Methods of treating cancer using antibodies and molecules that immunospecifically bind to BTN1a1

Abstract

To provide a method of treating an anti-PD-1 therapy or anti-PD-L1 therapy resistant or refractory cancer in a subject.SOLUTION: Provided herein are methods for treating cancer using molecules having an antigen binding fragment that immunospecifically binds to BTN1A1, such as anti-BTN1A1 antibodies. These molecules include those having an antigen binding fragment that immunospecifically binds to glycosylated BTN1A1, such as anti-glycosylated BTN1A1 antibodies. Also included are molecules having an antigen binding fragment that immunospecifically bind to BTN1A1 dimers, such as anti-BTN1A1 dimer antibodies.SELECTED DRAWING: Figure 1-1

Description

Technical field

[0001] (Cross reference to related application) This application claims the benefit of U.S. Provisional Application No. 62 / 513,393, filed May 31, 2017. and the disclosure of which is fully incorporated herein by reference.

[0002] (see sequence listing) This application is filed May 25, 2018 and is May 25, 2018 bytes in size, 13532-0 submitted with a computer readable form (CRF) copy of the sequence listing named 19-228_ST25.txt. and which is fully incorporated herein by reference.

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

[0004] (2. Background) The immune system of humans and other mammals protects them from infection and disease. some thorns Acute and inhibitory ligands and receptors maximize the immune response to infection while It provides a tight control system that limits autoimmunity. Recently, anti-PD1 antibody or anti-PDL1 antibody, such as Therapies that modulate the immune response have been found to be effective in some cancer treatments. deer while developing new therapies that safely and effectively treat diseases by modulating the immune system. Development is urgent, especially for anti-PD1 or anti-PD-L1 therapy-resistant or refractory cancers continue to be a need. The methods described herein meet these needs and It offers other related advantages. [Outline of the invention]

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

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

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

[0008] In another aspect, provided herein are anti-PD-1 therapy or anti-PD-L1 therapy refractory 1. A method of killing cancer cells or inhibiting proliferation of said cancer cells, wherein said cells are immunospecific for BTN1A1. contacting with an effective amount of a molecule comprising an antigen-binding fragment that specifically binds to the antigen.

[0009] In another aspect, provided herein is a method of treating cancer comprising: (i) a cancer cell; obtaining a sample containing cells from a subject with said cancer; (ii) determining the level of BTN1A1 in said sample; (iii) if the level of BTN1A1 in the sample is equal to or greater than the BTN1A1 reference level, the subject is Diagnose as likely to respond to a molecule containing an antigen-binding fragment that immunospecifically binds to N1A1 and (iv) treating the subject with a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1. A method comprising administering an effective amount.

[0010] In another aspect, provided herein is a method of treating cancer comprising: (i) a cancer cell; obtaining a sample containing cells from a subject with said cancer; (ii) determining the level of PD-L1 in said sample; (iii) if the level of PD-L1 in the sample is below the PD-L1 reference level, then the subject is classified as BTN1A1 to diagnose a likely response to a molecule containing an antigen-binding fragment that immunospecifically binds to and (iv) therapeutic efficacy in said subject of a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1. A method comprising administering an amount.

[0011] In another aspect, provided herein are anti-PD1 therapy or anti-PD-L1 therapy refractory or A method of treating a refractory cancer comprising: (i) treating a sample comprising cancer cells with said anti-PD1 therapy or anti-PD-L1 therapy; obtaining from a subject with a resistant or refractory cancer; (ii) determining the level of BTN1A1 in said sample; (iii) if the level of BTN1A1 in the sample is equal to or greater than the BTN1A1 reference level, the subject is Diagnose as likely to respond to a molecule containing an antigen-binding fragment that immunospecifically binds to N1A1 and (iv) treating the subject with a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1. A method comprising administering an effective amount.

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

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

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

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

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

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

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

[0019] In some embodiments, the method determines levels of BTN1A1 and PD-L1 in the sample including doing

[0020] In some embodiments, the level of BTN1A1 in said sample is higher than the BTN1A1 reference level If not, the subject can respond to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1. diagnosed as having high potential.

[0021] In some embodiments, the level of PD-L1 in said sample is lower than the PD-L1 reference level the subject is capable of responding to a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 diagnosed as having high

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

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

[0024] In some embodiments, the antigen-binding fragment that immunospecifically binds to BTN1A1 is BTN1A1 Binds preferentially to the BTN1A1 dimer over the monomer.

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

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

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

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

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

[0030] In some embodiments, the method comprises administering anti-PD-1 therapy and anti-PD-L1 therapy including.

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

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

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

[0034] In some embodiments, the antigen-binding fragment that immunospecifically binds to BTN1A1 is BTN1A1 Binds preferentially to the BTN1A1 dimer over the monomer.

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

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

[0037] In some embodiments, the treatment is a decrease in tumor size, number of metastatic lesions over time result in at least one therapeutic effect, such as a reduction in vinegar.

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

[0039] In some embodiments, the anti-PD-1 therapy or anti-PD-L1 therapy is anti-PD-1 or anti-PD-L1 Antibodies or antibody fragments, or soluble PD-1 or PD-L1 ligands, or Fc-fusions thereof Contains protein.

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

[0041] In some embodiments, the anti-PD-1 therapy is provided in International Application No. PCT / US2016 / 64394 including anti-PD-1 antibodies that are

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

[0043] In some embodiments, the anti-PD-L1 therapy is International Application No. PCT / US2016 / 024691 and International Including antibodies provided in application PCT / US2017 / 024027.

[0044] In some embodiments, the antigen-binding fragment that immunospecifically binds to BTN1A1 is a non-glycosylated Binds preferentially to glycosylated BTN1A1 over cosylated BTN1A1.

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

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

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

[0048] In some embodiments, the antigen-binding fragment comprises (a)(1) SEQ ID NO: 7, 10, 13, 16, 35 , 38, 41, 44, 63, 66, 69, and 72. H C. DR1; (2) selected from the group consisting of SEQ ID NOs:8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, and 73; V having a selected amino acid sequence H CDR2; and (3) SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, V having an amino acid sequence selected from the group consisting of 46, 65, 68, 71, and 74 H contains CDR3 heavy chain variable (V H ) region; or (b) (1) SEQ ID NO: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81, and V having an amino acid sequence selected from the group consisting of 84 L CDR1; (2) SEQ ID NOs: 20, 23, 26 , 29, 48, 51, 54, 57, 76, 79, 82, and 85. to V L CDR2; and (3) SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, and 86 V having an amino acid sequence selected from the group consisting of L Light chain variable (V L ) region .

[0049] In some embodiments, the antigen-binding fragment has (1) SEQ ID NO: 7, 10, 13, 16, 35, 38 , 41, 44, 63, 66, 69, and 72. H CDR1; (2) selected from the group consisting of SEQ ID NOs:8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, and 73; V with the amino acid sequence H CDR2; and (3) SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, 46, V having an amino acid sequence selected from the group consisting of 65, 68, 71, and 74 H Heavy chain containing CDR3 Variable (V H ) region.

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

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

[0052] In some embodiments, the antigen-binding fragment has (1) SEQ ID NOs: 19, 22, 25, 28, 47, 5 V having an amino acid sequence selected from the group consisting of 0, 53, 56, 75, 78, 81, and 84 L CDR1 (2) selected from the group consisting of SEQ ID NOs: 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, and 85; V having the amino acid sequence L CDR2; and (3) SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 5 V having an amino acid sequence selected from the group consisting of 8, 77, 80, 83, and 86 L CDR3: contains light chain variable (V L ) region.

[0053] In some embodiments, the light chain variable (V L ) region is (a)(1) SEQ ID NO: 19, 47, or has a sequence of 75 amino acids V L CDR1; (2) the amino acid sequence of SEQ ID NO: 20, 48, or 76; have V L CDR2; and (3) V having the amino acid sequence of SEQ ID NO: 21, 49, or 77 L CDR3;(b) (1) V having the amino acid sequence of SEQ ID NO: 22, 50, or 78 L CDR1; (2) SEQ ID NO: 23, 51, also or V having a sequence of 79 amino acids L CDR2; and (3) an amino acid of SEQ ID NO: 24, 52, or 80 V with acid sequence L CDR3; (c)(1) V having the amino acid sequence of SEQ ID NO: 25, 53, or 81 L C. DR1; (2) V having the amino acid sequence of SEQ ID NO: 26, 54, or 82 L CDR2; and (3) SEQ ID NO:27 , 55, or 83 amino acid sequences of V L CDR3; or (d)(1) SEQ ID NO: 28, 56, or V with 84 amino acid sequence L CDR1; (2) having the amino acid sequence of SEQ ID NO: 29, 57, or 85; to V L CDR2; and (3) V having the amino acid sequence of SEQ ID NO: 30, 58, or 86 L contains CDR3 .

[0054] In some embodiments, the light chain variable (V L ) regions are SEQ ID NOs: 5, 35, 61, 89, 117, or contains a sequence of 145 amino acids.

[0055] In some embodiments, the antigen-binding fragment comprises (a)(1) SEQ ID NO: 7, 10, 13, 16, 35 , 38, 41, 44, 63, 66, 69, and 72. H C. DR1; (2) selected from the group consisting of SEQ ID NOs:8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, and 73; V having a selected amino acid sequence H CDR2; and (3) SEQ ID NOs: 9, 12, 15, 18, 37, 40, 43, V having an amino acid sequence selected from the group consisting of 46, 65, 68, 71, and 74 H contains CDR3 heavy chain variable (V H ) regions; and (b) (1) SEQ ID NOs: 19, 22, 25, 28, 47, 50, 53, 56, 75, 78, 81. , or V having an amino acid sequence selected from the group consisting of 84 L CDR1; (2) SEQ ID NO: 20, 23, 2 an amino acid sequence selected from the group consisting of 6, 29, 48, 51, 54, 57, 76, 79, 82, or 85 have V L CDR2; and (3) SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86 V having an amino acid sequence selected from the group consisting of L Light chain variable (V L ) region .

[0056] In some embodiments, the antigen-binding fragment comprises (i)(a)(1) SEQ ID NO: 7, 35, or V with 63 amino acid sequence H CDR1; (2) having the amino acid sequence of SEQ ID NO: 8, 36, or 64 V H CDR2; and (3) V having the amino acid sequence of SEQ ID NO: 9, 37, or 65 H Multiplex containing CDR3 chain variable (V H ) region; and (b) (1) V having the amino acid sequence of SEQ ID NO: 19, 47, or 75. L CDs R1; (2) V having the amino acid sequence of SEQ ID NO: 20, 48, or 76 L CDR2; and (3) SEQ ID NO:21 , 49, or 77 amino acid sequences of V L Light chain variable (V L ) region; (ii) (a) (1) V having the amino acid sequence of column number 10, 38, or 66 H CDR1; (2) SEQ ID NO: 11, 39, or has a sequence of 67 amino acids V H CDR2; and (3) the amino acid sequence of SEQ ID NO: 12, 40, or 68 V with columns H Heavy chain variable (V H ) region; and (b)(1) SEQ ID NO: 22, 50, or 78 V with amino acid sequence L CDR1; (2) V having the amino acid sequence of SEQ ID NO: 23, 51, or 79 L CDR2; and (3) V having the amino acid sequence of SEQ ID NO: 24, 52, or 80 L light chain containing CDR3 Variable (V L ) region; (iii) (a) (1) V having the amino acid sequence of SEQ ID NO: 13, 41, or 69; H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 14, 42, or 70 H CDR2; and (3) SEQ ID NO: 15, 43 , or V with a sequence of 71 amino acids H Heavy chain variable (V H ) regions; and (b)(1) sequences V having the amino acid sequence numbered 25, 53, or 81 L CDR1; (2) SEQ ID NO: 26, 54, or 8 V with an amino acid sequence of 2 L CDR2; and (3) the amino acid sequence of SEQ ID NO: 27, 55, or 83 have V L Light chain variable (V L ) region; or (iv) (a)(1) the address of SEQ ID NO: 16, 44, or 72 V with amino acid sequence H CDR1; (2) V having the amino acid sequence of SEQ ID NO: 17, 45, or 73 H CDR2; and (3) V having the amino acid sequence of SEQ ID NO: 18, 46, or 74 H Heavy chain including CDR3 available Weird (V H and (b) (1) V having the amino acid sequence of SEQ ID NO: 28, 56, or 84. L CDR1;( 2) V having the amino acid sequence of SEQ ID NO: 29, 57, or 85 L CDR2; and (3) SEQ ID NOs: 30, 58 , or V with a sequence of 86 amino acids L Light chain variable (V L ) region.

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

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

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

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

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

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

[0063] In some embodiments, the antigen-binding fragment comprises (a)(1) SEQ ID NOS:225, 228, 231, and and V having an amino acid sequence selected from the group consisting of H CDR1; (2) SEQ ID NO: 226, 229, 23 2, and V having an amino acid sequence selected from the group consisting of 235 H CDR2; and (3) SEQ ID NO:2 V having an amino acid sequence selected from the group consisting of 27, 230, 233, and 236 H Multiplex containing CDR3 chain variable (V H or (b) (1) selected from the group consisting of SEQ ID NOS: 237, 240, 243, and 246. V with amino acid sequence L CDR1; (2) selected from the group consisting of SEQ ID NOs: 238, 241, 244, and 247 V having the amino acid sequence L CDR2; and (3) from SEQ ID NOS: 239, 242, 245, and 248 V having an amino acid sequence selected from the group L Light chain variable (V L ) region.

[0064] In some embodiments, the antigen-binding fragment comprises (1) SEQ ID NOs:225, 228, 231, and 23 V having an amino acid sequence selected from the group consisting of 4 H CDR1; (2) SEQ ID NOs: 226, 229, 232, and V having an amino acid sequence selected from the group consisting of 235 H CDR2; and (3) SEQ ID NO:227 , 230, 233, and 236. H Heavy chain containing CDR3 Variable (V H ) region.

[0065] In some embodiments, the heavy chain variable (V H ) region consists of (a)(1) amino acids of SEQ ID NO:225 (2) VH CDR2 having the amino acid sequence of SEQ ID NO:226; and (3) SEQ ID NO:2. VH CDR3 having an amino acid sequence of 27; (b) (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 228; 2) a VH CDR2 having the amino acid sequence of SEQ ID NO:229; and (3) having the amino acid sequence of SEQ ID NO:230. c) (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 231; (2) the amino acid of SEQ ID NO: 232; (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 233; or (d) ( 1) VH CDR1 having the amino acid sequence of SEQ ID NO:234; (2) V having the amino acid sequence of SEQ ID NO:235; and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO:236.

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

[0067] In some embodiments, the antigen-binding fragment comprises (1) SEQ ID NOs: 237, 240, 243, and 24 V having an amino acid sequence selected from the group consisting of 6 L CDR1; (2) SEQ ID NOs: 238, 241, 244, and V having an amino acid sequence selected from the group consisting of 247 L CDR2; and (3) SEQ ID NO: 239 , 242, 245, and 248. L CDR3: including light chain variable (V L ) region.

[0068] In some embodiments, the light chain variable (V L ) region consists of (a)(1) amino acids of SEQ ID NO:237 (2) VL CDR2 having the amino acid sequence of SEQ ID NO:238; and (3) SEQ ID NO:2. VL CDR3 having an amino acid sequence of 39; (b)(1) VL CDR1 having the amino acid sequence of SEQ ID NO: 240; 2) VL CDR2 having the amino acid sequence of SEQ ID NO:241; and (3) having the amino acid sequence of SEQ ID NO:242. (c) (1) VL CDR1 having the amino acid sequence of SEQ ID NO:243; (2) the amino acid of SEQ ID NO:244; (3) VL CDR3 having the amino acid sequence of SEQ ID NO: 245; or (d) ( 1) VL CDR1 having the amino acid sequence of SEQ ID NO:246; (2) V having the amino acid sequence of SEQ ID NO:247; and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:248.

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

[0070] In some embodiments, the antigen-binding fragment comprises (a)(1) SEQ ID NOS:225, 228, 231, and and V having an amino acid sequence selected from the group consisting of H CDR1; (2) SEQ ID NO: 226, 229, 23 2, and V having an amino acid sequence selected from the group consisting of 235 H CDR2; and (3) SEQ ID NO:2 V having an amino acid sequence selected from the group consisting of 27, 230, 233, and 236 H Multiplex containing CDR3 chain variable (V H and (b) (1) selected from the group consisting of SEQ ID NOs: 237, 240, 243, and 246. V having an amino acid sequence L CDR1; (2) selected from the group consisting of SEQ ID NOS: 238, 241, 244, and 247; V having a selected amino acid sequence L CDR2; and (3) from SEQ ID NOS: 239, 242, 245, and 248 V having an amino acid sequence selected from the group consisting of L Light chain variable (V L ) region.

[0071] In some embodiments, the antigen-binding fragment comprises (i) (a) (1) the amino acid sequence of SEQ ID NO:225 V with columns H CDR1; (2) V having the amino acid sequence of SEQ ID NO:226 H CDR2; and (3) SEQ ID NO:227 V having the amino acid sequence of H Heavy chain variable (V H ) region; and (b)(1) the domain of SEQ ID NO:237. V with amino acid sequence L CDR1; (2) V having the amino acid sequence of SEQ ID NO:238 L CDR2; and (3) V having the amino acid sequence of row number 239 L Light chain variable (V L ) region; (ii) (a) (1) SEQ ID NO: 2 V with 28 amino acid sequence H CDR1; (2) V having the amino acid sequence of SEQ ID NO:229 H CDR2; and (3) V having the amino acid sequence of SEQ ID NO:230 H Heavy chain variable (V H ) region; and (b)(1) V having the amino acid sequence of row number 240 L CDR1; (2) V having the amino acid sequence of SEQ ID NO:241 L CDs R2; and (3) V having the amino acid sequence of SEQ ID NO:242 L Light chain variable (V L ) region; (iii) (a ) (1) V having the amino acid sequence of SEQ ID NO: 231 H CDR1; (2) having the amino acid sequence of SEQ ID NO:232 V H CDR2; and (3) V having the amino acid sequence of SEQ ID NO:233 H Heavy chain variable (V H )region; and (b) (1) V having the amino acid sequence of SEQ ID NO:243 L CDR1; (2) amino acid sequence of SEQ ID NO:244 V with columns L CDR2; and (3) V having the amino acid sequence of SEQ ID NO:245 L Light chain variable containing CDR3 ( V. L ) region; or (iv) (a) (1) V having the amino acid sequence of SEQ ID NO:234 H CDR1; (2) of SEQ ID NO:235 V with amino acid sequence H CDR2; and (3) V having the amino acid sequence of SEQ ID NO:236 H including CDR3 heavy chain variable (V H ) region; and (b) (1) V having the amino acid sequence of SEQ ID NO:246. L CDR1;(2) sequence V having the amino acid sequence numbered 247 L CDR2; and (3) V having the amino acid sequence of SEQ ID NO:248 L Light chain variable (V L ) region.

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

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

[0074] In some embodiments, the binding to BTN1A1 is the BT Competitively blocks binding to N1A1 in a dose-dependent manner.

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

[0076] In some embodiments, a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is ≤500nM, ≤400nM, ≤300nM, ≤200nM, ≤100nM, ≤50nM, ≤10nM, or a dissociation constant (K D ) binds to glycosylated BTN1A1.

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

[0078] In some embodiments, a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is ≤500nM, ≤400nM, ≤300nM, ≤200nM, ≤100nM, ≤50nM, ≤10nM, or a dissociation constant (K D ) binds to the BTN1A1 dimer.

