It has a piece.

[0214] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 147. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 148; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 149. It has a piece.

[0215] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 150. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 151; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 152. It has a piece.

[0216] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 153. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 154; and / or (4) Antigen binding cleavage containing a heavy chain variable (VH) region including VH CDR3: having the amino acid sequence at column number 155. It has a piece.

[0217] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 156. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 157; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 158. It has a piece.

[0218] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 203. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 204; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 205. It has a piece.

[0219] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 206. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 207; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 208. It has a piece.

[0220] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 209. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 210; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 211. It has a piece.

[0221] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 212. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 213; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 214. It has a piece.

[0222] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 231. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 232; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 233. It has a piece.

[0223] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 234. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 235; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 236. It has a piece.

[0224] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 237. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 238; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 239. It has a piece.

[0225] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 240. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 241; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 242 It has a piece.

[0226] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 259. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 260; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 261. It has a piece.

[0227] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 262. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 263; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 264. It has a piece.

[0228] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 265. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 266; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 267 It has a piece.

[0229] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 268. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 269; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 270. It has a piece.

[0230] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 287. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 288; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 289. It has a piece.

[0231] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 290. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 291; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 292. It has a piece.

[0232] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 293. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 294; and / or (4) Antigen binding cleavage containing a heavy chain variable (VH) region including VH CDR3: having the amino acid sequence at column number 295. It has a piece.

[0233] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 296. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 297; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 298. It has a piece.

[0234] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 315. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 316; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 317. It has a piece.

[0235] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 318. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 319; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 320. It has a piece.

[0236] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 321. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 322; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 323. It has a piece.

[0237] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 324. (2) VH CDR1 having an acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 325; and / or (4) Antigen binding cleavage with a heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence at column number 326. It has a piece.

[0238] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 3. The molecule has an antigen-binding fragment having a heavy chain variable (VH) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0239] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 31. The molecule has an antigen-binding fragment having a heavy chain variable (VH) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0240] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 59. The molecule has an antigen-binding fragment having a heavy chain variable (VH) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0241] In some embodiments, the molecules provided herein are amino acid sequences of SEQ ID NO: 87 The molecule has an antigen-binding fragment having a heavy chain variable (VH) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0242] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 115 It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0243] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 143 It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0244] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 199 It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0245] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 227 It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0246] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 255. It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0247] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 283. It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0248] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 311. It has an antigen-binding fragment having a heavy chain variable (VH) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be. In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NOs. 19, 22, 25, 28, 47, 50, 53, or 56; (2) VL CDR2 having the amino acid sequence of SEQ ID NOs. 20, 23, 26, 29, 48, 51, 54, or 57; and / or (3) VL C having the amino acid sequence of SEQ ID NOs. 21, 24, 27, 30, 49, 52, 55, or 58 It has an antigen-binding fragment that has a light chain variable (VL) region containing DR3.

[0249] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 75, 78, 81 , or VL CDR1 having an 84-amino acid sequence; (2) Sequence IDs 76, 79, 82, or 85 VL CDR2 having a amino acid sequence; and / or (3) amino acid sequence of SEQ ID NOs. 77, 80, 83, or 86 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has a column.

[0250] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 103, 106, 1 VL having the amino acid sequence 09, 112, 131, 134, 137, 140, 159, 162, 165, or 168 CDR1; (2) Sequence numbers 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 1 VL CDR2 having a 69-amino acid sequence; and / or (3) SEQ ID NOs: 105, 108, 111, 114, 133, 136 Light chain containing VL CDR3 having amino acid sequences of 139, 142, 161, 164, 167, or 170. It has an antigen-binding fragment that has a variable (VL) region.

[0251] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 215, 218, 2 VL CDR1 having an amino acid sequence of 21 or 224; (2) SEQ ID NOs. 216, 219, 222, or 2 VL CDR2 having a 25-amino acid sequence; and / or (3) SEQ ID NOs. 217, 220, 223, or 226 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence.

[0252] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 243, 246, 2 VL CDR1 having an amino acid sequence of 49 or 252; (2) SEQ ID NOs: 244, 247, 250, or 2 VL CDR2 having a 53-amino acid sequence; and / or (3) SEQ ID NOs. 245, 248, 251, or 254 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence.

[0253] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 271, 274, 2 VL CDR1 having an amino acid sequence of 77 or 280; (2) SEQ ID NOs: 272, 275, 278, or 2 VL CDR2 having an 81-amino acid sequence; and / or (3) SEQ ID NOs. 273, 276, 279, or 282 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence.

[0254] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 299, 302, 3 VL CDR1 having an amino acid sequence of 05 or 308; (2) SEQ ID NOs: 300, 303, 306, or 3 VL CDR2 having the amino acid sequence 09; and / or (3) SEQ ID NOs. 301, 304, 307, or 310 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence.

[0255] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 327, 330, 3 VL CDR1 having an amino acid sequence of 33 or 336; (2) SEQ ID NOs: 328, 331, 334, or 3 VL CDR2 having a 37-amino acid sequence; and / or (3) SEQ ID NOs. 329, 332, 335, or 338 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence.

[0256] In some embodiments, the molecules provided herein include (1) Sequence IDs 19, 22, and 25 VL CDR1 having amino acid sequences of 28, 47, 50, 53, or 56; and (2) SEQ ID NOs: 20, 23, 26 It has a light chain variable (VL) region containing VL CDR2: having an amino acid sequence of 29, 48, 51, 54, or 57. It has an antigen-binding fragment. In some embodiments, the molecules provided herein are (1) VL CDR1 having the amino acid sequence of SEQ ID NOs. 19, 22, 25, 28, 47, 50, 53, or 56; and (3) VL CDR3 having the amino acid sequence of SEQ ID NOs. 21, 24, 27, 30, 49, 52, 55, or 58: It has an antigen-binding fragment that includes a light chain variable (VL) region. In some embodiments, The molecules provided in the specification are (2) the amino acids of SEQ ID NOs: 20, 23, 26, 29, 48, 51, 54, or 57. VL CDR2 having an acid sequence; and (3) amino acids of SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, or 58. It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has an acid sequence.