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

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

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

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

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

[0084] In some embodiments, a molecule comprising an antigen-binding fragment that immunospecifically binds to BTN1A1 is recombinantly produced. [Brief description of the drawing]

[0085] (4.Brief description of the drawing) The following drawings form a part of this specification and are intended to further illustrate certain embodiments of the present invention. included. The invention may be implemented using one or more of these drawings as the specifics presented herein. may be better understood by reference in conjunction with the detailed description of specific embodiments. can.

[0086]

Figure 1

[0087]

Figure 2

[0088] [Fig.3] FIGS. 3A-D—Mutually exclusive expression of BTN1A1 and PD-L1 in cancer tissues. Figures 3A-D show fluorescence microscopy images of exemplary human lung squamous cell carcinoma tissue slices. FIG. 3A shows fluorescent staining of PD-L1 (green). FIG. 3B shows fluorescent staining (red) of BTN1A1. FIG. 3C shows fluorescent staining of cytokeratin (purple). FIG. 3D shows a composite image in which the images of FIGS. 3A-C are overlapped.

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

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

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

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

[0093] [Fig.8] Figures 8A and 8B - Anti-mBTN1A1 antibodies promote proliferation of T cells co-cultured with mBTN1A1 overexpressing 4T1 cells. Figures 8A and 8B show the results of 4T1-BTN1A1-mouse spleen cell co-culture experiments. 4T1 cells overexpressing BTN1A1 were co-cultured with mouse spleen cells and the indicated anti-mouse BTN1A1 antibodies. FIG. 8A shows the results of flow cytometric analysis of proliferating T cells in co-culture. FIG. 8B shows a bar graph showing the effect of STC1011, STC1012, and STC1029 on T cell proliferation in co-cultures. CFSE = fluorescent dye (5(6)-carboxyfluorescein N-hydroxysuccinimidyl ester).

[0094] [Fig.9] Figure 9 - Dosing schedule for PD-1 / PD-L1 therapy refractory cancer model. FIG. 9 shows a graph showing dosing schedules for anti-BTN1A1 antibody administration to Balb / c mice bearing breast cancer (4T1) grafts or C57BL / 6 mice bearing Lewis Lung Carcinoma (LLC) grafts. Sac=time the mouse was sacrificed

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

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

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

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

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

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

[0101] [Fig. 15] Figure 15 - Dimer specific binding of BTN1A1 antibody. The leftmost panel of FIG. 15 is an image of a Coomassie Blue stained SDS-PAGE gel showing the location of the BTN1A1 protein in its monomeric and dimeric forms in both native and reducing conditions, along with size standards. The second through fifth panels show Western blots visualizing the monomeric and dimeric forms of the BTN1A1 protein in both native and reducing conditions using the STC810, STC2602, STC2714, and STC2781 antibodies, respectively.

[0102] [Fig. 16] FIG. 16-B—Binding affinities (KD) of STC2714 for BTN1A1 in monomeric and dimeric forms. Figure 16A: Sensorgram showing real-time binding of soluble BTN1A1-Fc protein (Figure 16A) (2-64 nm at 2-fold dilution) to STC2714 immobilized on a protein A-CM5 chip (Biacore). Figure 16B: Sensorgram showing real-time binding of soluble BTN1A1-His protein (2-64 nm at 2-fold dilution) to STC2714 immobilized on a protein A-CM5 chip (Biacore). [Mode for carrying out the invention]

[0103] (5. Detailed description) The B7 family of co-stimulatory molecules can drive immune cell activation and inhibition. Seki A member of the B7 family of molecules - buryrophilin - is also similar to B7 family members. have immunomodulatory functions. Butyrophilin, subfamily 1, member A1 (“BTN1A1”) is a type I membrane glycoprotein and a major component of milk fat globule membranes, and is structurally related to the B7 family. 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 expressed in Treatment with recombinant BTN1A1 inhibits T-cell activation and prevents an animal model of EAE (Stefferl et al., J. Immunol. 165(5):2859-65 (2000)).

[0104] BTN1A1 is also specifically and highly expressed in cancer cells. BTN1A1 expressed in cancer cells is commonly Usually glycosylated. Expression of BTN1A1 can be used not only to aid in cancer diagnosis, but also in cancer treatment. The efficacy of therapy can also be assessed.

[0105] The present disclosure is based, at least in part, on the surprising fact that BTN1A1 is expressed across a variety of cancer cells. Based on what should be found. See, eg, Example 1.

[0106] The present disclosure provides, at least in part, that BTN1A1 and PD-L1 expression are mutually exclusive in certain cancers. Based on the surprising discovery that For example, see Example 2.

[0107] The present disclosure demonstrates, at least in part, that anti-BTN1A1 antibodies are anti-PD1 in the activation of certain lymphocytes. It is based on the surprising discovery that it can act synergistically with antibodies. For example, Example 3 See

[0108] The present disclosure provides, at least in part, that molecules capable of immunospecifically binding to BTN1A1 are anti-PD 1 and the surprising discovery that it is effective in the treatment of cancers refractory to anti-PD-L1 therapy. are there. See, eg, Example 4.

[0109] Provided herein are anti-BTN1A1 antibodies and antibodies capable of immunospecifically binding to BTN1A1. It is a method of treating cancer using other molecules that can be used to treat cancer. In some embodiments, the cancer is Cancer refractory to anti-PD-1 or anti-PD-L1 therapy. Also provided are anti-BTN1A1 antibodies and BTN Methods and patients for diagnosing cancer using other molecules capable of immunospecifically binding to 1A1 How to choose.

[0110] (5.1. Definition) As used herein, and unless otherwise specified, "a", "an", and "the" The article refers to one or more of the grammatical objects of that article. For example, an antibody refers to an antibody or antibodies.

[0111] As used herein, and unless otherwise specified, "butyrophilin, subfa The term Millie 1, member A1" or "BTN1A1" refers to mammals, e.g., primates (e.g. , humans, cynomolgus monkeys (cynos), dogs, and rodents (e.g., mice and rats) , refers to BTN1A1 from any vertebrate source. Unless otherwise specified, BTN1A1 A1 isoforms, related BTN1A1 polypeptides including SNP variants thereof, and without limitation but BTN1A1-like Various modified forms are also included. As used herein, glycosylated BTN1A1 is N55, N21 5, and / or BTN1A1 with N449 glycosylation.

[0112] The exemplary amino acid sequence of human BTN1A1 (BC096314.1 GI: 64654887) was replaced with potential glycosyl The modification sites are bolded and underlined and are provided below:

[0113] [formation]

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

[0115] [formation]

[0116] Exemplary amino acids of an exemplary dimeric BTN1A1 extracellular domain construct (BTN1A1-ECD-Fc). The noacid sequences are provided below. [formation]

[0117] Exemplary amino acids of an exemplary monomeric BTN1A1 extracellular domain construct (BTN1A1-His6) Acid sequences are provided below. [formation]

[0118] The exemplary amino acid sequence of murine BTN1A1 (GenBank: AAH11497.1) was analyzed for potential glycosylation. Bolded and underlined sites are provided below:

[0119] [formation]

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

[0121] [formation]

[0122] As used herein, and unless otherwise specified, "programmed death 1", "pro Gram cell death 1", "protein PD-1", "PD-1", "PD-1 polypeptide", or "PD1" The term is used in primates (e.g., humans and cynomolgus any mammals, including mammals such as dogs), dogs, and rodents (e.g., mice and rats). It encompasses polypeptides, including any naturally occurring polypeptide from a vertebrate source (“polypeptides”). "tide" and "protein" are used interchangeably herein). In one embodiment , these terms include "related PD-1 polypeptides," including SNP variants thereof. "PD-1" The term "full-length" unprocessed PD-1 and intracellularly processed PD-1 Any resulting form of PD-1 is also included. NCBI reference sequence NP_005009.2 is an exemplary A human PD-L1 amino acid sequence is provided. GenBank™ Accession No. L27440.1 is An exemplary human PD-1 nucleic acid sequence is provided.

[0123] As used herein, and unless otherwise specified, the term "anti-PD-1 therapy" refers to , including any inhibitor of PD-1. In some embodiments, the anti-PD-1 therapy is anti-PD-1 antibodies or antigen-binding fragments thereof, inhibitory nucleic acids, or soluble PD-1 ligands (e.g., soluble P D-L1), or fusion proteins thereof (e.g., Fc-fusion proteins) . In some embodiments, the anti-PD-1 therapy is nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-514, or AMP-224.

[0124] In some embodiments, the anti-PD-1 therapy is nivolumab (CAS Registry Number: 946414-94-4) including. Nivolumab is also known as MDX-1 106, MDX-1 106-04, ONO-4538, or BMS-936558 Are known. Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1 is. Nivolumab (clone 5C4) and other human monoclonals that specifically bind to PD-1 Antibodies are disclosed in US 8,008,449 and WO2006 / 121168.

[0125] In some embodiments, anti-PD-1 therapy comprises pembrolizumab. Pembroliz Mab is KEYTRUDA®, lambrolizumab, Merck 3745, MK-3475, or SCH-90047 Also known as 5. Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to PD-1 Antibody. Pembrolizumab is described, for example, in Hamid, O. et al. (2013) New England Jo urnal of Medicine 369(2): 134-44, WO2009 / 1 14335, and US 8,354,509. ing.

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

[0127] In some embodiments, the anti-PD-1 therapy is provided in International Application No. PCT / US2016 / 64394 including anti-PD-1 antibodies that are

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

[0129] In some embodiments, the anti-PD-1 therapy is the fusion protein AMP 514 (Amplimmune). include. AMP-224, also known as B7-DCIg, is described, for example, in WO2010 / 027827 and WO201 1 / 0 66342. AMP-224 is a PD-L2 Fc fusible that blocks the interaction of PD1 with B7-H1 It is a soluble receptor.

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

[0131] As used herein, and unless otherwise specified, "programmed death 1 ligand 1" , "programmed cell death 1 ligand 1", "protein PD-L1", "PD-L1", "PD-L1 polyp Unless otherwise indicated, the term "peptide" or "PD1-L1" refers to a primate (e.g., human and cynomolgus monkeys (Cynomolgus)), dogs, and rodents (e.g., mice and rats). Polypeptides, including any naturally occurring polypeptide from any vertebrate source, including any mammal ("polypeptide" and "protein" are used interchangeably herein) ). In some embodiments, these terms refer to "related PD-L1 poly peptide”. The term "PD-L1" refers to "full length" unprocessed PD-L1 and any form of PD-L1 that results from processing within the cell. Attend NCBI Reference sequence NP_054862.1 provides an exemplary human PD-L1 amino acid sequence. GenBank™ Accession No. NM_014143 provides an exemplary human PD-1 nucleic acid sequence.

[0132] As used herein and unless otherwise specified, the term "anti-PD-L1 therapy" includes any inhibitor of PD-L1. In some embodiments, the anti-PD-1 therapy is anti-P D-L1 antibody or antigen-binding fragment thereof, inhibitory nucleic acid, or soluble PD-L1 ligand (e.g., soluble PD-1), or fusion proteins thereof (e.g., Fc-fusion proteins). Wear. In some embodiments, the anti-PD-L1 therapy is YW243.55.S70, MPDL3280A, MEDI-4 736, MSB-0010718C, or MDX-1105.

[0133] In some embodiments, the anti-PD-Ll therapy comprises MDX-1105. MDX-1105 is BMS-936 Also known as 559. See, for example, WO2007 / 005874.

[0134] In some embodiments, anti-PD-Ll therapy is described, for example, in WO 2010 / 077634. antibody YW243.55.S70 (heavy and light chain variable regions shown in SEQ ID NOS: 20 and 21, respectively) array).

[0135] In some embodiments, the anti-PD-Ll therapy comprises MDPL3280A (Genentech / Roche). M. DPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-Ll. MDPL3280A and and other human monoclonal antibodies to PD-Ll are described, for example, in US Pat. No. 7,943,743 and US Pat. It is disclosed in National Publication No. 20120039906.

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

[0137] In some embodiments, the anti-PD-Ll therapy is a human Fc-optimized IgGl mononucleotide that binds PD-L1. Includes the clonal antibody MDPL3280A (Genentech / Roche). for MDPL3280A and PD-L1 Other human monoclonal antibodies are described in US Pat. No. 7,943,743 and US Publication No. 20120039906. disclosed.

[0138] In some embodiments, the anti-PD-Ll therapy was published as WO 2016 / 160792 A1 Antibodies provided in International Application PCT / US2016 / 024691 and International Application PCT / US2017 / 024027 including.

[0139] As used herein, and unless otherwise specified, the term "antibody" refers to capable of binding to a specific molecular antigen, and two identical polypeptide chain pairs (where each The pair has one heavy chain (approximately 50-70 kDa) and one light chain (approximately 25 kDa), with each amino The terminal portion includes a variable region of about 100 to about 130 or more amino acids, and each chain the carboxy-terminal portion of each of which includes a constant region) Refers to polypeptide products of B cells within the lobulin (or "Ig") class (Borrebaeck (ed.) (1995) , Antibody Engineering, 2nd ed., Oxford University Press.; K See Uby (1997), Immunology, 3rd ed., W.H. Freeman and Company, New York. reference). Here, specific molecular antigens include the target BTN1A1, which is the BTN1A1 polypep Tide, BTN1A1 fragment, or BTN1A1 epitope. The anti-antibacterial agents provided herein Monoclonal antibodies, synthetic antibodies, recombinantly produced antibodies, bispecific antibodies, multispecific antibodies, Heteromeric antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, intrabodies, anti-ideal antibodies including but not limited to biotypic (anti-Id) antibodies.

[0140] As used herein, and unless otherwise specified, the term "monoclonal antibody" The term refers to cells derived from a single cell clone or hybridoma or a single cell. Refers to an antibody that is the product of a population. Monoclonal antibodies produce single-molecule immunoglobulin species produced by recombinant methods from heavy and light chain encoding immunoglobulin genes to It is also intended to refer to an antibody produced by Amino Acid Sequences of Antibodies in Monoclonal Antibody Preparations are substantially homogeneous, and the binding activity of antibodies within such preparations has substantially the same antigen-binding activity. show gender. In contrast, polyclonal antibodies are obtained from various B cells within the population, which are , is a combination of immunoglobulin molecules that bind to specific antigens. each of the polyclonal antibodies immunoglobulins can bind to different epitopes of the same antigen. monochrome Methods for producing both null and polyclonal antibodies are well known in the art (Harlow et al. and Lane, Antibodies: A Laboratory Manual, Cold Sprin g Harbor Laboratory Press (1989) and Borrebaeck (eds.) Antibody Engineering: A Practical Guide (Antibody Engineering: A Practical Guide), W.H. Freeman and Co., Publishers, N. New York, pp. 103-120 (1991)).

[0141] As used herein, and unless otherwise specified, the term "human antibody" corresponding to human variable regions and / or human constant regions or human germline immunoglobulin sequences refers to an antibody having these portions. Such human germline immunoglobulin sequences are Ka bat et al. (1991), Sequences of Proteins of Immunological Interest. mmunological Interest), 5th ed., U.S. Department of Health and Human Services, NIH It is described in Publication No. 91-3242. Here, the human antibody binds to BTN1A1 and by a nucleic acid sequence that is a natural somatic variant of a human germline immunoglobulin nucleic acid sequence; can include antibodies that are encoded.

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

[0143] As used herein, and unless otherwise specified, the term "humanized antibody" refers to , the native complementarity determining region (“CDR”) residues possess the desired specificity, affinity and potency. , corresponding CDRs in non-human species such as mouse, rat, rabbit, or non-human primates (e.g. human immunoglobulin (e.g., recipient antibody) that has been replaced with residues from chimeric antibody). optionally one or more FR regions of a human immunoglobulin Residues are replaced by the corresponding non-human residues. Furthermore, humanized antibodies are It may have residues that are found neither in the donor antibody nor in the donor antibody. These modifications enhance antibody performance. This is done for further refinement. The heavy or light chain of the humanized antibody has at least one or more number of variable regions, wherein all or substantially all of the CDRs all correspond to non-human immunoglobulin CDRs and all or substantially all of the FRs are human immunoglobulin FR of the robin sequence. A humanized antibody has at least a portion of an immunoglobulin constant region (Fc) may have at least a portion of the constant region of a normal human immunoglobulin. For more details see Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332. :323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992); Carte R et al., Proc. Natl. Acd. Sci. USA 89:4285-4289 (1992); and U.S. Patent No. 6,800,73. 8, 6,719,971, 6,639,055, 6,407,213, and 6,054,297 stomach.

[0144] As used herein, and unless otherwise specified, the term "recombinant antibody" refers to , refers to an antibody that is prepared, expressed, produced, or isolated by recombinant means. Recombinant antibody Antibodies expressed using recombinant expression vectors transfected into host cells, recombinant Antibodies isolated from combinatorial antibody libraries, human immunoglobulin genes animals that are transgenic and / or transchromosomal (e.g., mouse (e.g., Taylor, L. D. et al., Nucl. Acids Res. 20:6287-6295 (1992)), or splicing immunoglobulin gene sequences onto other DNA sequences. antibodies prepared, expressed, generated, or isolated by any other means involving can Such recombinant antibodies are derived from human germline immunoglobulin sequences (Kabat, E. A. et al. (1991), immune Sequences of Proteins of Immunological Interest ), 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3 242). Recombinant antibodies are produced by in vitro mutagenesis (or trans In vivo somatic mutagenesis may also be used when using genetic animals. , so that the amino acid sequences of the VH and VL regions of the recombinant antibody are identical to the human germline VH and VL sequences. derived from, and related to, the human antibody germline repertoire in vivo. can be a non-existent sequence.

[0145] As used herein, and unless otherwise specified, "neutralizing antibody" refers to BTN1A1 and binding to its natural ligand, signaling pathways mediated by BTN1A1 and / or Or refers to antibodies that inhibit other physiological activities. The IC50 of the neutralizing antibody was higher than that of BTN1 in the neutralization assay. Refers to the concentration of antibody required to neutralize 50% of A1. The IC50 of a neutralizing antibody can range from 0.01 to 10 μg / ml.

[0146] As used herein, and unless otherwise specified, the term "antigen-binding fragment" and similar terms immunospecifically bind to an antigen and describe its specificity and affinity for the antigen refers to the portion of an antibody that contains the amino acid residues that impart to the antibody the Antigen-binding fragments are functional can be called fragments. Antigen-binding fragments can be monovalent, bivalent, or multivalent.

[0147] Examples of molecules having an antigen-binding fragment include Fd, Fv, Fab, F(ab'), F(ab) 2 , F(ab') 2 , single-chain Fv (scFv), diabodies, triabodies, tetrabodies, minibodies, or single-chain Fvs A main antibody is included. A scFv can be a monovalent scFv or a bivalent scFv. antigen binding Other molecules having fragments include, for example, heavy or light chain polypeptides, variable region polypeptides, or CDR polypeptides, as long as or parts thereof. Such antigen-binding fragments are, for example, Harl ow and Lane, Antibodies: A Laboratory Manual, Cold Spr ing Harbor Laboratory, New York (1989); Myers (ed.), Molecular Biology and Biotechnology: Comprehensive. Molec. Biology and Biotechnology: A Comprehensive Desk Reference, Ne w York: VCH Publisher; Huston et al., Cell Biophysics, 22:189-224 (1993); Plu ckthun and Skerra, Meth. Enzymol., 178:497-515 (1989), and Day, E.D. , Advanced Immunochemistry, 2nd ed., Wiley-Liss Co., New York, NY (1990 ) can be found described in The antigen-binding fragment has at least 5 consecutive Amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acids no acid residue, at least 20 consecutive amino acid residues, at least 25 consecutive amino acids residue, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues , at least 60 contiguous amino acid residues, at least 70 contiguous amino acid residues, at least at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 20 An amino acid sequence of 0 contiguous amino acid residues or at least 250 contiguous amino acid residues It can be a polypeptide with strings.