[0257] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 75, 78, 81 , or VL CDR1 having an amino acid sequence of 84; and (2) amino acids of sequence numbers 76, 79, 82, or 85 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR2: which has an acid sequence. In that embodiment, the molecules provided herein are (1) SEQ ID NOs. 75, 78, 81, or 84 VL CDR1 having the amino acid sequence; and (3) the amino acid sequence of SEQ ID NOs. 77, 80, 83, or 86 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3. Several implementations In one embodiment, the molecules provided herein are (2) the amino acids of SEQ ID NOs: 76, 79, 82, or 85. VL CDR2 having an acid sequence; and (3) VL having the amino acid sequence of SEQ ID NOs. 77, 80, 83, or 86 It has an antigen-binding fragment containing a light chain variable (VL) region including CDR3.

[0258] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 103, 106, 1 VL CDR1 having the amino acid sequence 09, 112, 131, 134, 137, 140, 159, 162, 165, or 168 ; and (2) Sequence numbers 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 169 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR2: which has an amino acid sequence. In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 103, 106, 109 VL CDR1 having the amino acid sequence 112, 131, 134, 137, 140, 159, 162, 165, or 168; and (3) Sequence numbers 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence. In some embodiments, the molecules provided herein include (2) SEQ ID NOs: 104, 107, 110 VL CDR2 having the amino acid sequence 113, 132, 135, 138, 141, 160, 163, 166, or 169; and (3) Sequence numbers 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has an amino acid sequence.

[0259] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 215, 218, 2 VL CDR1 having an amino acid sequence of 21 or 224; and (2) Sequence IDs 216, 219, 222, or 225 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR2: which has an amino acid sequence. In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 215, 218, 221 VL CDR1 having an amino acid sequence of 224; and (3) SEQ ID NOs. 217, 220, 223, or 226 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has a minoic acid sequence. In some embodiments, the molecules provided herein include (2) Sequence IDs 216, 219, 222, or VL CDR2 having an amino acid sequence of 225; and (3) amino acids of sequence numbers 217, 220, 223, or 226. It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has a noacid sequence.

[0260] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 243, 246, 2 VL CDR1 having an amino acid sequence of 49 or 252; and (2) SEQ ID NOs. 244, 247, 250, or 253 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR2: which has an amino acid sequence. In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 243, 246, 249 , or VL CDR1 having an amino acid sequence of 252; and (3) SEQ ID NOs. 245, 248, 251, or 254 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has a minoic acid sequence. In some embodiments, the molecules provided herein include (2) SEQ ID NOs: 244, 247, 250, or VL CDR2 having an amino acid sequence of 253; and (3) SEQ ID NOs. 245, 248, 251, or 254 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has a noacid sequence.

[0261] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 271, 274, 2 VL CDR1 having an amino acid sequence of 77 or 280; and (2) SEQ ID NOs. 272, 275, 278, or 281 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR2: which has an amino acid sequence. In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 271, 274, 277 , or VL CDR1 having an amino acid sequence of 280; and (3) SEQ ID NOs. 273, 276, 279, or 282 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has a minoic acid sequence. In some embodiments, the molecules provided herein include (2) Sequence IDs 272, 275, 278, or VL CDR2 having an amino acid sequence of 281; and (3) amino acids of sequence numbers 273, 276, 279, or 282 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has a noacid sequence.

[0262] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 299, 302, 3 VL CDR1 having an amino acid sequence of 05 or 308; and (2) SEQ ID NOs: 300, 303, 306, or 309 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR2: which has an amino acid sequence. In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 299, 302, 305 , or VL CDR1 having an amino acid sequence of 308; and (3) SEQ ID NOs. 301, 304, 307, or 310 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has a minoic acid sequence. In some embodiments, the molecules provided herein include (2) SEQ ID NOs: 300, 303, 306, or VL CDR2 having an amino acid sequence of 309; and (3) the amino acids of SEQ ID NOs. 301, 304, 307, or 310. It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has a noacid sequence.

[0263] In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 327, 330, 3 VL CDR1 having an amino acid sequence of 33 or 336; and (2) SEQ ID NOs. 328, 331, 334, or 337 It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR2: which has an amino acid sequence. In some embodiments, the molecules provided herein include (1) SEQ ID NOs: 327, 330, 333 , or VL CDR1 having an amino acid sequence of 336; and (3) SEQ ID NOs. 329, 332, 335, or 338 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: which has a minoic acid sequence. In some embodiments, the molecules provided herein include (2) SEQ ID NOs: 328, 331, 334, or VL CDR2 having an amino acid sequence of 337; and (3) the amino acids of sequence numbers 329, 332, 335, or 338. It has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: which has a noacid sequence.

[0264] In some embodiments, the molecules provided herein are sequence numbers 19, 22, 25, and 28. , 47, 50, 53, 56, 75, 78, 81, 84, 103, 106, 109, 112, 131, 134, 137, 140, 159, 1 62, 165, 168, 215, 218, 221, 224, 243, 246, 249, 252, 271, 274, 277, 280, 299, 3 Light chain variable (VL CDR1) containing amino acid sequence 02, 305, 308, 327, 330, 333, or 336 V L It has an antigen-binding fragment having a region. The VL CDR1 has the amino acid sequence of SEQ ID NO: 19. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 22. CDR1 may have the amino acid sequence of SEQ ID NO: 25. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 28. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 47. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 50. R1 may have the amino acid sequence of SEQ ID NO: 53. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 56. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 75. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 78. The VL CDR1 It may have the amino acid sequence of SEQ ID NO: 81. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 84. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 103. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 106. The VL CDR1 It may have the amino acid sequence of SEQ ID NO: 109. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 112. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 131. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 134. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 137. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 140. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 159. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 162. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 165. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 168. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 215. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 218. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 221. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 224. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 243. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 246. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 249. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 252. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 271. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 274. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 277. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 280. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 215. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 218. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 221. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 224. It may have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 299. This is possible. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 302. The VL CDR 1 may have the amino acid sequence of SEQ ID NO: 305. The VL CDR1 may have the amino acid sequence of SEQ ID NO: 308. It may have a mino acid sequence.