[0148] The heavy chain of an antibody has a variable region of about 120-130 or more amino acids at the amino terminal portion. and the carboxy-terminal portion includes a constant region, a polypeptide chain of about 50-70 kDa vinegar. Based on the amino acid sequence of the heavy chain constant region, the constant regions are alpha (α), delta (δ), one of five different types, called epsilon (ε), gamma (γ), and mu (μ) can be one. Different heavy chains differ in size: α, δ, and γ contain approximately 450 amino acids. contains no acids, while μ and ε contain approximately 550 amino acids. combined with a light chain These different types of heavy chains are then divided into four subclasses of IgG: IgG1, IgG2, The five groups of antibodies, IgA, IgD, IgE, IgG, and IgM, respectively, including IgG3 and IgG4. give rise to a class of knowledge. The heavy chain can be a human heavy chain.

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

[0150] The variable domain or variable region of an antibody is usually located at the amino terminus of the light or heavy chain, has a length of about 120-130 amino acids for light chains, and about 100-110 amino acids for light chains. antibody light or heavy chain used for the binding and specificity of the antibody for its particular antigen refers to the part of Variable domains vary widely in sequence between different antibodies. Sequence variation is It is concentrated in the CDRs, while the less variable portion within the variable domain is in the framework regions. called the region (FR). The light and heavy chain CDRs are primarily involved in antibody-antigen interactions. The numbering of amino acid positions used herein is based on Kabat et al. (1991) Immunological Interests. Sequences of proteins of immunological interest (U.S. Department of ent of Health and Human Services, Washington, D.C.), 5th ed. index. The variable regions can be human variable regions.

[0151] CDRs are non-framework of the immunoglobulin (Ig or antibody) VH β-sheet framework. 1 of the 3 hypervariable regions (H1, H2, or H3) within the arc region, or the antibody VL β-sheet Among the three hypervariable regions (L1, L2, or L3) within the non-framework regions of the framework point to one of the Thus, the CDRs are the variable region sequences interspersed within the framework region sequences. is. CDR regions are well known to those of skill in the art, e.g., the most hypervariable within antibody variable (V) domains. defined by Kabat (Kabat et al., J. Biol. Chem. 252:6609) as the region of -6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). Also, the CDR region sequence is not part of a conserved β-sheet framework and therefore adopts a variety of conformations As a residue that can be Literature, J. Mol. Biol. 196:901-917 (1987)). Both terminologies are well recognized in the art. ing. CDR locations within canonical antibody variable domains are determined by numerous structural comparisons (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Since the number of residues in the hypervariable regions varies in different antibodies, , in the standard variable domain numbering system, additional residues to the standard positions, conventionally residues The number is followed by a, b, c, etc. (Al-Lazikani et al., supra (1997)). ancestor Nomenclature systems such as are also well known to those skilled in the art.

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

table 1

[0153] Alternatively, one or more CDRs may be covalently or non-covalently incorporated into a molecule to It can be made into an adhesin. Immunoadhesins bind CDRs to larger polypeptide chains or covalently link the CDRs to another polypeptide chain. or the CDRs can be incorporated non-covalently. CDR is an immunoad Allows Hesin to bind to a specific antigen of interest.

[0154] "Framework" or "FR" residues refer to the variable domain residues flanking the CDRs. FR remaining Groups include, for example, chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bi- Present in bispecific antibodies. FR residues are variable other than hypervariable region residues as herein defined. domain residues.

[0155] As used herein, and unless otherwise specified, used in the context of antibodies The term "isolated" when used means that the antibody is derived from cellular material or from a cell or tissue source. substantially free of other contaminating proteins and / or other contaminating components from which antibodies are derived, or or, if chemically synthesized, means substantially free of chemical precursors or other chemicals. do. The phrase "substantially free of cellular material" refers to the antibody from which it was isolated or Includes preparations of antibodies that have been separated from cellular components of recombinantly-produced cells. but Thus, antibodies substantially free of cellular material may contain (by dry weight) about 30%, 20%, 10%, or 5% % heterologous protein (also referred to herein as "contaminant protein") Includes body preparations. In some embodiments, when the antibody is recombinantly produced, It is substantially free of culture medium, e.g., the culture medium contains about 20% of the volume of the protein preparation. %, 10%, or less than 5%. In some embodiments, the antibody is produced by chemical synthesis. When produced, it is substantially free of chemical precursors or other chemicals, e.g. is separated from chemical precursors or other chemicals involved in protein synthesis. death Accordingly, preparations of such antibodies have a concentration of less than about 30%, 20%, 10%, 5% (by dry weight). chemical precursors or compounds other than the antibody of interest. Contaminants include, but are not limited to, Substances that interfere with therapeutic use of antibodies may also be mentioned, as well as enzymes, hormones, and other Proteinaceous or non-proteinaceous solutes can be mentioned. In some embodiments, anti- (1) Lowry method (Lowry et al., J. Bio. Chem. 193: 265-275, 192

[0156] 1) greater than 95%, e.g., up to 99% by weight of the antibody, (2) spinning Obtain at least 15 residues of the N-terminal or internal amino acid sequence using a sequencenator. or (3) using Coomassie blue staining or preferably silver staining Purify to homogeneity by SDS-PAGE under reducing or non-reducing conditions. antibody natural Isolated antibody may contain an antibody within recombinant cells, since at least one component of the environment will not be present. In situ antibodies are included. Ordinarily, however, the isolated antibody will contain at least one prepared by the purification process of In a specific embodiment, an antibody provided herein has been isolated.

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

[0158] As used herein, and unless otherwise specified, used in the context of a nucleic acid molecule. The term "isolated" as used means that the nucleic acid molecule is present in the natural source of the nucleic acid molecule other than is a nucleic acid molecule that is separated from the nucleic acid molecule of the In addition, "isolated" When the nucleic acid molecule, e.g., cDNA molecule, is produced by other cellular material or by recombinant techniques is substantially free of culture medium or, if chemically synthesized, chemical precursors It can be substantially free of chemicals or other chemicals. Specific implementation In, a nucleic acid molecule encoding an antibody provided herein is isolated or purified.

[0159] As used herein, and unless otherwise specified, "bind" or "bind The term "thing" refers to interactions between molecules. Interactions are e.g. hydrogen bonding, ionic non-covalent phases, including bonds, hydrophobic interactions, and / or van der Waals interactions can be interactive. between an antibody and a target molecule, e.g. a single epitope of BTN1A1 is the affinity of the antibody for its epitope . "Binding affinity" generally refers to a single binding affinity of a molecule (e.g., binding protein, e.g., antibody). The total strength of non-covalent interactions between a site and its binding partner (e.g. antigen) Point.

[0160] a binding molecule X, e.g., an antibody's binding partner Y, e.g., a parent for an antibody's cognate antigen Compatibility is usually determined by the dissociation constant (K D ). Low-affinity antibodies are usually High-affinity antibodies usually It tends to bind faster and stay bound longer. To measure binding affinity A variety of methods are known in the art, any of which can be used for the purposes of this disclosure. be able to. "K D ” or “K D "value" can be determined by assays known in the art, e.g. It can be measured by a binding assay. K. D is, for example, the Fab-type antibody of interest and It can be measured in a radiolabeled antigen binding assay (RIA) performed with the antigen and its antigen. (Chen et al. (1999) J. Mol Biol 293:865-881). K. D or K D The value is, for example, BIAcore( Biacore using a BIAcore™-2000 or BIAcore™-3000 (BIAcore Inc., Piscataway, NJ). by using a surface plasmon resonance assay according to, for example, OctetQK384 cis It can also be measured by biolayer interferometry using a system (ForteBio, Menlo Park, CA). can.

[0161] As used herein, and unless otherwise specified, a molecule means that such binding is anti- "immunospecifically binds" to a second molecule when it exhibits specificity and affinity for its cognate antigen of the body It is said to be able to "match". Antibodies such binding comprises the antibody's antigen-recognition site In some cases, it immunospecifically binds to a target region or conformation (“epitope”) of an antigen. specific anti Antibodies that immunospecifically bind to the antigen may be tested for other antigens by, e.g., immunoassays, BIACORE® antigen-recognition portion, as determined by a target assay, or other assays known in the art by other antigens if they have some degree of sequence or conformational similarity recognized by the position It can bind with low affinity. Antibodies in general do not bind to any unrelated antigen. part antibodies (and antigen-binding fragments thereof) do not cross-react with other antigens. Antibodies are immune to other molecules. Other regions of the antibody that do not contain antigen recognition sites / Binding may also be due to a domain, eg, a binding domain in the Fc region.

[0162] An antibody or antibody that immunospecifically binds to an antigen or epitope of an antigen that contains a glycosylation site A native binding fragment can bind to an antigen or epitope in both glycosylated or non-glycosylated form. can be combined. In some embodiments, the antibody or antigen-binding fragment is non-glycemic Preferential binding to glycosylated antigens or epitopes over lycosylated antigens or epitopes be. Preferential binding can be determined by binding affinity. For example, non-glycosylated Antibodies or antigen-binding fragments that preferentially bind glycosylated BTN1A1 over BTN1A1 are non-glycosylated. K shown for sylated BTN1A1 D less than K D can bind to glycosylated BTN1A1 at . In some embodiments, the antibody or antigen-binding fragment is directed against unglycosylated BTN1A1. K denoted by D K less than half of D binds to glycosylated BTN1A1 at in some embodiments wherein the antibody or antigen-binding fragment has a K shown against non-glycosylated BTN1A1 D less than K at least 10 times smaller D binds to glycosylated BTN1A1 at In some embodiments, The antibody or antigen-binding fragment is the K shown against non-glycosylated BTN1A1 D about 75%, about 50% of , about 25%, about 10%, about 5%, about 2.5%, or about 1% D binds to glycosylated BTN1A1 at be.

[0163] Antibodies or antigen-binding fragments that immunospecifically bind to BTN1A1 are BTN1A1 monomers or BTN1A1 dimers. Can be attached to the body. In some embodiments, the antibody or antigen-binding fragment comprises Binds preferentially to BTN1A1 dimers over BTN1A1 monomers. BTN1A1 binding, for example, or soluble BTN1A1 domain constructs such as BTN1 A1 extracellular domain (ECD) constructs (e.g., flag-tagged BTN1A1-ECD or BTN1A1-C ED-Fc fusion constructs). In some embodiments, BTN1A1 monomers or dimers are glycosylated at one or more positions. some implementations Similarly, the antibody or antigen-binding fragment has a K D less than half of K. Dbinds to the BTN1A1 dimer. In some embodiments, the antibody or antigen-binding fragment is , K shown for the BTN1A1 monomer D K that is at least 10 times smaller than D binds to the BTN1A1 dimer at do. In some embodiments, the antibody or antigen-binding fragment is directed against BTN1A1 monomer K indicated D about 75%, about 50%, about 25%, about 10%, about 5%, about 2.5%, or about 1% of K D BTN1A in 1 binds to the dimer.

[0164] Preferential binding is determined by binding assays and, for example, by means of mean fluorescence intensity (“MFI”). Therefore, it can also be shown For example, an antibody or antigen that preferentially binds glycosylated BTN1A1 The binding fragment bounded glycosylated BT with a higher MFI than that shown for unglycosylated BTN1A1. Can bind to N1A1. In some embodiments, the antibody or antigen-binding fragment is , glycosylated BTN with an MFI at least 2-fold higher than that shown for unglycosylated BTN1A1 Binds to 1A1. In some embodiments, the antibody or antigen-binding fragment is non-glycosyl binds glycosylated BTN1A1 with an MFI that is at least 3-fold higher than that shown for glycosylated BTN1A1 . In some embodiments, the antibody or antigen-binding fragment is directed to unglycosylated BTN1A1. at least 5x, at least 10x, at least 15x, or at least 20x the indicated MFI Binds glycosylated BTN1A1 with high MFI.

[0165] As used herein, and unless otherwise specified, a molecule may be an antigen or epitope. glycosylation at specific glycosylation sites thereof, or "immunospecifically masks" (1) non-glycosylated so that the antigen or epitope cannot be glycosylated; block the glycosylation sites of the sylated antigen or epitope; or (2) the glycosylated antigen or to an epitope or to a specific glycosylation part of a glycosylated antigen or epitope downstream mediated by the physiological effects of glycosylation, e.g. refers to its ability to either interfere with the signaling of For example, BTN1A1 glycosylation An antibody or antigen-binding fragment that immunospecifically masks (1) the glycosylation of unglycosylated BTN1A1; either block the lylation site and prevent its glycosylation, or (2) bind to glycosylated BTN1A1. , the physiological effects of glycosylation, e.g., immunosuppressive effects mediated by glycosylation It refers to any antibody or antigen-binding fragment that interferes. As another example, in N55 and N215 Antibodies or antigen-binding fragments that immunospecifically mask BTN1A1 glycosylation are: (1) non-glycosylated block N55 and N215 of sylated BTN1A1 and prevent glycosylation of N55 and N215, or (2) N Binds BTN1A1 that is glycosylated at 55 and N215 and demonstrates the physiological effects of glycosylation, e.g. for example, any antibody or antigen that prevents immunosuppressive effects mediated by glycosylation Refers to binding fragments.

[0166] As used herein, and unless otherwise specified, the term "carrier" refers to The diluent with which the therapeutic is administered, an adjuvant (e.g., Freund's adjuvant ( complete or incomplete)), excipient, stabilizer, or vehicle. “Pharmaceutically acceptable A “carrier” that is effective for cells or mammals exposed to it at the dosages and concentrations employed It is a carrier that is non-toxic and can be sterile liquids, such as water and oils. Of petroleum, animal, vegetable or synthetic origin, e.g. peanut oil, soybean oil, mineral oil, sesame oil and so on.

[0167] As used herein, and unless otherwise specified, the term "vector" refers to Refers to substances used to introduce nucleic acid molecules into host cells. applicable basis for use. Examples of vectors include expression vectors, plasmids, phage vectors, viral vectors terminology, episomes, and artificial chromosomes, which are stably integrated into the host cell's chromosomes. A selection sequence or marker operable for integration may be included. Additionally, vector can include one or more selectable marker genes and appropriate expression control sequences. including Selectable marker genes that can be used are, for example, resistance to antibiotics or toxins. to compensate for autotrophic deficiencies or supply critical nutrients not present in the culture medium. expression control The sequences are known in the art for constitutive and inducible promoters, transcriptional enhancers, transcriptional It can include photo terminator and the like. Two or more nucleic acid molecules (e.g. antibody heavy and light chains) ) are to be co-expressed, both nucleic acid molecules are to be co-expressed, e.g. or can be inserted into a separate expression vector. For single vector expression, code Nucleic acids may be operably linked to one common expression control sequence, or different expression control sequences, e.g. For example, they can be linked to one inducible promoter and one constitutive promoter. Introduction of a nucleic acid molecule into a host cell can be confirmed using methods well known in the art. . Such methods include, for example, nucleic acid analysis, Northern blotting of mRNA, or is polymerase chain reaction (PCR) amplification or immunoblotting for gene product expression or other suitable method for testing the expression of an introduced nucleic acid sequence or its corresponding gene product. analysis method. The nucleic acid molecule is a desired product (e.g., the anti-BTN 1A1 antibody) is understood by those skilled in the art, and expression Current levels can be optimized using methods well known in the art to obtain sufficient expression It is further understood that

[0168] As used herein, and unless otherwise specified, the term "host cell" Specific subject cells transfected with nucleic acid molecules and the progeny or potential of such cells refers to descendants. The progeny of such cells are susceptible to mutations or environmental changes that may occur in subsequent generations. transfected nucleic acid molecule due to influence or integration of the nucleic acid molecule into the host cell genome It does not have to be identical to the parent cell obtained.

[0169] As used herein, and unless otherwise specified, the term "subject" refers to treatment , an animal that is the object of observation and / or experimentation. “animal” includes vertebrates and invertebrates; animals such as fish, crustaceans, reptiles, birds, especially mammals. in "mammal" are mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, spirits Long mammals such as monkeys, chimpanzees, apes, and humans include, but are not limited to, do not have.

[0170] As used herein, and unless otherwise specified, the term “cancer” or “cancerous” The term typically refers to a physiological condition in mammals characterized by unregulated cell proliferation. vinegar. Examples of cancers include, but are not limited to, hematological cancers and solid tumors.

[0171] As used herein, and unless otherwise specified, when used in relation to cancer patients The terms "treat," "treating," and "treatment" are used to reduce the severity of cancer. or refers to the act of stopping or slowing the progression of cancer, which includes (a) inhibiting the growth of cancer; and (b) causing regression of cancer or stopping cancer survival. including delaying or minimizing one or more symptoms associated with cancer.

[0172] As used herein, and unless otherwise specified, "resistant" or "refractory" The term is used to indicate that a patient has residual cancer cells (e.g., lung or breast cancer cells) even after intensive care. cysts) in a tissue or organ (eg, lungs or chest).

[0173] The term "responsive" or "responsive" when used in reference to treatment refers to disease, e.g., anti-PD1 therapy or anti-PD-L1 therapy-resistant or refractory cancer refers to the degree of effectiveness of treatment in e.g. used for treatment of cells or subjects The term "increased responsiveness" when measured using any method known in the art when compared to a reference treatment (e.g., in the same cell or subject, or in a different cell or subject) It refers to increased effectiveness in alleviating or reducing the symptoms of a disease compared to other drugs. In one embodiment , the increase in efficacy is at least about 5%, at least about 10%, at least about 20%, at least is also about 30%, at least about 40%, or at least about 50%.

[0174] As used herein, "effective subject response," "effective patient response," and "efficacy." The term "effective patient tumor response" refers to any increase in therapeutic benefit to the patient. " An "effective patient tumor response" is, for example, about 5%, about 10%, about 25%, about 50% , or a reduction of about 100%. An "effective patient tumor response" is e.g. It can be about a 5%, about 10%, about 25%, about 50%, or about 100% reduction in physical symptoms. " "Effective patient tumor response," e.g., gene expression, cell number, assay results, tumor size, etc. which, about 5%, about 10%, about 25% of patient response, as measured by any suitable means %, about 50%, about 100%, about 200%, or more.

[0175] Improvement in cancer or cancer-related disease can be characterized as a complete or partial response. "Complete response ” indicates any previous abnormal radiographic, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal It refers to the absence of clinically detectable disease with normalization of sexual protein measurements. "partial response “Answer” is the total measurable tumor burden (i.e., number of malignant cells or tumor mass measured or amount of abnormal monoclonal protein ) at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or refers to a reduction of about 90%. The term "treatment" contemplates both complete and partial responses. be.

[0176] The term "probability" generally refers to an increase in the probability of an event. regarding efficacy of patient tumor response. The term "likelihood" when used as a term usually refers to the rate of tumor progression or tumor cell growth is intended to increase the probability that when used with respect to efficacy of patient tumor response The term "probability" usually refers to mRNA or protein that may be evidence of increased therapeutic progress of a tumor. It can also mean an increase in an indicator, such as protein expression.

[0177] The term "predict" generally means to determine or refer to in advance. When used to "predict" the efficacy of a cancer treatment, e.g., the term "predict" is the best way to determine the likelihood of cancer treatment outcome before treatment begins or substantially advances the duration of treatment. means that it can be determined first.