[0265] In some embodiments, the molecules provided herein are SEQ ID NOs: 20, 23, 26, 29 ,48,51,54,57,76,79,82,85,104,107,110,113,132,135,138,141,160,1 63, 166, 169, 204, 207, 210, 213, 232, 235, 238, 241, 260, 263, 266, 269, 288, 2 Light chain variable (VL CDR2) containing amino acid sequences 91, 294, 297, 316, 319, 322, or 325 V L It has an antigen-binding fragment having a region. The VL CDR2 has the amino acid sequence of SEQ ID NO: 20. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 23. CDR2 may have the amino acid sequence of SEQ ID NO: 26. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 29. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 48. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 51. R2 may have the amino acid sequence of SEQ ID NO: 54. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 57. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 76. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 79. The VL CDR2 It may have the amino acid sequence of SEQ ID NO: 82. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 85. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 104. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 107. The VL CDR2 It may have the amino acid sequence of SEQ ID NO: 110. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 113. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 132. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 135. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 138. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 141. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 160. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 163. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 166. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 169. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 204. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 207. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 210. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 213. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 232. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 235. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 238. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 241. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 260. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 263. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 266. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 269. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 288. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 291. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 294. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 297. It may have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO: 316. This is possible. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 319. The VL CDR 2 may have the amino acid sequence of SEQ ID NO: 322. The VL CDR2 may have the amino acid sequence of SEQ ID NO: 325. It may have a mino acid sequence.

[0266] In some embodiments, the molecules provided herein are SEQ ID NOs: 21, 24, 27, 30 ,49,52,55,58,77,80,83,86,105,108,111,114,133,136,139,142,161,1 64, 167, 170, 217, 220, 223, or 226, 245, 248, 251, or 254, 273, 276, 279, or VL CD has an amino acid sequence of 282, 301, 304, 307, or 310, 329, 332, 335, or 338. It has an antigen-binding fragment having a light chain variable (VL) region containing R3. The VL CDR3 is the same as in SEQ ID NO: 21 It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 24. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 27. R3 may have the amino acid sequence of SEQ ID NO: 30. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 49. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 52. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 55. The VL CDR3 It may have the amino acid sequence of SEQ ID NO: 58. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 77. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 80. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 83. The VL CDR3 is It may have the amino acid sequence of SEQ ID NO: 86. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 105. It may have an acid sequence. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 108. Yes, it is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 111. The VL CDR3 is It may have the amino acid sequence of SEQ ID NO: 114. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 133. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 136. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 139. The VL CDR3 It may have the amino acid sequence of SEQ ID NO: 142. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 161. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 164. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 167. The VL CDR 3 may have the amino acid sequence of SEQ ID NO: 170. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 217. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 220. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 223. The VL CDR 3 may have the amino acid sequence of SEQ ID NO: 226. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 245. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 248. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 251. The VL CDR 3 may have the amino acid sequence of SEQ ID NO: 254. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 273. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 276. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 279. The VL CDR 3 may have the amino acid sequence of SEQ ID NO: 282. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 301. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 304. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 307. The VL CDR 3 may have the amino acid sequence of SEQ ID NO: 310. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 329. It may have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO: 332. This is possible. The VL CDR3 may have the amino acid sequence of SEQ ID NO: 335. The VL CDR 3 may have the amino acid sequence of SEQ ID NO: 338.

[0267] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 19. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 20; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence of column number 21 It has a piece.

[0268] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 22. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 23; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence of column number 24 It has a piece.

[0269] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 25. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence of column number 27 It has a piece.

[0270] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 28. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 29; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence of column number 30 It has a piece.

[0271] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 47. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 48; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 49 It has a piece.

[0272] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 50. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 51; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 52 It has a piece.

[0273] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 53. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 54; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at row number 55 It has a piece.

[0274] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 56. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 57; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 58 It has a piece.

[0275] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 75. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 76; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence of column number 77 It has a piece.

[0276] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 78. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 79; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence at column number 80 It has a piece.

[0277] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 81. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 82; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence of column number 83 It has a piece.

[0278] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 84. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 85; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence at column number 86 It has a piece.

[0279] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 103. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 104; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 105 It has a piece.

[0280] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 106. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 107; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 108 It has a piece.

[0281] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 109. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 110; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence number 111 It has a piece.

[0282] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 112. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 113; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence number 114 It has a piece.

[0283] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 131. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 132; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence number 133 It has a piece.

[0284] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 134. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 135; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 136 It has a piece.

[0285] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 137. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 138; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 139 It has a piece.

[0286] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 140. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 141; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 142 It has a piece.

[0287] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 159. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 160; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 161 It has a piece.

[0288] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 162. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 163; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 164 It has a piece.

[0289] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 165 (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 166; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 167 It has a piece.

[0290] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 168 (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 169; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 170 It has a piece.

[0291] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 215. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 216; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 217 It has a piece.

[0292] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 218. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 219; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 220 It has a piece.

[0293] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 221. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 222; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 223 It has a piece.

[0294] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 224. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 225; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 226 It has a piece.

[0295] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 243. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 244; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 245 It has a piece.

[0296] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 246. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 247; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 248 It has a piece.

[0297] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 249. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 250; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at sequence number 251 It has a piece.

[0298] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 252. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 253; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 254 It has a piece.

[0299] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 271. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 272; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 273 It has a piece.

[0300] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 274. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 275; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 276 It has a piece.

[0301] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 277. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 278; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 279 It has a piece.

[0302] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 280. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 281; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 282 It has a piece.

[0303] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 299. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 300; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence of column number 301 It has a piece.

[0304] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 302. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 303; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 304 It has a piece.

[0305] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 305. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 306; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence at column number 307 It has a piece.

[0306] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 308. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 309; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 having the amino acid sequence at column number 310 It has a piece.

[0307] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 327. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 328; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 329 It has a piece.

[0308] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 330. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 331; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 332 It has a piece.

[0309] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 333. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 334; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with the amino acid sequence at column number 335 It has a piece.