[0178] The term "monitoring" as used herein generally refers to the monitoring, supervision, Refers to regulation, observation, follow-up, or investigation. For example, "monitoring the efficacy of a compound" The term is used to track the efficacy of cancer treatments in patients or in tumor cell cultures. Point. Similarly, the term “monitoring” refers to patient When used in the context of compliance, the It refers to tracking or confirming that a drug is being taken. Monitoring is for example mRNA or can be done by following the expression of protein biomarkers.

[0179] As used herein, a "tumor" is any neoplastic cell growth, whether malignant or benign. and proliferation, and all precancerous and cancerous cells and tissues. As used herein, " “Neoplastic” includes all forms of dysregulation, whether malignant or benign, that result in abnormal tissue growth. Refers to total or unregulated cell growth. Thus, "neoplastic cells" include dysregulated or Included are malignant and benign cells with unregulated cell growth.

[0180] As used herein, and unless otherwise specified, the term "therapeutically effective amount" is , the severity of a given disease, disorder or condition, and / or symptoms associated therewith and / or Agents that are sufficient to reduce and / or improve duration (e.g., as described herein) antibody or any other agent described herein). Drug therapy, including therapeutic agents A therapeutically effective amount is defined as: (i) reducing or ameliorating the development or progression of a given disease, disorder, or condition; (ii) recurrence, onset, or reduction or amelioration of the occurrence of a given disease, disorder, or condition; and / or (iii) anticipation of another therapy (e.g., a therapy other than administration of an antibody provided herein). It can be the amount necessary to improve or enhance the preventive or therapeutic effect. Substances of the present disclosure / A therapeutically effective amount of a molecule / agent (e.g., an anti-BTN1A1 antibody) may vary depending on the individual's medical condition, age, sex, and weight. , as well as the ability of said substance / molecule / agent to elicit a desired response in an individual. can differ. A therapeutically effective amount means that any toxic or detrimental effect of the substance / molecule / drug is therapeutically beneficial. including an amount that outweighs the desired effect.

[0181] As used herein, and unless otherwise specified, "administer" or "administration" The term is used to convey substances in an extracorporeal state to a patient, e.g., mucosally, intradermally, intravenously, intramuscular delivery and / or any other described herein or known in the art Refers to the act of injecting or otherwise physically delivering by physical delivery method. disease, disability When treating an injury or disease, or a symptom thereof, administration of the substance is usually after the onset of the disorder or disease or symptoms thereof. disease, disorder, or disease , or when preventing these symptoms, administration of the substance is usually associated with the disease, disorder, or condition. disease, or before the onset of these symptoms.

[0182] A "biological marker" or "biomarker" means that its detection indicates, for example, the presence of cancer is a substance that exhibits a specific biological state of In some embodiments, biomarkers - may be determined on a case-by-case basis. In other embodiments, some biomarkers can be measured simultaneously. In some embodiments of the methods provided herein BTN1A1 is a biomarker for the presence of cancer. In some embodiments, PD-L1 is a biomarker that indicates the presence of cancer. In some embodiments, BTN1A1 and PD-L1 in combination to treat cancers (e.g., responsive to treatment with anti-BTN1A1 antibodies, e.g. (e.g., anti-PD1 or anti-PD-L1 therapy-resistant or refractory cancer).

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

[0184] In a further embodiment, the "biomarker" is disease risk or progression, or Changes in levels of polypeptide or protein expression that may correlate with patient susceptibility to therapy indicates In some embodiments, biomarkers are polypeptides or proteins proteins, or fragments thereof (eg, BTN1A1 or PD-L1 proteins). special Relative levels of a given protein can be determined by methods known in the art. Wear. For example, antibody-based methods such as immunoblotting, enzyme-linked immunosorbent assays (E LISA), or other methods can be used.

[0185] The terms "expressed" or "expression" as used herein refer to the two nucleic acids of a gene from a gene that produces an RNA nucleic acid molecule that is at least partially complementary to a region of one of the strands refers to the transcription of The term "expressed" or "expression" as used herein refers to protein Also refers to translation from an RNA molecule to produce a protein, polypeptide, or portion thereof.

[0186] The term "level" refers to the amount, accumulation , or percentage. The level is determined, for example, by the messenger RNA encoded by the gene ( amount or rate of synthesis of mRNA), polypeptide or protein encoded by the gene the amount or rate of synthesis of a protein, or the amount or amount of biomolecules accumulated in a cell or biological fluid It can be expressed by the synthetic speed. The term "level" refers to steady-state or non-steady-state Refers to the absolute amount of a molecule or the relative amount of that molecule in a sample determined under conditions of

[0187] As used herein, "determining", "measuring", "evaluating", "evaluating" The terms "assessing" and "assaying" generally refer to any form of measurement. , including determining whether an element exists. These terms are used for quantitative determination and / or or including both qualitative determinations. Assessing is absolute, even if it is relative. It may be a specific one. "Assessing the presence of" to determine the amount of something that exists and to determine whether it exists or does not exist can include

[0188] The term "sample" as used herein generally, but need not necessarily, refer to It relates to a material or mixture of materials in fluid form, containing one or more components of

[0189] A "biological sample" as used herein is obtained in vivo or in situ, Biological objects, including samples of biological tissue or fluid origin, that are touched or collected refers to a sample obtained from The biological sample may contain precancerous cells or tissue or cancer cells if any. Also included are samples derived from regions of biological interest, including cancerous tissue. Such samples are Can be, but is not limited to, organs, tissues, and cells isolated from mammals. stomach. Exemplary biological samples include cell lysates, cell cultures, cell lines, tissues, oral tissues. , gastrointestinal tissue, organs, organelles, biological fluids, blood samples, urine samples, skin samples, etc. include but are not limited to: Preferred biological samples include whole blood, partially purified blood, Examples include, but are not limited to, PBMC, tissue biopsy, and the like.

[0190] (5.2 Molecules having antigen-binding fragments that immunospecifically bind to BTN1A1) Antigen binders that immunospecifically bind to BTN1A1 are useful in the methods provided herein. Molecules with synthesizing fragments are disclosed, for example, in international patents Application PCT / US2016 / 064436 and “BTN1A1 Immunospecifically Binds” filed May 31, 2017 ANTIBODIES AND MOLECULES THAT IMMUNOSPECIFIC LLY BIND TO BTN1A1 AND THERAPEUTIC USES THEREOF). No. 13532-018-888).

[0191] Provided herein are antigens that immunospecifically bind to BTN1A1, including anti-BTN1A1 antibodies A molecule that has a binding fragment. In some embodiments, immunospecifically binding to BTN1A1 An antigen-binding fragment that does bind to a fragment, or epitope, of BTN1A1. in some embodiments , the antigen-binding fragment immunospecifically binds to the BTN1A1 dimer. some implementations In, the BTN1A1 epitope can be a linear epitope. some implementations In embodiments, the BTN1A1 epitope can be a conformational epitope. how many In some embodiments, the BTN1A1 epitope is found on the BTN1A1 dimer and is found on the BTN1A1 monomer. can not see. In some embodiments, an antigen-binding fragment that immunospecifically binds to BTN1A1 A molecule provided herein having a inhibits the immunosuppressive function of BTN1A1.

[0192] Translation that N-glycosylation is initiated in the endoplasmic reticulum (ER) and subsequently processed in the Golgi post-modification (Schwarz and Aebi, Curr. Opin. Struc. Bio., 21(5): 576-582 (2011) ). This type of modification converts preformed glycans composed of oligosaccharides into NXT moieties. Membrane translocation to the asparagine (Asn) side chain acceptor located inside the -Asn-X-Ser / Thr- It is first catalyzed by the related oligosaccharyltransferase (OST) complex (Cheung and Reithmeier, Methods, 41: 451-459 2007); Helenius and Aebi, Science e, 291(5512):2364-9(2001). Addition or Removal of Saccharides from Preformed Glycans each tightly regulates the N-glycosylation cascade in a cell- and position-dependent manner. It is mediated by a group of glycosyltransferases and glycosidases.

[0193] In some embodiments, the molecule is selected for one or more glycosylation motifs of BTN1A1. It has an antigen-binding fragment that selectively binds. In some embodiments, the antigen-binding fragment is , which immunospecifically binds to glycopeptides with glycosylation motifs and adjacent peptides be. In some embodiments, the antigen-binding fragment comprises a glycosylation motif in three dimensions. It immunospecifically binds to peptide sequences located near one or more of them. Several In embodiments, the antigen-binding fragment is more than one or more glycosylation motifs of the BTN1A1 monomer. Limo also selectively binds to one or more glycosylation motifs of the BTN1A1 dimer.

[0194] In some embodiments, the antigen-binding fragment is directed against unglycosylated BTN1A1. K D K of at least 30%, 40%, 50%, 60%, 70%, 80%, or less than 90% of D Glycosi in Binds glycosylated BTN1A1 (eg, glycosylated BTN1A1 dimer). In some embodiments, the Antigen-binding fragment is K shown for non-glycosylated BTN1A1 D K less than 50% of D Glycosyl at Binds to BTN1A1. In some embodiments, the antigen-binding fragment is non-glycosylated K shown against BTN1A1 D 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% of %, 20%, 30%, 40%, K less than 50% D binds to glycosylated BTN1A1 at Several In embodiments, the antigen-binding fragment is the K shown for non-glycosylated BTN1A1. D than K at least 10 times smaller D binds to glycosylated BTN1A1 at

[0195] A specific glycosylation site of a particular BTN1A1 isoform or variant is Amino acids at positions 55, 215, or 449 of the A1 isoform or variant may vary. this In these situations, those skilled in the art would be well-versed in sequence alignments and other collaborations in the art. Corresponds, based on common knowledge, to N55, N215, and N449 of human BTN1A1 exemplified above. Glycosylation sites of any particular BTN1A1 isoform or variant can be determined would be Accordingly, provided herein are non-glycosylated BTN1A1 isophors Immunospecific for glycosylated forms of BTN1A1 isoforms or variants compared to omega or variants It is also a molecule that has an antigen-binding fragment that specifically binds to it. Group of BTN1A1 isoforms or variants The lycosylation sites correspond to N55, N215, and N449 of the human BTN1A1 sequence provided above. It can be a part that

[0196] In some embodiments, the molecule is glycosylated BTN1A1 (e.g., glycosylated B It has an antigen-binding fragment that immunospecifically binds to TN1A1 dimer). In some embodiments wherein the antigen-binding fragment is BTN1A1 glycosylated at positions N55, N215, and / or N449 binds immunospecifically to In some embodiments, the antigen-binding fragment has Binds immunospecifically to glycosylated BTN1A1. In some embodiments, The antigen-binding fragment immunospecifically binds to BTN1A1 that is glycosylated at position N215. In some embodiments, the antigen-binding fragment is BT that is glycosylated at position N449. Binds immunospecifically to N1A1. In some embodiments, the antigen-binding fragment comprises one or more binds immunospecifically to glycosylation motifs of In some embodiments, the antigen The binding fragment immunospecifically binds to BTN1A1 glycosylated at positions N55 and N215 . In some embodiments, the antigen-binding fragment is glycosylated at positions N215 and N449. immunospecifically binds to BTN1A1. In some embodiments, the antigen-binding fragment binds immunospecifically to BTN1A1 that is glycosylated at positions N55 and N449. how many In some embodiments, the antigen-binding fragment is glycosylated at positions N55, N215, and N449. immunospecifically binds to BTN1A1.

[0197] In some embodiments, the molecule is glycosylated BTN1A1 (e.g., glycosylated B TN1A1 dimer) having an antigen-binding fragment that immunospecifically binds to a TN1A1 dimer, wherein the antigen-binding fragment comprises Binds preferentially to glycosylated BTN1A1 over non-glycosylated BTN1A1. some implementations In a manner, the antigen-binding fragment has positions N55, N215, and / or Binds preferentially to BTN1A1 which is glycosylated at N449. In some embodiments , the antigen-binding fragment is a BTN that is glycosylated at position N55 relative to unglycosylated BTN1A1 Binds preferentially to 1A1. In some embodiments, the antigen-binding fragment is non-glycosylated. Binds preferentially to BTN1A1 glycosylated at position N215 over glycosylated BTN1A1. how many In some embodiments, the antigen-binding fragment is more glycated at position N449 than unglycosylated BTN1A1. Binds preferentially to cosylated BTN1A1. In some embodiments, the antigen binding Synthetic fragments preferentially bind to one or more glycosylation motifs. In some embodiments wherein the antigen-binding fragment is glycosylated at positions N55 and N215 over non-glycosylated BTN1A1 binds preferentially to BTN1A1 In some embodiments, the antigen-binding fragment is , preferring BTN1A1 glycosylated at positions N215 and N449 over non-glycosylated BTN1A1 physically connect. In some embodiments, the antigen-binding fragment is unglycosylated BTN1A1 preferentially binds BTN1A1, which is glycosylated at positions N55 and N449, rather than BTN1A1. some In embodiments of , the antigen-binding fragment has positions N55, N215, than non-glycosylated BTN1A1. and binds preferentially to BTN1A1 which is glycosylated at N449.

[0198] Preferential binding can be determined by binding affinity. For example, glycosylated BTN1 Antibodies or antigen-binding fragments that preferentially bind A1 (e.g., glycosylated BTN1A1 dimers) K shown for glycosylated BTN1A1 D less than K D can bind to glycosylated BTN1A1 at can. In some embodiments, the antibody or antigen-binding fragment is non-glycosylated BTN1 K shown against A1 D K less than half of D binds to glycosylated BTN1A1 at some implementations In embodiments, the antibody or antigen-binding fragment has a K D world K D binds to glycosylated BTN1A1 at In some embodiments wherein the antibody or antigen-binding fragment has a K D less than K at least 5 times smaller D binds to glycosylated BTN1A1 at In some embodiments, the Antibodies or antigen-binding fragments are K D at least 10 than times smaller K D binds to glycosylated BTN1A1 at In some embodiments, the antibody or Antigen-binding fragment is K shown for non-glycosylated BTN1A1 D at least 15 times smaller than K. D binds to glycosylated BTN1A1 at In some embodiments, the antibody or antigen binding Fragment K shown for unglycosylated BTN1A1 D K at least 20 times smaller than D Guri in Binds to cosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment comprises K shown for unglycosylated BTN1A1 D K at least 25 times smaller than D glycosylation at Binds to BTN1A1. In some embodiments, the antibody or antigen-binding fragment is non-glycosylated. K shown for sylated BTN1A1 D K at least 30 times smaller than D to glycosylated BTN1A1 at Join. In some embodiments, the antibody or antigen-binding fragment is non-glycosylated BT K shown against N1A1 D K at least 40 times smaller than D binds to glycosylated BTN1A1 at . In some embodiments, the antibody or antigen-binding fragment is directed against unglycosylated BTN1A1. K denoted by D K at least 50 times smaller than D binds to glycosylated BTN1A1 at how many In some embodiments, the antibody or antigen-binding fragment is directed against unglycosylated BTN1A1. K D K, which is about 75% of D binds to glycosylated BTN1A1 at In some embodiments , the antibody or antigen-binding fragment is K shown against non-glycosylated BTN1A1 D is about 50% of K. D binds to glycosylated BTN1A1 at In some embodiments, the antibody or antigen binding Fragment K shown for unglycosylated BTN1A1 D K, which is about 25% of D Glycosylated BTN1 at Bind to A1. In some embodiments, the antibody or antigen-binding fragment is non-glycosyl K shown for BTN1A1 D K, which is about 10% of D binds to glycosylated BTN1A1 at how many In some embodiments, the antibody or antigen-binding fragment is directed against unglycosylated BTN1A1. K D K, which is about 5% of D binds to glycosylated BTN1A1 at In some embodiments , the antibody or antigen-binding fragment is K shown against non-glycosylated BTN1A1 D about 2.5% of K D binds to glycosylated BTN1A1 at In some embodiments, the antibody or antigen binding Synthetic fragments are K shown for unglycosylated BTN1A1 D K, which is about 1% of D Glycosylated BTN at Binds to 1A1.

[0199] Preferential binding is determined, for example, in binding assays as indicated by fluorescence intensity (“MFI”) can also For example, preference for glycosylated BTN1A1 (e.g., glycosylated BTN1A1 dimer) Antibodies or antigen-binding fragments that specifically bind to can also bind glycosylated BTN1A1 with high MFI. In some embodiments , the antibody or antigen-binding fragment has an MFI of at least 2 Binds glycosylated BTN1A1 with a fold higher MFI. In some embodiments, an antibody or anti- The original binding fragment was glycated with an MFI at least 2-fold higher than that shown for unglycosylated BTN1A1. Binds lycosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment is Glycosylated BTN1A with an MFI at least 3-fold higher than that shown for unglycosylated BTN1A1 Combine to 1. In some embodiments, the antibody or antigen-binding fragment is non-glycosylated B Binds glycosylated BTN1A1 with an MFI that is at least 5-fold higher than that shown for TN1A1. stomach In some embodiments, the antibody or antigen-binding fragment is directed against unglycosylated BTN1A1. Binds glycosylated BTN1A1 with an MFI that is at least 10-fold higher than that of glycosylated BTN1A1. some implementations Similarly, the antibody or antigen-binding fragment reduces the MFI exhibited against non-glycosylated BTN1A1. Binds glycosylated BTN1A1 with at least 15-fold higher MFI. In some embodiments, The antibody or antigen-binding fragment exhibits at least 20-fold the MFI exhibited against non-glycosylated BTN1A1 Binds glycosylated BTN1A1 with high MFI. In some embodiments, an antibody or antigen The binding fragment was glycated with an MFI at least 25-fold higher than that shown for unglycosylated BTN1A1. Binds to cosylated BTN1A1. In some embodiments, the antibody or antigen-binding fragment is a non- Glycosylated BTN1A1 with an MFI at least 30-fold higher than that shown for glycosylated BTN1A1 bind to In some embodiments, the antibody or antigen-binding fragment is non-glycosylated BT Binds glycosylated BTN1A1 with an MFI that is at least 40-fold higher than that shown for N1A1. stomach In some embodiments, the antibody or antigen-binding fragment is directed against unglycosylated BTN1A1. Binds glycosylated BTN1A1 with an MFI that is at least 50-fold higher than the MFI displayed.

[0200] In some embodiments, the antigen-binding fragment is (e.g., a glycosylated BTN1A1 dimer to immunospecifically mask BTN1A1 glycosylation at positions N55, N215, and / or N449 in the body) to In some embodiments, the antigen-binding fragment comprises the BTN1A1 glycine at position N55. Immunospecifically masks cosylation. In some embodiments, the antigen-binding fragment comprises Immunospecifically masks BTN1A1 glycosylation at position N215. in some embodiments wherein the antigen-binding fragment immunospecifically masks BTN1A1 glycosylation at position N449 do. In some embodiments, the antigen-binding fragment comprises one or more glycosylation of BTN1A1 Immunospecifically masks the motif. In some embodiments, the antigen-binding fragment comprises Immunospecifically masks BTN1A1 glycosylation at positions N55 and N215. some fruit In embodiments, the antigen-binding fragment immunizes BTN1A1 glycosylation at positions N215 and N449. Epidemic-specific mask. In some embodiments, the antigen-binding fragment comprises positions N55 and N Immunospecifically masks BTN1A1 glycosylation at 449. In some embodiments Thus, the antigen-binding fragment is immunospecific for BTN1A1 glycosylation at positions N55, N215, and N449. mask differently.

[0201] In some embodiments, the molecule is selective for BTN1A1 dimer over BTN1A1 monomer. It has an antigen-binding fragment that binds. In some embodiments, the BTN1A1 dimer is a cell expressed on the surface. In some embodiments, the BTN1A1 dimer is a soluble protein of BTN1A1. protein fragments, e.g. extracellular domain constructs of BTN1A1, e.g. Fc-fusion proteins A protein construct (eg, BTN1A1-ECD-Fc). In some embodiments, The BTN1A1 monomer is a BTN1A1 extracellular domain construct, e.g., Flag-tagged or Hi s6-tagged BTN1A1-ECD construct. In some embodiments, the BTN1A1 dimer Molecules that selectively bind to are provided herein that selectively bind to glycosylated BTN1A1 is a molecule that In some embodiments, for BTN1A1 dimer compared to BTN1A1 monomer Preferential binding to BTN can be determined, for example, using surface plasmon resonance assays (e.g., BIAcore). BTN1A1-ECD-Fc construct compared to 1A1-ECD-His6 or BTN1A1-ECD-Flag constructs is determined by determining the preferential binding to

[0202] In some embodiments, the antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosyl K shown for the BTN1A1 monomer) D at least 30%, 40%, 50%, 60%, 70%, 80% of , or K less than 90% D binds to BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). a In certain embodiments, the antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). K shown for D K less than 50% of D BTN1A1 dimer (e.g., glycosylated BTN1A1 dimer polymer). In some embodiments, the antigen-binding fragment is a BTN1A1 monomer (e.g. K shown for glycosylated BTN1A1 monomer) D 1%, 2%, 3%, 4%, 5%, 6%, 7% of K less than %, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50% D in the BTN1A1 dimer (for example Binds to glycosylated BTN1A1 dimer). In some embodiments, the antigen binding Fragments are K shown for BTN1A1 monomers (eg, glycosylated BTN1A1 monomers) D less than K at least 10 times smaller D binds to BTN1A1 dimers (eg, glycosylated BTN1A1 dimers).

[0203] Preferential binding can be determined by binding affinity. For example, the BTN1A1 dimer (e.g. For example, an antibody or antigen-binding fragment that preferentially binds a glycosylated BTN1A1 dimer) is BTN1A1 K shown for monomers (e.g. glycosylated BTN1A1 monomers) D less than K D BTN1A1 dimer in (eg, glycosylated BTN1A1 dimer). In some embodiments wherein the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) K shown against D K less than half of D to BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers) at Join. In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g. For example, the K shown for the glycosylated BTN1A1 monomer) D K that is at least two times smaller than D in BT Binds N1A1 dimers (eg, glycosylated BTN1A1 dimers). In some embodiments Thus, the antibody or antigen-binding fragment is directed against a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). K denoted by D K at least 5 times smaller than D BTN1A1 dimer (e.g., glycosylated BTN1 A1 dimer). In some embodiments, the antibody or antigen-binding fragment is BTN1A K shown for one monomer (e.g. glycosylated BTN1A1 monomer) D at least 10 times greater than Small K. D binds to BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). some fruit In embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A K shown for 1 monomer) D K at least 15 times smaller than D BTN1A1 dimer (e.g., Binds the lycosylated BTN1A1 dimer). In some embodiments, the antibody or antigen binding Synthetic fragments are K shown for BTN1A1 monomers (e.g., glycosylated BTN1A1 monomers) D than K at least 20 times smaller D binds to BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers) at . In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a K shown for lycosylated BTN1A1 monomer) D K at least 25 times smaller than D BTN1A1 in two Binds to mers (eg, glycosylated BTN1A1 dimers). In some embodiments, the Antibodies or antigen-binding fragments are directed against BTN1A1 monomers (e.g., glycosylated BTN1A1 monomers). K to be D K at least 30 times smaller than D BTN1A1 dimer (e.g., glycosylated BTN1A1 dimer polymer). In some embodiments, the antibody or antigen-binding fragment is BTN1A1 alone. K shown for monomers (e.g. glycosylated BTN1A1 monomers) D at least 40 times smaller than K D binds to BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). some implementations Alternatively, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). K shown for D K at least 50 times smaller than D BTN1A1 dimer (e.g., glycation Binds sylated BTN1A1 dimer). In some embodiments, the antibody or antigen binding Pieces are K shown for BTN1A1 monomers (e.g., glycosylated BTN1A1 monomers) D about 75% of There is K D binds to BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). some implementations In embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 K shown for monomer) D K, which is about 50% of D BTN1A1 dimer (e.g., glycosylated BTN1 A1 dimer). In some embodiments, the antibody or antigen-binding fragment is BTN1A K shown for one monomer (e.g. glycosylated BTN1A1 monomer) D K, which is about 25% of D in BTN Binds 1A1 dimers (eg, glycosylated BTN1A1 dimers). In some embodiments Thus, the antibody or antigen-binding fragment is directed against a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). K denoted by D K, which is about 10% of D to BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers) at Join. In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g. For example, the K shown for the glycosylated BTN1A1 monomer) D K, which is about 5% of D at the BTN1A1 dimer ( For example, it binds to glycosylated BTN1A1 dimers). In some embodiments, the antibody Or the antigen-binding fragment is directed against a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) K D K, which is about 2.5% of D binds to BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers) at . In some embodiments, the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a K shown for lycosylated BTN1A1 monomer) D K, which is about 1% of D binds to the BTN1A1 dimer at .

[0204] Preferential binding is determined, for example, in binding assays as indicated by fluorescence intensity (“MFI”) can also For example, preferentially bind to BTN1A1 dimers (e.g., glycosylated BTN1A1 dimers). A suitable antibody or antigen-binding fragment is directed against a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer). bound to BTN1A1 monomers (e.g., glycosylated BTN1A1 monomers) with MFIs higher than those indicated by can be combined. In some embodiments, the antibody or antigen-binding fragment is BTN1A1 MF at least 2-fold higher than the MFI shown for the monomer (e.g. glycosylated BTN1A1 monomer) Binds BTN1A1 dimers (eg, glycosylated BTN1A1 dimers) at I. some implementations wherein the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) BTN1A1 dimers (e.g., glycosylated BTN1 A1 dimer). In some embodiments, the antibody or antigen-binding fragment is BTN1A1 An MF that is at least 5-fold higher than the MFI shown for the monomer (e.g., glycosylated BTN1A1 monomer) Binds BTN1A1 dimers (eg, glycosylated BTN1A1 dimers) at I. some implementations wherein the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) BTN1A1 dimers (e.g., glycosylated BTN 1A1 dimer). In some embodiments, the antibody or antigen-binding fragment is BTN1A1 M at least 15-fold higher than the MFI shown for the monomer (e.g. glycosylated BTN1A1 monomer) FI binds BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). some implementations wherein the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) BTN1A1 dimers (e.g., glycosylated BTN 1A1 dimer). In some embodiments, the antibody or antigen-binding fragment is BTN1A1 M at least 25-fold higher than the MFI shown for the monomer (e.g. glycosylated BTN1A1 monomer) FI binds BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). some implementations wherein the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) BTN1A1 dimers (e.g., glycosylated BTN 1A1 dimer). In some embodiments, the antibody or antigen-binding fragment is BTN1A1 M at least 40-fold higher than the MFI shown for the monomer (e.g. glycosylated BTN1A1 monomer) FI binds BTN1A1 dimers (eg, glycosylated BTN1A1 dimers). some implementations wherein the antibody or antigen-binding fragment is a BTN1A1 monomer (e.g., a glycosylated BTN1A1 monomer) BTN1A1 dimers (e.g., glycosylated BTN 1A1 dimer).

[0205] In some embodiments, the antibody or antigen-binding fragment comprises the glycosylated monomeric BTN1A1 binds preferentially to the glycosylated dimer BTN1A1 than to 2 in the glycosylated BTN1A1 dimer The two BTN1A1 monomers may be independently glycosylated at the same position or at different positions. stomach. In some embodiments, one of the monomers in the BTN1A1 dimer is a glycosyl not converted. The glycosylated BTN1A1 monomer in the glycosylated BTN1A1 dimer is located at position N55 , N215, and / or N449. In some embodiments , the glycosylated BTN1A1 monomer is glycosylated at position N55. some implementations In a similar manner, the glycosylated BTN1A1 monomer is glycosylated at position N215. how many In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at position N449. be. In some embodiments, the glycosylated BTN1A1 monomer is glycosylated at positions N55 and N215. lycosylated. In some embodiments, the glycosylated BTN1A1 monomer is at the position It is glycosylated at positions N55 and N449. In some embodiments, glycosylated B The TN1A1 monomer is glycosylated at positions N215 and N449. In some embodiments , the glycosylated BTN1A1 monomer is glycosylated at positions N55, N215, and N449. be.

[0206] (5.2.1. Antibodies and Other Molecules with Antigen-Binding Fragments) In some embodiments, anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody or anti-BTN1 A1 dimer antibodies can be IgG, IgM, IgA, IgD, or IgE. anti-BTN1A1 antibody or Anti-glycosylated BTN1A1 antibodies or anti-BTN1A1 dimeric antibodies are chimeric antibodies, affinity matured antibodies, human It can also be a humanized antibody or a human antibody. anti-BTN1A1 antibody or anti-glycosylated BTN1A1 anti- anti-BTN1A1 dimeric antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) It can also be an antibody. In some embodiments, anti-BTN1A1 antibody or anti-glycosyl Anti-BTN1A1 antibody or anti-BTN1A1 dimer antibody is a polyclonal antibody or monoclonal antibody can be. In some embodiments, the anti-BTN1A1 antibody is STC703, STC810, ST C820, or humanized variants thereof.

[0207] Antibodies can be produced from any animal source, including birds and mammals. some In this embodiment, the antibody is ovine, murine (e.g., mouse and rat), rabbit, goat. of guinea pigs, camels, horses, or chickens. In addition, newer technology , development and screening of human antibodies derived from human combinatorial antibody libraries enable For example, bacteriophage antibody expression technology is fully incorporated herein by reference. As described in U.S. Pat. No. 6,946,546, incorporated herein, specific antibodies are Allows it to be produced in the absence of epidemics. These techniques are described in Marks (1992); Stemm (1994); Gram et al. (1992); Barbas et al. (1994); and Schier et al. ); these documents are fully incorporated herein by reference. .

[0208] Methods for Producing Polyclonal Antibodies in Various Animal Species, and Humanized, Chimeric, and Whole Methods for producing various types of monoclonal antibodies, including human, are well known in the art. be. For example, the following US patents provide enabling descriptions of such methods and are cited: Incorporated herein by: U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350 3,996,345; 4,196,265; 4,275,149; 4,277,437; 4,366,241; 4,469,7 97; 4,472,509; 4,606,855; 4,703,003; 4,742,159; 4,767,720; 16,567; 4,867,973; 4,938,948; 4,946,778; 5,021,236; 5,164,296; 5,196,066; 5,223,409; 5,403,484; 5,420,253; 5,565,332; 5,571,69 No. 8; No. 5,627,052; No. 5,656,434; No. 5,770,376; No. 5,789,208; No. 5,821,337; 4,091; 5,858,657; 5,861,155; 5,871,907; 5,969,108; 6,054,297; 6,165,464; 6,365,157; ​​6,406,867; 6,709,659; 6,709,873; 6,753,407 6,814,965; 6,849,259; 6,861,572; 6,875,434; 6,891,024; 7,407 , 659; and 8,178,098, which are fully incorporated herein by reference. ).

[0209] Anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody or anti-BTN1A1 dimer antibody (e.g. STC703 , STC810, STC2714) that immunospecifically binds to or glycosylate BTN1A1 A molecule that specifically binds or has an antigen-binding fragment that specifically binds to a BTN1A1 dimer is any method known in the art useful for producing a polypeptide, e.g., in vitro synthesis, It can also be produced, such as by recombinant DNA production. Humanized antibodies are produced by recombinant DNA technology can be produced by The antibodies described herein are produced using recombinant immunoglobulin expression technology. can also be produced using Recombinant production of immunoglobulin molecules, including humanized antibodies, U.S. Patent No. 4,816,397 (Boss et al.), U.S. Patent Nos. 6,331,415 and 4,816,567 (both Ca billy et al.), British Patent GB 2,188,638 (Winter et al.), and British Patent GB 2,209,7. 57; these references are fully incorporated herein by reference. Techniques for recombinant expression of immunoglobulins, including humanized immunoglobulins, are described in Goeddel et al. Literature, Gene Expression Technology, Methods in Enzymo logy), vol. 185, Academic Press (1991), and Borreback, Antibody Engineering ( Antibody Engineering), W. H. Freeman (1992); is fully incorporated herein by reference. for the production, design and expression of recombinant antibodies Further information can be found in Mayforth, Designing Antibodies, Academic Press , San Diego (1993).

[0210] In certain embodiments, anti-BTN1A1 antibodies or anti-glycosylated BTN1A1 antibodies or anti-BTN1A1 dimers A body antibody is a human antibody. Human antibodies are antibody libraries derived from human immunoglobulin sequences by a variety of methods known in the art, including the phage display methods described above using (U.S. Pat. Nos. 4,444,887 and 4,716,111; and International Publication WO 9 8 / 46645, WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 337 35, and WO 91 / 10741). Human antibodies express functional endogenous immunoglobulins. transgenic cells that are incapable of expressing human immunoglobulin genes but are capable of expressing human immunoglobulin genes. can be produced using a mouse. For example, human heavy and light chain immunoglobulin genes Gene complexes can be introduced into mouse embryonic stem cells randomly or by homologous recombination. be. Alternatively, human variable regions, constant regions, and diversity regions in addition to human heavy and light chain genes. regions can be introduced into mouse embryonic stem cells. Mouse heavy and light chain immunoglobulin genetics the offspring individually or simultaneously by introduction of human immunoglobulin loci by homologous recombination. can be disabled. In particular, homozygous deletion of the JH region inhibits endogenous antibody production. hinder The modified embryonic stem cells are expanded and microinjected into blastocysts to generate chimeric mice. Let The chimeric mice are then bred to produce homozygous offspring that express human antibodies. Let Transgenic mice are immunized using conventional methods with selected antigens, such as BTN1A1 polypeptide or glycosylated BTN1A1 polypeptide or BTN1A1 polypeptide dimer immunize with all or part of Monoclonal antibodies against the antigen can be produced using conventional hybrid can be obtained from the immunized transgenic mice using the mouse technique (e.g., See U.S. Pat. No. 5,916,771). Human immunoglobules possessed by this transgenic mouse Phosphorus transgenes rearrange during B cell differentiation, followed by class switching and somatic undergo a mutation. Thus, using such techniques, therapeutically useful IgG, IgA, IgM , and can produce IgE antibodies. For an overview of this technology for producing human antibodies, see For example, Lonberg and Huszar (1995, fully incorporated herein by reference, Int. Rev. Immunol. 13:65-93). human antibodies and human monoclonal antibodies For a detailed discussion of this technology to produce as well as protocols for producing such antibodies For example, International Publication No. WO 98 / 24893, W O 96 / 34096, and WO 96 / 33735; and U.S. Patents 5,413,923, 5,625,126, 5, 633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,9 See 39,598. In addition, Abgenix (Freemont, Calif.) and Medarex (Princeton) , N.J.) have tested human immunoglobulins against selected antigens using techniques similar to those described above. It can be contracted to provide antibodies.

[0211] In some embodiments, anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody or anti-BTN1 A1 dimeric antibodies are chimeric antibodies, e.g. , human, or humanized sequences (e.g., framework and / or constant domain sequences). It is an antibody that is known to In one embodiment the non-human donor is a rat. in one embodiment In some cases, the antigen-binding sequence is synthetic, for example, by mutagenesis (e.g., human phage display screening of phage libraries). one In embodiments, the chimeric antibody can have mouse V regions and human C regions. one In embodiments, the mouse light chain V region is fused to a human kappa light chain. In one embodiment , the mouse heavy chain V region is fused to the human IgG1 C region.

[0212] Methods for producing chimeric antibodies are known in the art. For example, Morrison, 1985 , Science 229:1202; Oi et al., 1986, BioTechniques 4:214; Gillies et al., 1989. , J. Immunol. Methods 125:191-202; See US Pat. Nos. 4,816,567 and 4,816,397; all of which are fully incorporated by reference. is incorporated herein. One or more CDRs from non-human species and from human immunoglobulin molecules Chimeric antibodies containing native framework regions can be used, for example, by CDR-grafting (EP 239,400 International Publication No. WO 91 / 09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,0. 89), veneering or resurfacing (EP 592,106; EP 519,596; Padlan 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka et al., 1994, Protein E ngineering 7:805; and Roguska et al., 1994, Proc. Natl. Acad. Sci. USA 91:969), and various techniques known in the art, including chain shuffling (U.S. Pat. No. 5,565,332). all of which are fully incorporated herein by reference. swallowed.

[0213] An exemplary process for the production of recombinant chimeric anti-BTN1A1 antibodies is as follows: a) conventional By molecular biology methods, mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer body) CDRs and variable regions of monoclonal antibodies are fused to Fc regions derived from human immunoglobulin construct an expression vector that encodes and expresses an antibody heavy chain that contains a chimeric anti- producing a vector for the expression of the heavy chain; b) by conventional molecular biology methods, mouse Antibody light chain of anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) monoclonal antibody constructing an expression vector encoding and expressing the same, thereby expressing the chimeric antibody light chain c) production of these expression vectors by conventional molecular biology methods; into a host cell to produce a transfected host cell for expression of the chimeric antibody and d) transfection by conventional cell culture techniques to produce chimeric antibodies. culturing the infected cells.

[0214] An exemplary process for the production of recombinant humanized anti-BTN1A1 antibodies is as follows: a) conventional Required by molecular biology methods to retain CDR and donor antibody binding specificity The minimal portion of the variable region framework is mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-B derived from a non-human immunoglobulin, such as a monoclonal antibody (TNA1 dimer), and the rest of the antibody an expression vector that encodes and expresses an antibody heavy chain that is derived from a human immunoglobulin constructing, thereby producing a vector for the expression of a humanized antibody heavy chain; b) conventional molecules Variables required to retain CDRs and donor antibody binding specificity by means of biology A minimal portion of the region framework is mouse anti-BTN1A1 (or anti-glycosylated BTN1A1 or anti-BTNA1 dimer) derived from a non-human immunoglobulin, such as a monoclonal antibody, in which the remainder of the antibody is Construct an expression vector that encodes and expresses an antibody light chain derived from human immunoglobulin and thereby producing vectors for the expression of humanized antibody light chains; c) these expression vectors; The vector is transferred into host cells by conventional molecular biology methods to provide a vector for expression of humanized antibodies. producing transfected host cells; and d) producing humanized antibodies. culturing the transfected cells by conventional cell culture techniques. Wear.

[0215] For either exemplary method, the host cell is co-transfected with such an expression vector. These expression vectors contain different selectable markers Although they can be, they are preferably identical except for the sequences encoding the heavy and light chains. This procedure results in equal expression of heavy and light chain polypeptides. or A single vector may be used that encodes both heavy and light chain polypeptides. stomach. Heavy and light chain coding sequences can comprise cDNA or genomic DNA or both. Wear. The host cell used to express the recombinant antibody is Escherichia coli. or, more preferably, eukaryotic cells such as Chinese Hamster Ovary ( CHO) cells or HEK-293 cells). The choice of expression vector is Depending on the choice of host cell, the desired expression and regulatory characteristics in the host cell of choice may be obtained. You can choose to Other cell lines that can be used include CHO-K1, NSO, and PER.C6 (Crucell, Leiden, Netherlands). difference In addition, host cell Codon usage can be optimized when choosing For example, for CHO cell expression, The DNA encoding the antibody was obtained from Cricetulus griseus (Chinese ham). Incorporating codons preferentially used by can be Take advantage of codon optimization methods to facilitate improved expression by the desired host cell. (see, e.g., Wohlgemuth, I. et al., Philos. Trans. R. Soc. Lond. B Bi ol. Sci. 366(1580):2979-2986(2011); Jestin, J. L. et al., J. Mol. Evol. 69(5):4. 52-457 (2009); Bollenbach, T. et al., Genome Res. 17(4):401-404 (2007); Kurland, C. G. et al., Prog. Nucleic Acid Res. Mol. Biol. 31:191-219 (1984); Grosjean, H. et al., Gene 18(3): 199-209 (1982)).