[0310] In some embodiments, the molecules provided herein are (1) the amino acid of SEQ ID NO: 336. (2) VL CDR1 having an acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 337; and / or (4) Antigen binding cleavage with a light chain variable (VL) region having a VL CDR3 with amino acid sequence at column number 338 It has a piece.

[0311]

[0312] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 5 The molecule has an antigen-binding fragment having a light chain variable (VL) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0313] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 33. The molecule has an antigen-binding fragment having a light chain variable (VL) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0314] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 61. The molecule has an antigen-binding fragment having a light chain variable (VL) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0315] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 89 The molecule has an antigen-binding fragment having a light chain variable (VL) region with columns. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It is possible.

[0316] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 117 It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0317] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 145 It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0318] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 201. It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0319] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 229. It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0320] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 257 It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0321] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 285. It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0322] In some embodiments, the molecule provided herein is the amino acid of SEQ ID NO: 313. It has an antigen-binding fragment having a light chain variable (VL) region with a sequence. The molecule is an antibody. This can be done. The antibody can be a monoclonal antibody. The antibody is a humanized antibody. It can be.

[0323] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 7, 10, 1 VH CDR1 having amino acid sequences of 3, 16, 35, 38, 41, or 44; (2) SEQ ID NOs: 8, 11, 14 VH CDR2 having amino acid sequences of 17, 36, 39, 42, or 45; and / or (3) SEQ ID NO: 9 Heavy chain variable containing VH CDR3 having amino acid sequences of 12, 15, 18, 37, 40, 43, or 46. (VH) region; and (b)(1) amino acid sequence of SEQ ID NOs: 19, 22, 25, 28, 47, 50, 53, or 56 VL CDR1 having a column; (2) amino acid sequence of SEQ ID NOs. 20, 23, 26, 29, 48, 51, 54, or 57 VL CDR2 having a column; and / or (3) sequence numbers 21, 24, 27, 30, 49, 52, 55, or 58 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: having a mino acid sequence. The molecule may be an antibody. The antibody may be a monoclonal antibody. The antibody may be a humanized antibody.

[0324] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 63, 66, VH CDR1 having an amino acid sequence of 69 or 72; (2) Sequence IDs 64, 67, 70, or 73 VH CDR2 having an amino acid sequence; and / or (3) amino acids of SEQ ID NOs. 65, 68, 71, or 74 A heavy chain variable (VH) region containing VH CDR2: having the sequence; and (b)(1) Sequence IDs 65, 68, 71, if (1) VL CDR1 having a sequence of 74 amino acids; (2) SEQ ID NOs. 65, 68, 71, or 74 amino acids VL CDR3 having the sequence; and / or (3) having the amino acid sequence of SEQ ID NOs. 77, 80, 83, or 86 The molecule has an antigen-binding fragment having a light chain variable (VL) region containing VL CDR3. It is possible. The antibody may be a monoclonal antibody. The antibody is human It can be a chemical antibody.

[0325] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 91, 94, VH having amino acid sequences of 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156 CDR1; (2) Sequence IDs 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 VH CDR2 having the amino acid sequence; and / or (3) SEQ ID NOs: 93, 96, 99, 102, 121, 124, 127 Heavy chain variable (VH) CDR3 containing amino acid sequences of 130, 149, 152, 155, or 158 ) domain; and (b)(1) Sequence IDs 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165 , or VL CDR1 having a 168-amino acid sequence; (2) SEQ ID NOs: 104, 107, 110, 113, 132, 1 VL CDR2 having amino acid sequences of 35, 138, 141, 160, 163, 166, or 169; and / or ( 3) Sequence numbers 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 It has an antigen-binding fragment having a light chain variable (VL) region containing a VL CDR3: having a mino acid sequence. The molecule may be an antibody. The antibody may be a monoclonal antibody. The antibody may be a humanized antibody.

[0326] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 203, 206 VH CDR1 having an amino acid sequence of 209 or 212; (2) Sequence IDs 204, 207, 210, or (3) VH CDR2 having a 213 amino acid sequence; and / or (3) SEQ ID NOs. 205, 208, 211, or 21 A heavy chain variable (VH) region containing VH CDR3 having an amino acid sequence of 4; and (b)(1)SEQ ID NO: 215, 2 VL CDR1 having amino acid sequences of 18, 221, or 224; (2) Sequence IDs 216, 219, 222, if (3) VL CDR2 having an amino acid sequence of 225; and / or (3) SEQ ID NOs. 217, 220, 223, or It has an antigen-binding fragment containing a light chain variable (VL) region that includes VL CDR3: having a 226-amino acid sequence. The molecule may be an antibody. The antibody may be a monoclonal antibody. Yes, it is possible. The antibody can be a humanized antibody.

[0327] In some embodiments, the molecules provided herein include (a)(1)SEQ ID NOs: 231, 234 VH CDR1 having an amino acid sequence of 237 or 240; (2) Sequence IDs 232, 235, 238, or (3) VH CDR2 having a 241 amino acid sequence; and / or (3) SEQ ID NOs. 233, 236, 239, or 24 A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 2; and (b)(1)SEQ ID NO: 243, 2 VL CDR1 having amino acid sequences of 46, 249, or 252; (2) Sequence IDs 244, 247, 250, if (3) VL CDR2 having a 253-amino acid sequence; and / or (3) SEQ ID NOs. 245, 248, 251, or It has an antigen-binding fragment containing a light chain variable (VL) region that includes VL CDR3: having a 254-amino acid sequence. The molecule may be an antibody. The antibody may be a monoclonal antibody. Yes, it is possible. The antibody can be a humanized antibody.

[0328] In some embodiments, the molecules provided herein include (a) (1) Sequence IDs 259, 262 VH CDR1 having an amino acid sequence of 265 or 268; (2) Sequence IDs 260, 263, 266, or (3) SEQ ID NOs: 261, 264, 267, or 27 A heavy chain variable (VH) region containing VH CDR3 having an amino acid sequence of 0; and (b)(1)SEQ ID NOs: 271, 2 VL CDR1 having amino acid sequences of 74, 277, or 280; (2) SEQ ID NOs. 272, 275, 278, if (3) VL CDR2 having an amino acid sequence of 281; and / or (3) SEQ ID NOs. 273, 276, 279, or It has an antigen-binding fragment containing a light chain variable (VL) region that includes VL CDR3: having a 282-amino acid sequence. The molecule may be an antibody. The antibody may be a monoclonal antibody. Yes, it is possible. The antibody can be a humanized antibody.