[0216] In some embodiments, anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody or anti-BTN1 The A1 dimer antibody can be a monoclonal antibody. In some embodiments , anti-BTN1A1 antibody or anti-glycosylated BTN1A1 antibody or anti-BTN1A1 dimer antibody is polyclonal antibody. BTN1A1 polypeptide or glycosylated BTN1A1 polypeptide or In order to produce antibodies specific for BTN1A1 dimers, animals are injected with an antigen, e.g., BTN1A1 polypep inoculating peptide or glycosylated BTN1A1 polypeptides or BTN1A1 dimer polypeptides; can be Antigens are often attached or conjugated to another molecule to enhance the immune response. enhance the Conjugate binds to antigen used to elicit an immune response in animals any peptide, polypeptide, protein, or non-proteinaceous substance containing can be Antibodies produced in animals in response to challenge are produced by a variety of individual antibody-producing B-phosphorus It has various non-identical molecules (polyclonal antibodies) made from paocytes. Polik in animals Considering the precise conditions for lonal antibody production, most of the antibodies in animal sera are Animals recognize collective epitopes on the antigenic compound to which they are immunized.

[0217] This specificity is further enhanced by affinity purification to recognize antigens or epitopes of interest You can select only antibodies that Methods for generating monoclonal antibodies (MAbs) are You can begin in a similar way to how to prepare reclonal antibodies. some implementations in the use of rodents such as mice and rats in the production of monoclonal antibodies . In some embodiments, rabbit, sheep, or frog cells are used in the production of The use of rats is well known and can offer certain advantages. be. Mice (e.g., BALB / c mice) are routinely used and usually have a high percentage of stable fusions. produces

[0218] Hybridoma technology involves the use of BTN1A1 polypeptides or glycosylated BTN1A1 polypeptides or Single B-lymphocytes and immortal myeloma from mice previously immunized with BTN1A1 dimer polypeptide It involves fusion with cells (usually mouse myeloma). This technique is based on the same antigen or epitope specificity capable of producing unlimited quantities of structurally identical antibodies (monoclonal antibodies) with As such, a method is provided for propagating a single antibody-producing cell for an infinite number of generations.

[0219] In one embodiment, the antibody is derived from a camelid antibody that lacks a light chain, preferably , an immunoglobulin single variable domain derived from a heavy-chain camelid antibody, which is V. H Known as H domain sequences or Nanobodies™. Nanobody™ (Nb) A minimal functional fragment or single variable domain (V H H), which is open to those skilled in the art. It is knowledge. They 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 of "camelids", an immune system lacking a light polypeptide chain globulin can be seen. "Camelids" include Old World camelids (Bactrian camels (Ca melus bactrianus) and dromedaries (Camelus dromedarius) and New World camelids things (e.g., alpaca (Lama paccos), llama (Lama glama), guanaco (Lama guanicoe), and Lama vicugna). A single variable domain heavy chain antibody is herein Nanobody (trademark) or V H Denoted as H antibody. Small size and unique biophysics of Nb properties are related to the recognition of uncommon or hidden epitopes and to the cavity of protein targets. or outperform conventional antibody fragments in terms of binding into the active site. In addition, Nb is a polyspecific can be engineered as multivalent and multivalent antibodies, conjugated to reporter molecules, or humanized . Nb is stable, persists in the gastrointestinal system, and can be easily manufactured.

[0220] Combining two antigen-binding sites with different specificities into a single construct results in two Bispecific antibodies can combine two separate antigens with excellent specificity into one Therefore, it has great potential as a therapeutic agent. Bispecific antibodies are It is produced by fusing two hybridomas capable of producing loblin. can be Bispecific antibodies connect two scFv antibody fragments while forming a complete immunoglobulin. It can also be produced by deleting the Fc portion present in lobulin. such Each scFv unit in the construct is connected to each other by a synthetic polypeptide linker. It can consist of one variable domain from each of the heavy (VH) and light (VL) antibody chains. the latter to minimize immunogenicity while maximizing resistance to proteolytic degradation. As such, they are often genetically modified. each scFv unit, two scFv units several, including the incorporation of short (usually less than 10 amino acids) polypeptide spacers that bridge can be joined by any technique, thereby generating a bispecific single chain antibody. Thus, the resulting bispecific single-chain antibody has different specificities on a single polypeptide chain. A species containing two VH / VL pairs, where a VH domain and a VL domain in each scFv unit. The main is a polypeptide long enough to allow intramolecular association between these two domains. The scFv units separated by a drinker and thus formed are, for example, prevent unwanted association between the VH domain of one scFv unit and the VL of the other scFv unit. are closely connected to each other by polypeptide spacers that are kept sufficiently short.

[0221] An antigen-binding fragment that immunospecifically binds to BTN1A1 or a glycosylated BTN1A1 or BTN1A1 dimer (i) Fab fragments consisting of VL, VH, CL, and CH1 domains; (ii) VH and and a "Fd" fragment consisting of the CH1 domain; (iii) an "Fv" fragment consisting of the VL and VH domains of a single antibody; fragment; (iv) a "dAb" fragment consisting of the VH domain; (v) an isolated CDR region; (vi) two joined F F(ab')2 fragment, which is a bivalent fragment containing the ab fragment; (vii) the VH and VL domains are domains by peptide linkers that allow them to associate to form binding domains. (viii) a bispecific single-chain Fv dimer (U.S. Patent No. 5,091,513); and (ix) multivalent or multispecific fragments constructed by gene fusion. (U.S. Patent Application Publication No. 20050214860), which is not. Fv, scFv, or diabody molecules are dissimilar molecules that connect the VH and VL domains. It can be stabilized by the incorporation of ulfide bridges. scFv binds to the CH3 domain It is also possible to generate minibodies that contain (Hu et al., Cancer Res., 56(13):3055-61 (199 6)).

[0222] Antibody-like binding peptidomimetics are also contemplated in embodiments. Murali et al., Cell Mol. Biol., 49(2):209-216 (2003) have reported that it acts as a Antibiotics, which are peptides with particular advantages of short half-life and less cumbersome synthetic methods. body-like binding peptide mimetics" (ABiPs) have been described and this article is incorporated by reference. fully incorporated herein.

[0223] (5.2.2. Anti-BTN1A1 antibody) Cloning a total of 68 mouse monoclonal antibodies that immunospecifically bind to human BTN1A1 and characterized (Table 7). In addition, three murine monoclones that immunospecifically bind to murine BTN1A1 Lonal antibodies were cloned and characterized (see Example 4). For example, STC703, STC810 , and STC820 showed glycosylation-specific binding with high affinity (STC K between 703 and hBTN1A1-Fc D was determined to be 286 nM by Biacore, STC810 ​​and hBTN1A1 K between -Fc D was determined to be 0.92 nM by Biacore, the K between STC820 and hBTN1A1-His D was determined to be 16.2 nM by Biacore). STC703 and STC810 ​​are BTN1A1 monomers It was found to preferentially bind to the BTN1A1 dimer over the BTN1A1 dimer. STC703, STC810, and STC820 , was found to preferentially bind to human BTN1A1 over mouse BTN1A1. STC1011, STC1012 , and STC1029 were found to preferentially bind to mouse BTN1A1 over human BTN1A1. Treatment with monoclonal anti-BTN1A1 antibody enhances T cell-dependent apoptosis of cancer cells , inhibits cancer cell proliferation and also induces glycosylation-dependent internalization of BTN1A1 into lysosomes. dropped. Therefore, anti-BTN1A1 antibodies with specific sequence characteristics, immune to specific epitopes Also provided herein are anti-BTN1A1 antibodies that bind immunospecifically, and their use in treating cancer. be

[0224] In some embodiments, the anti-BTN1A1 antibodies provided herein are described herein Monoclonal Antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC26 02, STC2714, STC2739, STC2778, or STC2781, or the VH domains of these humanized variants in, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 including. In certain embodiments, the anti-BTN1A1 antibody is human germline immunoglobulin amino VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and acid sequences or variants thereof and / or VL FR4.

[0225] In some embodiments, the anti-BTN1A1 antibodies provided herein are described herein Monoclonal Antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC26 02, STC2714, STC2739, STC2778, or STC2781, or the VH domains of these humanized variants in, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 including. In certain embodiments, the anti-BTN1A1 antibody is human germline immunoglobulin amino VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and acid sequences or variants thereof and / or VL FR4.

[0226] In some embodiments, the anti-BTN1A1 antibodies provided herein are described herein monoclonal antibodies STC703 or STC810, or the VH domains of their humanized variants VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 include. In certain embodiments, the anti-BTN1A1 antibody is human germline immunoglobulin amino acid VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and sequences or variants thereof / or VL FR4 can be further included.

[0227] In some embodiments, the anti-BTN1A1 antibodies provided herein are described herein VH domain, VL domain, VH C of monoclonal antibody STC820 or a humanized variant thereof DR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3. in one embodiment wherein the anti-BTN1A1 antibody is a human germline immunoglobulin amino acid sequence or variant thereof VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4 further can contain.

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

[0229] In some embodiments, the anti-BTN1A1 antibodies provided herein are described herein monoclonal antibody STC2602, STC2714, STC2739, STC2778, or STC2781, or are the VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CD of these humanized variants including R1, VL CDR2, and / or VL CDR3. In certain embodiments, the anti-BTN1A1 antibody is VH FR1, VH FR2, VH FR3, VH F of the germline immunoglobulin amino acid sequence or variants thereof It can further include R4, VL FR1, VL FR2, VL FR3, and / or VL FR4.

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

[0231] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In a specific embodiment, the antibody is a monoclonal antibody described herein. Null antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC VH CDR1, VH CDR2, VH C of 2739, STC2778, or STC2781, or humanized variants thereof 1, 2, 3, 4 selected from the group consisting of DR3, VL CDR1, VL CDR2, and / or VL CDR3 contains or consists of one or five CDRs. In a specific embodiment, said antibody VH FR1, VH FR2, VH FR3 of the human germline immunoglobulin amino acid sequence or variants thereof , VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4.

[0232] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In a specific embodiment, the antibody is a monoclonal antibody described herein. Null antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC VH CDR1, VH CDR2, VH C of 2739, STC2778, or STC2781, or humanized variants thereof 1, 2, 3, 4 selected from the group consisting of DR3, VL CDR1, VL CDR2, and / or VL CDR3 contains or consists of one or five CDRs. In a specific embodiment, said antibody VH FR1, VH FR2, VH FR3 of the human germline immunoglobulin amino acid sequence or variants thereof , VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4.

[0233] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In a specific embodiment, the antibody is STC703 or STC703 described herein. or STC810, or humanized variants thereof VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR 2, and / or 1, 2, 3, 4, or 5 CDRs selected from the group consisting of VL CDR3 comprising or consisting of In a specific embodiment, the antibody is human germline immune VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL of globulin amino acid sequences or variants thereof Further includes FR2, VL FR3, and / or VL FR4.

[0234] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In specific embodiments, the antibody is STC820 or VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of humanized variants thereof or 1, 2, 3, 4, or 5 CDRs selected from the group consisting of It consists In a specific embodiment, the antibody has a human germline immunoglobulin amino acid sequence. VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or a sequence or variant thereof or further comprising VL FR4.

[0235] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In a specific embodiment, the antibody is STC1011, S described herein VH CDR1, VH CDR2, VH CDR3, VL of TC1012, or STC1029, or humanized variants thereof 1, 2, 3, 4 selected from the group consisting of CDR1, VL CDR2, and / or VL CDR3, if or 5 CDRs. In a specific embodiment, the antibody is human VH FR1, VH FR2, VH FR3, VH FR4 of germline immunoglobulin amino acid sequences or variants thereof , VL FR1, VL FR2, VL FR3, and / or VL FR4.

[0236] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In a specific embodiment, the antibody is STC2602, S described herein VH CDR1, VH of TC2714, STC2739, STC2778, or STC2781, or humanized variants thereof one, two selected from the group consisting of CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 It comprises or consists of 1, 3, 4 or 5 CDRs. in a specific embodiment the antibody is a human germline immunoglobulin amino acid sequence or variant thereof VH FR1, VH F Further comprising R2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and / or VL FR4.

[0237] In some embodiments, the anti-BTN1A1 antibody comprises less than 6 CDRs. some implementations In embodiments, the antibody is VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL or comprising 1, 2, 3, 4, or 5 CDRs selected from the group consisting of CDR3 consists of In a specific embodiment, the antibody is STC2714 or humanized variants thereof VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR 1, 2, 3, 4, or 5 CDRs selected from the group consisting of or consists of In a specific embodiment, the antibody is human germline immunoglobulin amino acid VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and sequences or variants thereof / or further comprising VL FR4.

[0238] In some embodiments, the antibody is a humanized antibody, monoclonal antibody, recombinant anti- antigen-binding fragment, or any combination thereof. In some embodiments, the Antibodies are humanized monoclonal antibodies or antigen-binding fragments thereof.

[0239] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein Antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC27 39, STC2778, or STC2781, or humanized variants thereof, are BTN1A1 polypeptides (e.g. cell surface expressed or soluble BTN1A1), BTN1A1 fragments, or BTN1A1 epitopes competitively blocks (eg, in a dose-dependent manner) from binding to In another embodiment the antibody is the monoclonal antibody BTN1A1 described herein or a humanized variant thereof ( BTN1A1 epitope bound by (e.g., recognized) by, e.g., a humanized anti-BTN1A1 antibody group.

[0240] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) competitively interfere; and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein. Antibodies STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC27 39, STC2778, or STC2781, or humanized variants thereof, are BTN1A1 polypeptides (e.g. cell surface expressed or soluble BTN1A1), BTN1A1 fragments, or BTN1A1 epitopes competitively blocks (eg, in a dose-dependent manner) from binding to In another embodiment the antibody is the monoclonal antibody BTN1A1 described herein or a humanized variant thereof ( BTN1A1 epitope bound by (e.g., recognized) by, e.g., a humanized anti-BTN1A1 antibody group.

[0241] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) competitively interfere; and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein. Antibodies STC703 or STC810, or humanized variants thereof, have a BTN1A1 polypeptide (e.g. , cell surface expressed or soluble BTN1A1), BTN1A1 fragments, or BTN1A1 epitopes competitively blocks (eg, in a dose-dependent manner) from binding to In another embodiment , the antibody is the monoclonal antibody BTN1A1 described herein or a humanized variant thereof (e.g. BTN1A1 epitope bound by (e.g., recognized) by (e.g., a humanized anti-BTN1A1 antibody) bind to

[0242] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) competitively interfere; and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein. The antibody STC820 or a humanized variant thereof is a BTN1A1 polypeptide (e.g., expressed on the cell surface) or soluble BTN1A1), BTN1A1 fragments, or binding to BTN1A1 epitopes (e.g. , in a dose-dependent manner) competitively blocks. In another embodiment, the antibody is described herein or a humanized variant thereof (e.g., humanized anti-BTN1A1 binds to the BTN1A1 epitope that is bound (eg, recognized) by the antibody).

[0243] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) competitively interfere; and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein Antibodies STC1011, STC1012, or STC1029, or humanized variants thereof, peptides (e.g., cell surface expressed or soluble BTN1A1), BTN1A1 fragments, or BTN1 Competitively blocks (eg, in a dose-dependent manner) binding to the A1 epitope. other practices In embodiments, the antibody is the monoclonal antibody BTN1A1 described herein or its human BTN1A1 bound (eg, recognized) by a humanized variant (eg, a humanized anti-BTN1A1 antibody) Binds to an epitope.

[0244] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) competitively interfere; and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein. antibody STC2602, STC2714, STC2739, STC2778, or STC2781, or humanized variations thereof variant is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN1A1), BT Competitively (e.g., in a dose-dependent manner) binding to the N1A1 fragment, or BTN1A1 epitope Cut off. In other embodiments, the antibody is a monoclonal antibody described herein bound by BTN1A1 or a humanized variant thereof (e.g., humanized anti-BTN1A1 antibody) (e.g. , recognized) binds to the BTN1A1 epitope.

[0245] In some embodiments, provided herein are (i) The anti-BTN1A1 antibody is a BTN1A1 polypeptide (e.g., cell surface expressed or soluble BTN 1A1), a BTN1A1 fragment, or binding to a BTN1A1 epitope (e.g., in a dose-dependent manner) competitively interfere; and / or (ii) anti-BTN1A1 antibodies provided herein (e.g., humanized anti-BTN1A1 antibodies, including humanized antibodies, that bind to the BTN1A1 epitope that is bound by the anti-BTN1A1 antibody) is the body. In some embodiments, the antibody is a monoclonal antibody described herein. The antibody STC2714 or a humanized variant thereof is a BTN1A1 polypeptide (e.g. or soluble BTN1A1), BTN1A1 fragments, or binding to BTN1A1 epitopes (e.g. , in a dose-dependent manner) competitively blocks. In another embodiment, the antibody is described herein or a humanized variant thereof (e.g., humanized anti-BTN1A1 binds to the BTN1A1 epitope that is bound (eg, recognized) by the antibody). Table 2a: Heavy chain variable (VH) region and light chain variable (VL) region 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) region and light chain variable (VL) region of mouse monoclonal anti-human BTN1A1 antibody STC810 ) array of regions [Table 4] Table 3b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC810 [Table 5] Table 4a: Heavy chain variable (VH) region and light chain variable (VL) region of mouse monoclonal anti-human BTN1A1 antibody STC820 ) array of regions [Table 6] Table 4b: CDR sequences of mouse monoclonal anti-human BTN1A1 antibody STC820 [Table 7] Table 5a: Heavy chain variable (VH) region and light chain variable of mouse monoclonal anti-mouse BTN1A1 antibody STC1011 Sequence of (VL) region [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 of mouse monoclonal anti-mouse BTN1A1 antibody STC1012 Sequence of (VL) region [Table 10] Table 6b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC1012 [Table 11] Table 7a: Heavy chain variable (VH) region and light chain variable of mouse monoclonal anti-mouse BTN1A1 antibody STC1029 Sequence of (VL) region [Table 12] Table 7b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC1029 [Table 13] Table 8a: Heavy chain variable (VH) region and light chain variable of mouse monoclonal anti-mouse BTN1A1 antibody STC2602 Sequence of (VL) region [Table 14] Table 8b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2602 [Table 15] Table 9a: Heavy chain variable (VH) region and light chain variable of mouse monoclonal anti-mouse BTN1A1 antibody STC2714 Sequence of (VL) region [Table 16] Table 9b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2714 [Table 17] Table 10a: Heavy chain variable (VH) region and light chain of mouse monoclonal anti-mouse BTN1A1 antibody STC2739 Sequence of the variable (VL) region [Table 18] Table 10b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2739 [Table 19] Table 11a: Heavy chain variable (VH) region and light chain of mouse monoclonal anti-mouse BTN1A1 antibody STC2778 Sequence of the variable (VL) region [Table 20] Table 11b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2778 [Table 21] Table 12a: Heavy chain variable (VH) region and light chain of mouse monoclonal anti-mouse BTN1A1 antibody STC2781 Sequence of the variable (VL) region [Table 22] Table 12b: CDR sequences of mouse monoclonal anti-mouse BTN1A1 antibody STC2781 [Table 23]

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

[0247] In some embodiments, provided herein are (a)(1) SEQ ID NOS: 7, 10, 13 , 16, 35, 38, 41, 44, 63, 66, 69, or 72 amino acid sequences; (2) SEQ ID NO: VH CDR2 having amino acid sequence No. 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73 and (3) the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74 and (b) (1) SEQ ID NOs: 19, 22, 25, 28, 47, 5 VL CDR1 having an amino acid sequence of 0, 53, 56, 75, 78, 81, or 84; (2) SEQ ID NOs: 20, 23, 26 , 29, 48, 51, 54, 57, 76, 79, 82, or 85 amino acid sequences; VL having the amino acid sequence of row numbers 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or 86 An antibody with a light chain variable (VL) region containing CDR3:. The antibody is a monoclonal antibody can The antibody can be a humanized antibody.

[0248] In another aspect, provided herein is a BTN1A1 or group having the following sequence characteristics: A molecule having an antigen-binding fragment that immunospecifically binds to lycosylated BTN1A1. Several In embodiments, the molecules provided herein have (a)(1) SEQ ID NOs: 91, 94, 97, 100, 119 , 122, 125, 128, 147, 150, 153, or 156 amino acid sequences; (2) a sequence amino acid sequence numbered 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 and (3) SEQ ID NOs: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, a heavy chain variable (VH) region comprising: a VH CDR3 having a sequence of 155 or 158 amino acids; and / or (b) (1) SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168 (2) SEQ ID NOS: 104, 107, 110, 113, 132, 135, 138, 141 , 160, 163, 166, or 169 amino acid sequences; and (3) SEQ ID NOs: 105, 10; has an amino acid sequence of 8, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 has an antigen-binding fragment with a light chain variable (VL) region containing the VL CDR3:

[0249] In some embodiments, provided herein are (a)(1) SEQ ID NOs: 91, 94, 97 , 100, 119, 122, 125, 128, 147, 150, 153, or 156 amino acid sequences; 2) amino acids of SEQ ID NOs: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 and (3) SEQ ID NOs: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152 a heavy chain variable (VH) region comprising: a VH CDR3 having a sequence of 155, or 158 amino acids; and (b)(1) amino acids of SEQ ID NO: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165, or 168 VL CDR1 with sequence; (2) SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163 , 166, or 169 amino acid sequences; and (3) SEQ ID NOs: 105, 108, 111, 114, 1 a VL CDR3 having an amino acid sequence of 33, 136, 139, 142, 161, 164, 167, or 170; An antibody with a variable chain (VL) region. The antibody can be a monoclonal antibody . The antibody can be a humanized antibody.

[0250] Accordingly, provided herein are BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: It is a molecule having an antigen-binding fragment that immunospecifically binds to lylated BTN1A1. some implementations In the same manner, the molecules provided herein are (a)(1) SEQ ID NOS: 197, 200, 203, or 206 (2) the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207; and (3) having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208 and / or (b)(1) SEQ ID NOs: 209, 212, 215, or has a 218 amino acid sequence; (2) an amino acid of SEQ ID NO: 210, 213, 216, or 219; and (3) the amino acid sequence of SEQ ID NO: 211, 214, 217, or 220. has an antigen-binding fragment with a light chain variable (VL) region containing a VL CDR3:

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

[0252] Accordingly, provided herein are BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: It is a molecule having an antigen-binding fragment that immunospecifically binds to lylated BTN1A1. some implementations In the same manner, the molecules provided herein are (a)(1) SEQ ID NOS: 225, 228, 231, or 234 (2) the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; and (3) having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236 and / or (b)(1) SEQ ID NOs: 237, 240, 243, or has a 246 amino acid sequence; (2) an amino acid of SEQ ID NO: 238, 241, 244, or 247; and (3) the amino acid sequence of SEQ ID NO: 239, 242, 245, or 248; has an antigen-binding fragment with a light chain variable (VL) region containing a VL CDR3:

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

[0254] Accordingly, provided herein are BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: It is a molecule having an antigen-binding fragment that immunospecifically binds to lylated BTN1A1. some implementations In the same manner, the molecules provided herein are (a)(1) SEQ ID NOs: 253, 256, 259, or 262 (2) the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263; and (3) having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264 and / or (b)(1) SEQ ID NOs: 265, 268, 271, or has a 274 amino acid sequence; (2) an amino acid of SEQ ID NO: 266, 269, 272, or 275; and (3) the amino acid sequence of SEQ ID NO: 267, 270, 273, or 276; has an antigen-binding fragment with a light chain variable (VL) region containing a VL CDR3:

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

[0256] Accordingly, provided herein are BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: It is a molecule having an antigen-binding fragment that immunospecifically binds to lylated BTN1A1. some implementations In the same manner, the molecules provided herein have (a)(1) SEQ ID NOs: 281, 284, 287, or 290 (2) the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291; and (3) having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292 and / or (b)(1) SEQ ID NOs: 293, 296, 299, or has a 302 amino acid sequence; (2) an amino acid of SEQ ID NO: 294, 297, 300, or 303; and (3) the amino acid sequence of SEQ ID NO: 295, 298, 301, or 304; has an antigen-binding fragment with a light chain variable (VL) region containing a VL CDR3:

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

[0258] Accordingly, provided herein are BTN1A1 or glycosylated BTN1A1 having the following sequence characteristics: It is a molecule having an antigen-binding fragment that immunospecifically binds to lylated BTN1A1. some implementations In the same manner, the molecules provided herein are (a)(1) SEQ ID NOs: 309, 312, 315, or 318 (2) the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319; and (3) having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320 and / or (b)(1) SEQ ID NOs: 321, 324, 327, or has a 330 amino acid sequence; (2) an amino acid of SEQ ID NO: 322, 325, 328, or 331; and (3) the amino acid sequence of SEQ ID NO: 323, 326, 329, or 332; has an antigen-binding fragment with a light chain variable (VL) region containing a VL CDR3:

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

[0260] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 7, 10, 13; (2) a VH CDR1 having a sequence of 16, 35, 38, 41, 44, 63, 66, 69, or 72 amino acids; V having the amino acid sequence numbered 8, 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73 H CDR2; and / or (3) SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74 has an antigen-binding fragment with a VH CDR3 having a heavy chain variable (VH) region comprising the amino acid sequence of . In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NO: 7, 10, 13, 16, 35 , 38, 41, 44, 63, 66, 69, or 72 amino acid sequences; and (2) SEQ ID NO: 8, containing a VH CDR2 having an amino acid sequence of 11, 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73 nothing. In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NOs: 7, 10, 13, 16; a VH CDR1 having an amino acid sequence of 35, 38, 41, 44, 63, 66, 69, or 72; and (3) SEQ ID NO:9 , a VH CDR3 having an amino acid sequence of 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74 include. In some embodiments, the molecules provided herein are (2) SEQ ID NOs:8, 11, VH CDR2 having an amino acid sequence of 14, 17, 36, 39, 42, 45, 64, 67, 70, or 73; and (3) V having the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 37, 40, 43, 46, 65, 68, 71, or 74 H CDR3: has an antigen-binding fragment with a heavy chain variable (VH) region.

[0261] In some embodiments, the molecules provided herein are (1) SEQ ID NOS: 91, 94, 97 , 100, 119, 122, 125, 128, 147, 150, 153, or 156 amino acid sequences (2) of SEQ ID NO: 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 A heavy chain variable (VH) comprising: a VH CDR3 having a sequence of 130, 149, 152, 155, or 158 amino acids It has an antigen-binding fragment with a region. In some embodiments, the heavy chain variable (VH) region (1) the amino acid of SEQ ID NO: 91, 94, 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156 and (2) SEQ ID NOS: 92, 95, 98, 101, 120, 123, 126, 129, 148. , 151, 154, or 157 amino acid sequences. In some embodiments and the heavy chain variable (VH) region has (1) SEQ ID NOs: VH CDR1 having a sequence of 50, 153, or 156 amino acids; and (3) SEQ ID NOs: 93, 96, 99, 102, 12 including VH CDR3 having a sequence of 1, 124, 127, 130, 149, 152, 155, or 158 amino acids. stomach In some embodiments, the molecules provided herein are (2) SEQ ID NOS: 92, 95, 98, 101 , 120, 123, 126, 129, 148, 151, 154, or 157 amino acid sequences; and (3 ) amino acid sequence of SEQ ID NO: 93, 96, 99, 102, 121, 124, 127, 130, 149, 152, 155, or 158 has an antigen-binding fragment with a heavy chain variable (VH) region comprising: a VH CDR3 with a sequence;

[0262] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 197, 200, 2 VH CDR1 having an amino acid sequence of 03, or 206; (2) SEQ ID NOs: 198, 201, 204, or 2 and / or (3) a VH CDR2 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208 It has an antigen-binding fragment with a heavy chain variable (VH) region comprising: a VH CDR3 with an amino acid sequence. In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NO: 197, 200, 203, or a VH CDR1 having a sequence of 206 amino acids; and (2) amino acids of SEQ ID NOs: 198, 201, 204, or 207 VH CDR2 with sequence. In some embodiments, the heavy chain variable (VH) region has (1) VH CDR1 having the amino acid sequence of SEQ ID NO: 197, 200, 203, or 206; and (3) SEQ ID NO: 199, Includes VH CDR3 having a sequence of 202, 205, or 208 amino acids. In some embodiments , the molecules provided herein have (2) the amino acid sequence of SEQ ID NO: 198, 201, 204, or 207 and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 199, 202, 205, or 208. has an antigen-binding fragment with a heavy chain variable (VH) region containing:

[0263] In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 225, 228, 2 VH CDR1 having a 31 or 234 amino acid sequence; (2) SEQ ID NOs: 226, 229, 232, or 2 and / or (3) a VH CDR2 having a 35 amino acid sequence; It has an antigen-binding fragment with a heavy chain variable (VH) region comprising: a VH CDR3 with an amino acid sequence. stomach In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NO: 225, 228, 231, or 23 (2) the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235; Contains VH CDR2 with columns. In some embodiments, the heavy chain variable (VH) region comprises (1) the VH CDR1 having the amino acid sequence of SEQ ID NO: 225, 228, 231, or 234; and (3) SEQ ID NO: 227, 23 Includes VH CDR3s with 0, 233, or 236 amino acid sequences. In some embodiments, The molecules provided herein have (2) the amino acid sequence of SEQ ID NO: 226, 229, 232, or 235 and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 227, 230, 233, or 236: have an antigen-binding fragment with a heavy chain variable (VH) region comprising;

[0264] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 253, 256, 2 VH CDR1 having a sequence of 59 or 262 amino acids; (2) SEQ ID NO: 254, 257, 260 or 2 and / or (3) a VH CDR2 having a sequence of 63 amino acids; It has an antigen-binding fragment with a heavy chain variable (VH) region comprising: a VH CDR3 with an amino acid sequence. In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NO: 253, 256, 259, or a VH CDR1 having a sequence of 262 amino acids; and (2) amino acids of SEQ ID NOs: 254, 257, 260, or 263 VH CDR2 with sequence. In some embodiments, the heavy chain variable (VH) region has (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 253, 256, 259, or 262; and (3) SEQ ID NO: 255, It contains a VH CDR3 with a sequence of 258, 261, or 264 amino acids. In some embodiments , the molecules provided herein have (2) the amino acid sequence of SEQ ID NO: 254, 257, 260, or 263 and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 255, 258, 261, or 264. has an antigen-binding fragment with a heavy chain variable (VH) region containing:

[0265] In some embodiments, the molecules provided herein have (1) SEQ ID NOS: 281, 284, 2 VH CDR1 having a sequence of 87 or 290 amino acids; (2) SEQ ID NO: 282, 285, 288 or 2 and / or (3) a VH CDR2 having a 91 amino acid sequence; It has an antigen-binding fragment with a heavy chain variable (VH) region comprising: a VH CDR3 with an amino acid sequence. In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NO: 281, 284, 287, or a VH CDR1 having a sequence of 290 amino acids; and (2) amino acids of SEQ ID NOs: 282, 285, 288, or 291 VH CDR2 with sequence. In some embodiments, the heavy chain variable (VH) region has (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 281, 284, 287, or 290; and (3) SEQ ID NO: 283, It contains a VH CDR3 with a sequence of 286, 289, or 292 amino acids. In some embodiments , the molecules provided herein have (2) the amino acid sequence of SEQ ID NO: 282, 285, 288, or 291 and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 283, 286, 289, or 292. has an antigen-binding fragment with a heavy chain variable (VH) region containing:

[0266] In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 309, 312, 3 VH CDR1 having a 15 or 318 amino acid sequence; (2) SEQ ID NO: 310, 313, 316 or 3 and / or (3) a VH CDR2 having a 19 amino acid sequence; It has an antigen-binding fragment with a heavy chain variable (VH) region comprising: a VH CDR3 with an amino acid sequence. In some embodiments, the heavy chain variable (VH) region has (1) SEQ ID NO: 309, 312, 315, or a VH CDR1 having a sequence of 318 amino acids; and (2) amino acids of SEQ ID NOs: 310, 313, 316, or 319 VH CDR2 with sequence. In some embodiments, the heavy chain variable (VH) region has (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 309, 312, 315, or 318; and (3) SEQ ID NO: 311, It contains a VH CDR3 having a sequence of 314, 317, or 320 amino acids. In some embodiments , the molecules provided herein have (2) the amino acid sequence of SEQ ID NO: 310, 313, 316, or 319 and (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 311, 314, 317, or 320. has an antigen-binding fragment with a heavy chain variable (VH) region containing:

[0267] 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, 197, 200, 203, 206, 225, 228, 231, 234, 253, 256, 259, 262, 281, 284 , 287, 290, 309, 312, 315, or 318. It has an antigen-binding fragment with a variable (VH) region. The VH CDR1 has the amino acid sequence of SEQ ID NO:7 can have The VH CDR1 can have the amino acid sequence of SEQ ID NO:10. The VH CDR1 can have the amino acid sequence of SEQ ID NO:13. The VH CDR1 is represented by SEQ ID NO: It can have 16 amino acid sequences. The VH CDR1 has the amino acid sequence of SEQ ID NO:35. can do. The VH CDR1 can have the amino acid sequence of SEQ ID NO:38. the V H CDR1 can have the amino acid sequence of SEQ ID NO:41. The VH CDR1 is SEQ ID NO:44 can have an amino acid sequence of The VH CDR1 has the amino acid sequence of SEQ ID NO: 63 can The VH CDR1 can have the amino acid sequence of SEQ ID NO:66. the VH CDR1 can have the amino acid sequence of SEQ ID NO:69. The VH CDR1 is of SEQ ID NO:72 It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:91 be able to. The VH CDR1 can have the amino acid sequence of SEQ ID NO:94. The VH CD R1 can have the amino acid sequence of SEQ ID NO:97. The VH CDR1 is the address of SEQ ID NO:100. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:119. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:122. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:125. The VH CDR1 is the address of SEQ ID NO:128. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:147. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:150. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:153. The VH CDR1 is the address of SEQ ID NO:156. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:197. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:200. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:203. The VH CDR1 is the address of SEQ ID NO:206. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:225. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:228. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:231. The VH CDR1 is the address of SEQ ID NO:234. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:253. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:256. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:259. The VH CDR1 is the address of SEQ ID NO:262. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:281. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:284. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:287. The VH CDR1 is the address of SEQ ID NO:290. It can have an amino acid sequence. The VH CDR1 has the amino acid sequence of SEQ ID NO:309. can be The VH CDR1 can have the amino acid sequence of SEQ ID NO:312. The VH CDRs 1 can have the amino acid sequence of SEQ ID NO:315. The VH CDR1 is the address of SEQ ID NO:318. It can have an amino acid sequence.

[0268] 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, 198, 201, 204, 207, 226, 229, 232, 235, 254, 257, 260, 263, 282, 285 , 288, 291, 310, 313, 316, or a heavy chain variable (VH ) region. The VH CDR2 has the amino acid sequence of SEQ ID NO:8 be able to. The VH CDR2 can have the amino acid sequence of SEQ ID NO:11. The VH CD R2 can have the amino acid sequence of SEQ ID NO:14. The VH CDR2 is the address of SEQ ID NO:17. It can have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO:36. can be The VH CDR2 can have the amino acid sequence of SEQ ID NO:39. The VH CDR2 can have the amino acid sequence of SEQ ID NO:42. The VH CDR2 is the amino acid of SEQ ID NO:45. can have an acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 64 can be done. The VH CDR2 can have the amino acid sequence of SEQ ID NO:67. The VH CDR2 is , SEQ ID NO:70. The VH CDR2 is amino acid of SEQ ID NO:73 It can have an acid sequence. The VH CDR2 may have the amino acid sequence of SEQ ID NO:92. can. The VH CDR2 can have the amino acid sequence of SEQ ID NO:95. The VH CDR2 is It can have the amino acid sequence of SEQ ID NO:98. The VH CDR2 comprises amino acids of SEQ ID NO: 101 can have an array. The VH CDR2 can have the amino acid sequence of SEQ ID NO:120. Wear. The VH CDR2 can have the amino acid sequence of SEQ ID NO:123. The VH CDR2 is It can have the amino acid sequence of SEQ ID NO:126. The VH CDR2 is amino acid of SEQ ID NO: 129 It can have an acid sequence. The VH CDR2 may have the amino acid sequence of SEQ ID NO: 148. can. The VH CDR2 can have the amino acid sequence of SEQ ID NO:151. The VH CDR2 is , SEQ ID NO:154. The VH CDR2 is the amino acid of SEQ ID NO:157. can have an acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO: 198 can be done. The VH CDR2 can have the amino acid sequence of SEQ ID NO:201. The VH CDR2 can have the amino acid sequence of SEQ ID NO:204. The VH CDR2 is the address of SEQ ID NO:207. It can have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO:226. can be The VH CDR2 can have the amino acid sequence of SEQ ID NO:229. The VH CDRs 2 can have the amino acid sequence of SEQ ID NO:232. The VH CDR2 is the address of SEQ ID NO:235. It can have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO:254. can be The VH CDR2 can have the amino acid sequence of SEQ ID NO:257. The VH CDRs 2 can have the amino acid sequence of SEQ ID NO:260. The VH CDR2 is the address of SEQ ID NO:263. It can have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO:282. can be The VH CDR2 can have the amino acid sequence of SEQ ID NO:285. The VH CDRs 2 can have the amino acid sequence of SEQ ID NO:288. The VH CDR2 is the address of SEQ ID NO:291. It can have an amino acid sequence. The VH CDR2 has the amino acid sequence of SEQ ID NO:310. can be The VH CDR2 can have the amino acid sequence of SEQ ID NO:313. The VH CDRs 2 can have the amino acid sequence of SEQ ID NO:316. The VH CDR2 is the address of SEQ ID NO:319. It can have an amino acid sequence.