[0329] In some embodiments, the molecules provided herein include (a) (1) SEQ ID NOs: 287, 290 VH CDR1 having an amino acid sequence of 293 or 296; (2) Sequence IDs 288, 291, 294, or (3) VH CDR2 having a 297 amino acid sequence; and / or (3) SEQ ID NOs. 289, 292, 295, or 29 A heavy chain variable (VH) region containing VH CDR3 having an 8-amino acid sequence; and (b)(1)SEQ ID NOs: 299, 3 VL CDR1 having amino acid sequences 02, 305, or 308; (2) SEQ ID NOs: 300, 303, 306, if (3) VL CDR2 having a 309 amino acid sequence; and / or (3) SEQ ID NOs. 301, 304, 307, or It has an antigen-binding fragment containing a light chain variable (VL) region that includes VL CDR3: having a sequence of 310 amino acids. The molecule may be an antibody. The antibody may be a monoclonal antibody. Yes, it is possible. The antibody can be a humanized antibody.

[0330] In some embodiments, the molecules provided herein include (a)(1)SEQ ID NOs: 315, 318 VH CDR1 having an amino acid sequence of 321 or 324; (2) Sequence IDs 316, 319, 322, or (3) VH CDR2 having a 325 amino acid sequence; and / or (3) SEQ ID NOs: 317, 320, 323, or 32 A heavy chain variable (VH) region containing VH CDR3 having a sequence of 6 amino acids; and (b)(1)SEQ ID NO: 327, 3 VL CDR1 having amino acid sequences of 30, 333, or 336; (2) SEQ ID NOs. 328, 331, 334, if (3) VL CDR2 having an amino acid sequence of 337; and / or (3) SEQ ID NOs. 329, 332, 335, or It has an antigen-binding fragment containing a light chain variable (VL) region that includes VL CDR3: having a sequence of 338 amino acids. The molecule may be an antibody. The antibody may be a monoclonal antibody. Yes, it is possible. The antibody can be a humanized antibody.

[0331] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 7 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 8; and / or (4) A heavy chain variable (VH) region containing VH CDR3: having the amino acid sequence of column number 9; and (b)(1) Sequence ID VL CDR1 having the amino acid sequence of 19; (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 20; and / Or (3) an antibody having a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 21 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0332] In some embodiments, the molecules provided herein are (a) (1) the amine of SEQ ID NO: 10. (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 11; and / or (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 12; and (b)(1) sequence (2) VL CDR1 having amino acid sequence number 22; (2) VL CDR2 having amino acid sequence number 23; and / or (3) having a light chain variable (VL) region including VL CDR3: having the amino acid sequence of SEQ ID NO: 24 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monoclonal It can be a humanized antibody. This antibody can be a humanized antibody.

[0333] In some embodiments, the molecules provided herein are (a) (1) the amine of SEQ ID NO: 13. (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 14; and / or (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 15; and (b)(1) sequence (2) VL CDR1 having amino acid sequence number 25; (2) VL CDR2 having amino acid sequence number 26; and / or (3) having a light chain variable (VL) region including VL CDR3: having the amino acid sequence of SEQ ID NO: 27 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monoclonal It can be a humanized antibody. This antibody can be a humanized antibody.

[0334] In some embodiments, the molecules provided herein are (a) (1) the amine of SEQ ID NO: 16. (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 17; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 18; and (b)(1) SEQ ID NO: 28 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 29; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 30 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0335] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 35 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 36; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 37; and (b)(1) SEQ ID NO: 47 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 48; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 49 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0336] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 38 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 39; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 40; and (b)(1) SEQ ID NO: 50 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 51; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 52 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0337] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 41 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 42; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 43; and (b)(1) SEQ ID NO: 53 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 54; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 55 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0338] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 44 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 45; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 46; and (b)(1) SEQ ID NO: 56 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 57; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 58 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0339] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 63 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 64; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 65; and (b)(1) SEQ ID NO: 75 (2) VL CDR1 having the amino acid sequence of (1) SEQ ID NO: 76; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 77 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0340] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 66 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 67; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 68; and (b)(1) SEQ ID NO: 78 (2) VL CDR1 having the amino acid sequence of (1) SEQ ID NO: 79; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 80 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0341] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 69 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 70; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of number 71; and (b)(1) SEQ ID NO: 81 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 82; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 83 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0342] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 72 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 73; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of number 74; and (b)(1) SEQ ID NO: 84 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 85; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 86 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0343] In some embodiments, the molecules provided herein are (a)(1)Amyl of SEQ ID NO: 91 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 92; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 93; and (b)(1) SEQ ID NO: 103 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 104; and (3 Antigen binding with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 105 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0344] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 94 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 95; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 96; and (b)(1) SEQ ID NO: 106 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 107; and (3 Antigen binding with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 108 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0345] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 97 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 98; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 99; and (b)(1) SEQ ID NO: 109 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 110; and (3 ) Antigen binding with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 111 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0346] In some embodiments, the molecules provided herein are (a)(1) of SEQ ID NO: 100 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 101; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 102; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 112; (2) VL CDR2 having the amino acid sequence of sequence number 113; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 114 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0347] In some embodiments, the molecules provided herein are (a)(1) of SEQ ID NO: 1119 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 120; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 121; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 131; (2) VL CDR2 having the amino acid sequence of sequence number 132; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 133 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0348] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 122 (2) VH CDR1 having a amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 123; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 124; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 134; (2) VL CDR2 having the amino acid sequence of sequence number 135; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 136 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0349] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 125 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 126; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 127; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 137; (2) VL CDR2 having the amino acid sequence of sequence number 138; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 139 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0350] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 128 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 129; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 130; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 140; (2) VL CDR2 having the amino acid sequence of sequence number 141; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 142 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0351] In some embodiments, the molecules provided herein are (a)(1)Sequence ID 147 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 148; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 149; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 159; (2) VL CDR2 having the amino acid sequence of sequence number 160; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 161 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0352] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 150 (2) VH CDR1 having a amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 151; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 152; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 162; (2) VL CDR2 having the amino acid sequence of sequence number 163; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 164 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0353] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 153 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 154; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 155; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 165; (2) VL CDR2 having the amino acid sequence of sequence number 166; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 167 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0354] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 156 (2) VH CDR1 having a amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 157; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 158; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 168; (2) VL CDR2 having the amino acid sequence of sequence number 169; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 170 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0355] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 203 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 204; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 205; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 215; (2) VL CD having the amino acid sequence of sequence number 216 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 217 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0356] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 206 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 207; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 208; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 218; (2) VL CD having the amino acid sequence of sequence number 219 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 220 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0357] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 209 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 210; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 211; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 221; (2) VL CD having the amino acid sequence of sequence number 222 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 223 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0358] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 212 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 213; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 214; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 224; (2) VL CD having the amino acid sequence of sequence number 225 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 226 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0359] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 231 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 232; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 233; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 243; (2) VL CD having the amino acid sequence of sequence number 244 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 245 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0360] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 234 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 235; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 236; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 246; (2) VL CD having the amino acid sequence of sequence number 247 R2; and / or (3) a light chain variable (VL) region containing VL CDR3 having the amino acid sequence of SEQ ID NO: 248 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0361] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 237 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 238; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 239; and (b)(1) VL CDR1 having the amino acid sequence of sequence number 249; (2) VL CD having the amino acid sequence of sequence number 250 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 251 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0362] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 240 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 241; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 242; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 252; (2) VL CD having the amino acid sequence of sequence number 253 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 254 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0363] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 259 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 260; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 261; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 271; (2) VL CD having the amino acid sequence of sequence number 272 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 273 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0364] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 262 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 263; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 264; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 274; (2) VL CD having the amino acid sequence of sequence number 275 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 276 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0365] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 265 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 266; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 267; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 277; (2) VL CD having the amino acid sequence of sequence number 278 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 279 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0366] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 268 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 269; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 270; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 280; (2) VL CD having the amino acid sequence of sequence number 281 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 282 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0367] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 287 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 288; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 289; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 299; (2) VL CD having the amino acid sequence of sequence number 300 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 301 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0368] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 290 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 291; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 292; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 302; (2) VL CD having the amino acid sequence of sequence number 303 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 304 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0369] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 293 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 294; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 295; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 305; (2) VL CD having the amino acid sequence of sequence number 306 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 307 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0370] In some embodiments, the molecules provided herein are (a)(1)A of SEQ ID NO: 296 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 297; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 298; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 308; (2) VL CD having the amino acid sequence of sequence number 309 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 310 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0371] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 315 (2) VH CDR1 having a amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 316; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 317; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 327; (2) VL CD having the amino acid sequence of sequence number 328 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 329 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0372] In some embodiments, the molecules provided herein are (a)(1)SEQ ID NO: 318 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 319; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 320; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 330; (2) VL CD having the amino acid sequence of sequence number 331 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 332 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0373] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 321 (2) VH CDR1 having an amino acid sequence; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 322; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 323; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 333; (2) VL CD having the amino acid sequence of sequence number 334 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 335 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0374] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 324 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 325; and / or ( 3) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of SEQ ID NO: 326; and (b)(1) (2) VL CDR1 having the amino acid sequence of sequence number 336; (2) VL CD having the amino acid sequence of sequence number 337 R2; and / or (3) a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 338 It has an antigen-binding fragment. The molecule may be an antibody. The antibody is monochromatic. It can be a human antibody. The antibody can be a humanized antibody.

[0375] In some embodiments, the molecule provided herein is represented as mouse STC703. This refers to a monoclonal antibody or its humanized antibody version. The humanized STC703 antibody is described in this specification. The STC703 described in the document may have a VH region, a VL region, or both a VH region and a VL region. The humanized STC703 antibody contains six CDR regions of STC703 as described herein (VH CDR1, VH CDR 2. It may also contain VH CDR3, VL CDR1, VL CDR2, and VL CDR3. Humanized STC703 antibody It may also have fewer than six CDR areas of the STC703. In some embodiments, The t-modified STC703 antibody contains one, two, three, four, or five CDR regions (VH CDR1, VH CDR2) of STC703. It may also have VH CDR3, VL CDR1, VL CDR2, and VL CDR3.

[0376] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 7 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 8; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of number 9; and (b)(1) SEQ ID NO: 19 (2) VL CDR1 having an amino acid sequence; (3) VL CDR2 having the amino acid sequence of SEQ ID NO: 20; and (4) Antigen-binding fragment having a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of column number 21. It has. The molecule may be an antibody. The antibody may be a monoclonal antibody. This is possible. The antibody can be a humanized antibody.

[0377] In some embodiments, the molecules provided herein are (a) (1) the amine of SEQ ID NO: 10. (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 11; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 12; and (b)(1) SEQ ID NO: 22 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 23; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 24 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0378] In some embodiments, the molecules provided herein are (a) (1) the amine of SEQ ID NO: 13. (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 14; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 15; and (b)(1) SEQ ID NO: 25 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 26; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 27 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0379] In some embodiments, the molecules provided herein are (a) (1) the amine of SEQ ID NO: 16. (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 17; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 18; and (b)(1) SEQ ID NO: 28 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 29; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 30 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0380] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 3. An antigen-binding fragment having a VH region with a column and a VL region with the amino acid sequence of SEQ ID NO: 5 It possesses. The molecule may be an antibody. The antibody is a monoclonal antibody. This can be achieved. The antibody can be a humanized antibody.

[0381] In some embodiments, the molecule provided herein is represented as mouse STC810. This refers to a monoclonal antibody or its humanized antibody version. The humanized STC810 ​​antibody is described in this specification. The STC810 ​​described in the document may have a VH region, a VL region, or both a VH region and a VL region. The humanized STC810 ​​antibody contains six CDR regions of STC810 ​​as described herein (VH CDR1, VH CDR 2. It may also contain VH CDR3, VL CDR1, VL CDR2, and VL CDR3. Humanized STC810 ​​antibody It may also have fewer than six CDR areas of the STC810. In some embodiments, The t-modified STC810 ​​antibody contains one, two, three, four, or five CDR regions (VH CDR1, VH CDR2) of STC810. It may also have VH CDR3, VL CDR1, VL CDR2, and VL CDR3.

[0382] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 35 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 36; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 37; and (b)(1) SEQ ID NO: 47 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 48; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 49 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0383] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 38 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 39; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 40; and (b)(1) SEQ ID NO: 50 (2) VL CDR1 having the amino acid sequence of SEQ ID NO: 51; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 52 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0384] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 41 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 42; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 43; and (b)(1) SEQ ID NO: 53 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 54; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 55 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0385] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 44 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 45; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 46; and (b)(1) SEQ ID NO: 56 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 57; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 58 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0386] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 31. An antigen-binding fragment having a VH region with a column and a VL region with the amino acid sequence of SEQ ID NO: 35 It possesses. The molecule may be an antibody. The antibody is a monoclonal antibody. This can be achieved. The antibody can be a humanized antibody.

[0387] In some embodiments, the molecule provided herein is represented as mouse STC820. This refers to a monoclonal antibody or its humanized antibody version. The humanized STC820 antibody is described in this specification. The STC820 described in the document may have a VH region, a VL region, or both a VH region and a VL region. The humanized STC820 antibody contains six CDR regions of STC820 as described herein (VH CDR1, VH CDR 2. It may also contain VH CDR3, VL CDR1, VL CDR2, and VL CDR3. Humanized STC820 antibody It may also have fewer than six CDR areas of the STC820. In some embodiments, The t-modified STC820 antibody contains one, two, three, four, or five CDR regions (VH CDR1, VH CDR2) of STC820. It may also have VH CDR3, VL CDR1, VL CDR2, and VL CDR3.

[0388] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 63 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 64; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 65; and (b)(1) SEQ ID NO: 75 (2) VL CDR1 having the amino acid sequence of (1) SEQ ID NO: 76; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 77 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0389] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 66 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 67; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 68; and (b)(1) SEQ ID NO: 78 (2) VL CDR1 having the amino acid sequence of (1) SEQ ID NO: 79; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 80 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0390] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 69 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 70; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of number 71; and (b)(1) SEQ ID NO: 81 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 82; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 83 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0391] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 72 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 73; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of number 74; and (b)(1) SEQ ID NO: 84 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 85; and (3) Antigen binding cleavage with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 86 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0392] In some embodiments, the molecule provided herein is an amino acid compound of SEQ ID NO: 59. An antigen-binding fragment having a VH region with a column and a VL region with the amino acid sequence of SEQ ID NO: 61 It possesses. The molecule may be an antibody. The antibody is a monoclonal antibody. This can be achieved. The antibody can be a humanized antibody.

[0393] In some embodiments, the molecule provided herein is represented as STC1011. It is a smonoclonal antibody or its humanized antibody version. The humanized STC1011 antibody is this Having the VH region, VL region, or both the VH region and VL region of STC1011 as described in the specification. Humanized STC1011 antibody can be used to modify the six CDR regions (VH CDR1) of STC1011 as described herein. It may also have VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST The C1012 antibody may also have fewer than six CDR regions of STC1011. In some embodiments... In this context, the humanized STC1011 antibody contains one, two, three, four, or five CDR regions (VH CD) of STC1011. It may also have R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3.

[0394] In some embodiments, the molecules provided herein are (a)(1)Amyl of SEQ ID NO: 91 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 92; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 93; and (b)(1) SEQ ID NO: 103 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 104; and (3 Antigen binding with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 105 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0395] In some embodiments, the molecules provided herein are (a)(1)Amyl of Sequence ID No. 94 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO 95; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 96; and (b)(1) SEQ ID NO: 106 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 107; and (3 Antigen binding with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 108 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0396] In some embodiments, the molecules provided herein are (a) (1) ami of SEQ ID NO: 97 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of sequence number 98; and (4) sequence number A heavy chain variable (VH) region containing VH CDR3 having amino acid sequence 99; and (b)(1) SEQ ID NO: 109 (2) VL CDR1 having the amino acid sequence of (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 110; and (3 ) Antigen binding with a light chain variable (VL) region containing VL CDR3: having the amino acid sequence of SEQ ID NO: 111 It has a fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. This is possible. The antibody may be a humanized antibody.

[0397] In some embodiments, the molecules provided herein are (a)(1) of SEQ ID NO: 100 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 101; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 102; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 112; (2) VL CDR2 having the amino acid sequence of sequence number 113; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 114 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0398] In some embodiments, the molecules provided herein are amino acid sequences of SEQ ID NO: 87 An antigen-binding fragment having a VH region with a column and a VL region with the amino acid sequence of SEQ ID NO: 89 It possesses. The molecule may be an antibody. The antibody is a monoclonal antibody. This can be achieved. The antibody can be a humanized antibody.

[0399] In some embodiments, the molecule provided herein is represented as STC1012. It is a monoclonal antibody or its humanized antibody version. The humanized STC1012 antibody is this Having the VH region, VL region, or both the VH region and VL region of STC1012 as described in the specification. Humanized STC1012 antibody can be used to modify the six CDR regions of STC1012 described herein (VH CDR1 It may also have VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST The C1012 antibody may also have fewer than six CDR regions of STC1012. In some embodiments... In this context, the humanized STC1012 antibody contains one, two, three, four, or five CDR regions (VH CD) of STC1012. It may also have R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3.

[0400] In some embodiments, the molecules provided herein are (a)(1)SEQ ID NO: 119 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 120; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 121; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 131; (2) VL CDR2 having the amino acid sequence of sequence number 132; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 133 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0401] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 122 (2) VH CDR1 having a amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 123; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 124; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 134; (2) VL CDR2 having the amino acid sequence of sequence number 135; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 136 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0402] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 125 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 126; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 127; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 137; (2) VL CDR2 having the amino acid sequence of sequence number 138; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 139 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0403] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 128 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 129; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 130; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 140; (2) VL CDR2 having the amino acid sequence of sequence number 141; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 142 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0404] In some embodiments, the molecules provided herein are amino acid sequences of SEQ ID NO: 87 An antigen-binding fragment having a VH region with a column and a VL region with the amino acid sequence of SEQ ID NO: 89 It possesses. The molecule may be an antibody. The antibody is a monoclonal antibody. This can be achieved. The antibody can be a humanized antibody.

[0405] In some embodiments, the molecule provided herein is represented as STC1029. It is a monoclonal antibody or its humanized antibody version. The humanized STC1029 antibody is this Having the VH region, VL region, or both the VH region and VL region of STC1029 as described in the specification. Humanized STC1029 antibody can be used to modify the six CDR regions of STC1029 described herein (VH CDR1 It may also have VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST The C1029 antibody may also have fewer than six CDR regions of STC1029. In some embodiments... In this context, the humanized STC1029 antibody contains one, two, three, four, or five CDR regions (VH CD) of STC1029. It may also have R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3.

[0406] In some embodiments, the molecules provided herein are (a)(1)Sequence ID 147 (2) VH CDR1 having an amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 148; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 149; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 159; (2) VL CDR2 having the amino acid sequence of sequence number 160; (3) Antibody having a light chain variable (VL) region including VL CDR3 having the amino acid sequence of SEQ ID NO: 161 It has a protobinding fragment. The molecule may be an antibody. The antibody is a monoclonal antibody. It can be a body. The antibody can be a humanized antibody.

[0407] In some embodiments, the molecules provided herein are (a) (1) the a of SEQ ID NO: 150 (2) VH CDR1 having a amino acid sequence; (3) VH CDR2 having the amino acid sequence of SEQ ID NO: 151; and (4) A heavy chain variable (VH) region containing VH CDR3 having the amino acid sequence of column number 152; and (b)(1) sequence number (1) VL CDR1 having the amino acid sequence of sequence number 162; (2) VL CDR2 having the amino acid sequence of sequence number 163; (3) Antibody having a light chain variable (...

Claims

1. The use of an anti-BTN1A1 antibody or its antigen-binding fragment that preferentially binds to dimeric BTN1A1 rather than monomeric BTN1A1, for the purpose of manufacturing a pharmaceutical product for treating a target cancer, The anti-BTN1A1 antibody or its antigen-binding fragment can synergistically induce the secretion of IL-2 or IFNγ by blocking the interaction between PD-1 and the PD-1 ligand with a second antibody or its antigen-binding fragment. The anti-BTN1A1 antibody or its antigen-binding fragment (a) exhibits a dissociation constant (K) relative to monomer BTN1A1. D K is less than half of ) D (b) K is shown for non-glycosylated BTN1A1, which is bound to the dimer BTN1A1. D K less than half D It binds to glycosylated BTN1A1, The use described above, wherein the anti-BTN1A1 antibody or its antigen-binding fragment is not STC810 ​​or an antigen-binding fragment of STC810.

2. The use according to claim 1, wherein the cancer is selected from the group consisting of lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, liver cancer, head and neck cancer, breast cancer, and gastric cancer.

3. The use according to claim 2, wherein the lung cancer is non-small cell lung cancer (NSCLC).

4. The use according to claim 3, wherein the NSCLC is squamous epithelial NSCLC.

5. The use according to claim 2, wherein the lung cancer is small cell lung cancer.

6. The anti-BTN1A1 antibody or its antigen-binding fragment is shown to represent K against monomer BTN1A1. D K is at least 5 times smaller, at least 10 times smaller, at least 15 times smaller, at least 20 times smaller, at least 25 times smaller, at least 30 times smaller, at least 40 times smaller, or at least 50 times smaller than D The use according to any one of claims 1 to 5, wherein the dimer BTN1A1 is bound to it.

7. The anti-BTN1A1 antibody or its antigen-binding fragment is shown to be K against non-glycosylated BTN1A1. D K is at least 5 times smaller, at least 10 times smaller, at least 15 times smaller, at least 20 times smaller, at least 25 times smaller, at least 30 times smaller, at least 40 times smaller, or at least 50 times smaller than D The use according to any one of claims 1 to 6, wherein the glycosylated BTN1A1 is bound to it.

8. The use according to any one of claims 1 to 7, wherein BTN1A1 is human BTN1A1.

9. The anti-BTN1A1 antibody or antigen-binding fragment thereof specifically binds immunospecifically to dimeric BTN1A1 with a K of 1 μM or less D The use according to any one of claims 1 to 8, wherein the binding occurs.

10. The anti-BTN1A1 antibody or its antigen-binding fragment has a K content of 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, or 5 nM or less. D The use according to any one of claims 1 to 8, wherein the dimer BTN1A1 is bonded to the dimer BTN1A1.

11. The use according to claim 9 or 10, wherein the dimer BTN1A1 is glycosylated dimer BTN1A1.

12. The use according to any one of claims 1 to 11, wherein the anti-BTN1A1 antibody or its antigen-binding fragment is Fab', F(ab')2, F(ab')3, monovalent scFv, bivalent scFv, or a single-domain antibody.

13. (a) The anti-BTN1A1 antibody is a monoclonal antibody or a humanized antibody; (b) The anti-BTN1A1 antibody is IgG, IgM, or IgA; or (c) The anti-BTN1A1 antibody or its antigen-binding fragment is produced by recombinant The use according to any one of claims 1 to 12.

14. The use according to any one of claims 1 to 13, wherein the second antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody.

15. The use according to any one of claims 1 to 14, wherein the secretion of the induced cytokine is by lymphocytes.

16. The use according to claim 15, wherein the lymphocytes are B lymphocytes, T lymphocytes, or natural killer cells.

17. The use according to any one of claims 1 to 16, wherein the pharmaceutical is used in combination with the administration of high-dose radiotherapy to the subject.

18. The use according to any one of claims 1 to 17, wherein the pharmaceutical product is formulated for parenteral administration.

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