[0269] In some embodiments, the molecules provided herein are SEQ ID NOS: 9, 12, 15, 18 , 37, 40, 43, 46, 65, 68, 71, 74, 93, 96, 99, 102, 121, 124, 127, 130, 149, 152 , 155, 158, 199, 202, 205, 208, 227, 230, 233, 236, 255, 258, 261, 264, 283, 286 , 289, 292, 311, 314, 317, or a heavy chain variable (VH ) region. The VH CDR3 has the amino acid sequence of SEQ ID NO:9 be able to. The VH CDR3 can have the amino acid sequence of SEQ ID NO:12. The VH CD R3 can have the amino acid sequence of SEQ ID NO:15. The VH CDR3 is the address of SEQ ID NO:20. It can have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO:37. can be The VH CDR3 can have the amino acid sequence of SEQ ID NO:40. The VH CDR3 can have the amino acid sequence of SEQ ID NO:43. The VH CDR3 is the amino acid of SEQ ID NO:46. can have an acid sequence. said VH CDR3 having the amino acid sequence of SEQ ID NO: 65 can be done. The VH CDR3 can have the amino acid sequence of SEQ ID NO:68. The VH CDR3 is , SEQ ID NO:71. The VH CDR3 is amino acid of SEQ ID NO:74 It can have an acid sequence. The VH CDR3 may have the amino acid sequence of SEQ ID NO:93 can. The VH CDR3 can have the amino acid sequence of SEQ ID NO:96. The VH CDR3 is It can have the amino acid sequence of SEQ ID NO:99. The VH CDR3 has amino acids of SEQ ID NO: 102 can have an array. The VH CDR3 can have the amino acid sequence of SEQ ID NO:121. Wear. The VH CDR3 can have the amino acid sequence of SEQ ID NO:124. The VH CDR3 is It can have the amino acid sequence of SEQ ID NO:127. The VH CDR3 is amino acid of SEQ ID NO: 130 It can have an acid sequence. The VH CDR3 may have the amino acid sequence of SEQ ID NO: 149 can. The VH CDR3 can have the amino acid sequence of SEQ ID NO:152. The VH CDR3 is , SEQ ID NO:155. The VH CDR3 is the amino acid of SEQ ID NO:158. can have an acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO: 199 can be done. The VH CDR3 can have the amino acid sequence of SEQ ID NO:202. The VH CDR3 can have the amino acid sequence of SEQ ID NO:205. The VH CDR3 is the address of SEQ ID NO:208. It can have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO:227. can be The VH CDR3 can have the amino acid sequence of SEQ ID NO:230. The VH CDRs 3 can have the amino acid sequence of SEQ ID NO:233. The VH CDR3 is the address of SEQ ID NO:236. It can have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO:255. can be The VH CDR3 can have the amino acid sequence of SEQ ID NO:258. The VH CDRs 3 can have the amino acid sequence of SEQ ID NO:261. The VH CDR3 is the address of SEQ ID NO:264. It can have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO:283. can be The VH CDR3 can have the amino acid sequence of SEQ ID NO:286. The VH CDRs 3 can have the amino acid sequence of SEQ ID NO:289. The VH CDR3 is the address of SEQ ID NO:292. It can have an amino acid sequence. The VH CDR3 has the amino acid sequence of SEQ ID NO:311. can be The VH CDR3 can have the amino acid sequence of SEQ ID NO:314. The VH CDRs 3 can have the amino acid sequence of SEQ ID NO:317. The VH CDR3 is the address of SEQ ID NO:320. It can have an amino acid sequence.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0325] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 19, 22, 25 , 28, 47, 50, 53, 56, 75, 78, 81, or 84 amino acid sequences; having the amino acid sequence of row number 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85 and / or (3) SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83, or has an antigen-binding fragment with a light chain variable (VL) region containing a VL CDR3: with a sequence of 86 amino acids. do.

[0326] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 103, 106, 1 VL having an amino acid sequence of 09, 112, 131, 134, 137, 140, 159, 162, 165, or 168 CDR1; (2) SEQ ID NO: 104, 107, 110, 113, 132, 135, 138, 141, 160, 163, 166, or 1 VL CDR2 having a sequence of 69 amino acids; and / or (3) SEQ ID NOs: 105, 108, 111, 114, 133, 136 , 139, 142, 161, 164, 167, or 170 amino acid sequences. It has an antigen-binding fragment with a variable (VL) region.

[0327] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 209, 212, 2 VL CDR1 having a 15 or 218 amino acid sequence; (2) SEQ ID NOs: 210, 213, 216, or 2 VL CDR2 having a 19 amino acid sequence; and / or (3) SEQ ID NO: 211, 214, 217, or 220 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0328] In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 237, 240, 2 VL CDR1 having a 43 or 246 amino acid sequence; (2) SEQ ID NO: 238, 241, 244 or 2 VL CDR2 having a sequence of 47 amino acids; and / or (3) SEQ ID NO: 239, 242, 245, or 248 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0329] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 265, 268, 2 VL CDR1 having a sequence of 71 or 274 amino acids; (2) SEQ ID NOs: 266, 269, 272, or 2 VL CDR2 having a sequence of 75 amino acids; and / or (3) SEQ ID NO: 267, 270, 273, or 276 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0330] In some embodiments, the molecules provided herein are (1) SEQ ID NOS: 293, 296, 2 VL CDR1 having a 99 or 302 amino acid sequence; (2) SEQ ID NO: 294, 297, 300 or 3 VL CDR2 having the amino acid sequence of 03; and / or (3) SEQ ID NO: 295, 298, 301, or 304 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0331] In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 321, 324, 3 VL CDR1 having a sequence of 27 or 330 amino acids; (2) SEQ ID NOs: 322, 325, 328, or 3 VL CDR2 having a sequence of 31 amino acids; and / or (3) SEQ ID NO: 323, 326, 329, or 332 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0332] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 19, 22, 25 , 28, 47, 50, 53, 56, 75, 78, 81, or 84 amino acid sequences; VL having the amino acid sequence of row numbers 20, 23, 26, 29, 48, 51, 54, 57, 76, 79, 82, or 85 It has an antigen-binding fragment with a light chain variable (VL) region containing CDR2:. In some embodiments Thus, the molecules provided herein are: (1) SEQ ID NOs: 19, 22, 25, 28, 47, 50, 53, 56, 75 , 78, 81, or 84 amino acid sequences; and (3) SEQ ID NOs: 21, 24, 27, 30, 49; , 52, 55, 58, 77, 80, 83, or 86 amino acid sequences. It has an antigen-binding fragment with a region. In some embodiments, provided herein (2) an amino VL CDR2 with acid sequence; and (3) SEQ ID NOs: 21, 24, 27, 30, 49, 52, 55, 58, 77, 80, 83 , or an antigen-binding fragment having a light chain variable (VL) region comprising a VL CDR3 having a sequence of 86 amino acids: have

[0333] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 103, 106, 1 VL CDR1 having an amino acid sequence of 09, 112, 131, 134, 137, 140, 159, 162, 165, or 168 and (2) the It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR2. In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 103, 106, 109 , 112, 131, 134, 137, 140, 159, 162, 165, or 168 amino acid sequences; and (3) SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3. In some embodiments, the molecules provided herein are (2) SEQ ID NOs: 104, 107, 110 , 113, 132, 135, 138, 141, 160, 163, 166, or 169 amino acid sequences; and (3) SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0334] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 209, 212, 2 and (2) a VL CDR1 having a 15 or 21 amino acid sequence; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR2. In some embodiments, the molecules provided herein have (1) SEQ ID NOS: 209, 212, 215 or VL CDR1 having a sequence of 21 amino acids; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL CDR3 with amino acid sequences. stomach In some embodiments, the molecules provided herein are (2) SEQ ID NOS: 210, 213, 216; or VL CDR2 having the amino acid sequence of 219; It has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a no acid sequence.

[0335] In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 237, 240, 2 VL CDR1 having a 43 or 246 amino acid sequence; and (2) SEQ ID NOs: 238, 241, 244, or 247 has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR2 having an amino acid sequence of . In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 237, 240, 2 VL CDR1 having a 43 or 246 amino acid sequence; and (3) SEQ ID NOs: 239, 242, 245, or 248 has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with an amino acid sequence of . In some embodiments, the molecules provided herein are (2) SEQ ID NOs: 238, 241, 2 (3) a VL CDR2 having an amino acid sequence of 44 or 247; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR3.

[0336] In some embodiments, the molecules provided herein are (1) SEQ ID NOs: 265, 268, 2 (2) a VL CDR1 having an amino acid sequence of 71 or 274; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR2. In some embodiments, the molecules provided herein have (1) SEQ ID NOS: 265, 268, 271 or VL CDR1 having a sequence of 274 amino acids; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL CDR3 with amino acid sequences. stomach In some embodiments, the molecules provided herein are (2) SEQ ID NOs: 266, 269, 272; or VL CDR2 having a sequence of 275 amino acids; It has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a no acid sequence.

[0337] In some embodiments, the molecules provided herein are (1) SEQ ID NOS: 293, 296, 2 (2) a VL CDR1 having an amino acid sequence of 99 or 302; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR2. In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 293, 296, 299 or VL CDR1 having an amino acid sequence of 302; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL CDR3 with amino acid sequences. stomach In some embodiments, the molecules provided herein are (2) SEQ ID NOs: 294, 297, 300; or VL CDR2 having the amino acid sequence of 303; It has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a no acid sequence.

[0338] In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 321, 324, 3 (2) a VL CDR1 having a sequence of 27 or 330 amino acids; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL with the amino acid sequence CDR2. In some embodiments, the molecules provided herein have (1) SEQ ID NOs: 321, 324, 327 or VL CDR1 having a sequence of 330 amino acids; It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL CDR3 with amino acid sequences. stomach In some embodiments, the molecules provided herein are (2) SEQ ID NOs: 322, 325, 328; or VL CDR2 having the amino acid sequence of 331; It has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a no acid sequence.

[0339] In some embodiments, the molecules provided herein are SEQ ID NOs: 19, 22, 25, 28 , 47, 50, 53, 56, 75, 78, 81, 84, 103, 106, 109, 112, 131, 134, 137, 140, 159, 1 62, 165, 168, 209, 212, 215, 218, 237, 240, 243, 246, 265, 268, 271, 274, 293, 2 A light chain variable comprising a VL CDR1 having a sequence of 96, 299, 302, 321, 324, 327, or 330 amino acids ( It has an antigen-binding fragment with a VL) region. The VL CDR1 has the amino acid sequence of SEQ ID NO: 19 can The VL CDR1 can have the amino acid sequence of SEQ ID NO:22. the VL CDR1 can have the amino acid sequence of SEQ ID NO:25. The VL CDR1 is of SEQ ID NO:28 It can have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO:47 be able to. The VL CDR1 can have the amino acid sequence of SEQ ID NO:50. The VL CD R1 can have the amino acid sequence of SEQ ID NO:53. The VL CDR1 has the address of SEQ ID NO:56. It can have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO:75. can be The VL CDR1 can have the amino acid sequence of SEQ ID NO:78. The VL CDR1 can have the amino acid sequence of SEQ ID NO:81. The VL CDR1 is the amino acid of SEQ ID NO:84. can have an acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO: 103 can be done. The VL CDR1 can have the amino acid sequence of SEQ ID NO:106. The VL CDR1 can have the amino acid sequence of SEQ ID NO:109. The VL CDR1 is the address of SEQ ID NO:112 It can have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO:131. can be The VL CDR1 can have the amino acid sequence of SEQ ID NO:134. The VL CDR 1 can have the amino acid sequence of SEQ ID NO:137. The VL CDR1 has the address of SEQ ID NO:140. It can have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO:159. can be The VL CDR1 can have the amino acid sequence of SEQ ID NO:162. The VL CDR 1 can have the amino acid sequence of SEQ ID NO:165. The VL CDR1 has the address of SEQ ID NO:168. It can have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO:209. can be The VL CDR1 can have the amino acid sequence of SEQ ID NO:212. The VL CDR 1 can have the amino acid sequence of SEQ ID NO:215. The VL CDR1 has the address of SEQ ID NO:218. It can have an amino acid sequence. The VL CDR1 has the amino acid sequence of SEQ ID NO:237. can be The VL CDR1 can have the amino acid sequence of SEQ ID NO:162408. the VL CDR1 can have the amino acid sequence of SEQ ID NO:243. The VL CDR1 is SEQ ID NO:246 can have an amino acid sequence of The VL CDR1 has the amino acid sequence of SEQ ID NO:265 can The VL CDR1 can have the amino acid sequence of SEQ ID NO:268. the VL CDR1 can have the amino acid sequence of SEQ ID NO:271. The VL CDR1 is SEQ ID NO:274 can have an amino acid sequence of The VL CDR1 has the amino acid sequence of SEQ ID NO:293 can The VL CDR1 can have the amino acid sequence of SEQ ID NO:296. the VL CDR1 can have the amino acid sequence of SEQ ID NO:299. The VL CDR1 is SEQ ID NO:302 can have an amino acid sequence of The VL CDR1 has the amino acid sequence of SEQ ID NO:321 can The VL CDR1 can have the amino acid sequence of SEQ ID NO:324. the VL CDR1 can have the amino acid sequence of SEQ ID NO:327. The VL CDR1 is SEQ ID NO:330 can have an amino acid sequence of

[0340] 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, 210, 213, 216, 219, 238, 241, 244, 247, 266, 269, 272, 275, 294, 2 A light chain variable comprising a VL CDR2 having an amino acid sequence of 97, 300, 303, 322, 325, 328, or 331 ( It has an antigen-binding fragment with a VL) region. The VL CDR2 has the amino acid sequence of SEQ ID NO:20 can The VL CDR2 can have the amino acid sequence of SEQ ID NO:23. the VL CDR2 can have the amino acid sequence of SEQ ID NO:26. The VL CDR2 is of SEQ ID NO:29 It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:48 be able to. The VL CDR2 can have the amino acid sequence of SEQ ID NO:51. The VL CD R2 can have the amino acid sequence of SEQ ID NO:54. The VL CDR2 is the address of SEQ ID NO:57 It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:76. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:79. The VL CDR2 can have the amino acid sequence of SEQ ID NO:82. The VL CDR2 is the amino acid of SEQ ID NO:85. can have an acid sequence. the VL CDR2 having the amino acid sequence of SEQ ID NO: 104 can be done. The VL CDR2 can have the amino acid sequence of SEQ ID NO:107. The VL CDR2 can have the amino acid sequence of SEQ ID NO:110. The VL CDR2 is the address of SEQ ID NO: 113 It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:132. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:135. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:138. The VL CDR2 is the address of SEQ ID NO: 141 It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:160. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:163. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:166. The VL CDR2 is the address of SEQ ID NO: 169 It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:210. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:213. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:216. The VL CDR2 is the address of SEQ ID NO:219. It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:238. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:241. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:244. The VL CDR2 is the address of SEQ ID NO:247. It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:266. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:269. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:272. The VL CDR2 is the address of SEQ ID NO:275. It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:294. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:297. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:300. The VL CDR2 is the address of SEQ ID NO:303. It can have an amino acid sequence. The VL CDR2 has the amino acid sequence of SEQ ID NO:322. can be The VL CDR2 can have the amino acid sequence of SEQ ID NO:325. The VL CDR 2 can have the amino acid sequence of SEQ ID NO:328. The VL CDR2 is the address of SEQ ID NO:331. It can have an amino acid sequence.

[0341] 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, 211, 214, 217, 220, 239, 242, 245, 248, 267, 270, 273, 276, 295, 2 A light chain variable comprising a VL CDR3 having a sequence of 98, 301, 304, 323, 326, 329, or 332 amino acids ( It has an antigen-binding fragment with a VL) region. The VL CDR3 has the amino acid sequence of SEQ ID NO:21 can The VL CDR3 can have the amino acid sequence of SEQ ID NO:24. the VL CDR3 can have the amino acid sequence of SEQ ID NO:27. The VL CDR3 is of SEQ ID NO:30 It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:49 be able to. The VL CDR3 can have the amino acid sequence of SEQ ID NO:52. The VL CD R3 can have the amino acid sequence of SEQ ID NO:55. The VL CDR3 is the address of SEQ ID NO:58. It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:77. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:80. The VL CDR3 can have the amino acid sequence of SEQ ID NO:83. The VL CDR3 is the amino acid of SEQ ID NO:86. can have an acid sequence. the VL CDR3 having the amino acid sequence of SEQ ID NO: 105 can be done. The VL CDR3 can have the amino acid sequence of SEQ ID NO:108. The VL CDR3 can have the amino acid sequence of SEQ ID NO:111. The VL CDR3 is the address of SEQ ID NO: 114 It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:133. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:136. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:139. The VL CDR3 is the address of SEQ ID NO: 142 It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:161. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:164. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:167. The VL CDR3 is the address of SEQ ID NO:170. It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:211. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:214. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:217. The VL CDR3 is the address of SEQ ID NO:220 It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:239. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:242. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:245. The VL CDR3 is the address of SEQ ID NO:248. It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:267. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:270. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:273. The VL CDR3 has the address of SEQ ID NO:276. It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:295. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:298. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:301. The VL CDR3 is the address of SEQ ID NO:304 It can have an amino acid sequence. The VL CDR3 has the amino acid sequence of SEQ ID NO:323. can be The VL CDR3 can have the amino acid sequence of SEQ ID NO:326. The VL CDR 3 can have the amino acid sequence of SEQ ID NO:329. The VL CDR3 is the address of SEQ ID NO:332 It can have an amino acid sequence.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0398] In some embodiments, the molecules provided herein have (a)(1) SEQ ID NOS: 91, 94, VH having a sequence of 97, 100, 119, 122, 125, 128, 147, 150, 153, or 156 amino acids CDR1; (2) SEQ ID NO: 92, 95, 98, 101, 120, 123, 126, 129, 148, 151, 154, or 157 and / or (3) SEQ ID NOs: 93, 96, 99, 102, 121, 124, 127 a VH CDR3 having an amino acid sequence of 130, 149, 152, 155, or 158; ) regions; and (b) (1) SEQ ID NOS: 103, 106, 109, 112, 131, 134, 137, 140, 159, 162, 165. or VL CDR1 having a sequence of 168 amino acids; (2) SEQ ID NOs: 104, 107, 110, 113, 132, 1 VL CDR2 having an amino acid sequence of 35, 138, 141, 160, 163, 166, or 169; and / or ( 3) SEQ ID NO: 105, 108, 111, 114, 133, 136, 139, 142, 161, 164, 167, or 170 It has an antigen-binding fragment with a light chain variable (VL) region comprising: VL CDR3 with amino acid sequences. the A molecule can be an antibody. The antibody can be a monoclonal antibody. The antibody can be a humanized antibody.

[0399] In some embodiments, the molecules provided herein have (a)(1) SEQ ID NOs: 197, 200 , 203, or 206 amino acid sequences; (2) SEQ ID NOs: 198, 201, 204, or has a 207 amino acid sequence; and / or (3) SEQ ID NOs: 199, 202, 205, or 20 a heavy chain variable (VH) region comprising: a VH CDR3 having an amino acid sequence of 8; and (b) (1) SEQ ID NO: 209, 2 VL CDR1 having a 12, 215, or 218 amino acid sequence; (2) SEQ ID NOs: 210, 213, 216, if or VL CDR2 having an amino acid sequence of 219; and / or (3) SEQ ID NOs: 211, 214, 217, or has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a sequence of 220 amino acids; do. The molecule can be an antibody. the antibody is a monoclonal antibody can. The antibody can be a humanized antibody.

[0400] In some embodiments, the molecules provided herein have (a)(1) SEQ ID NOS: 225, 228 , 231, or 234 amino acid sequences; (2) SEQ ID NOS: 226, 229, 232, or has a 235 amino acid sequence; and / or (3) SEQ ID NOs: 227, 230, 233, or 236 and (b) (1) SEQ ID NOS: 237, 24, a heavy chain variable (VH) region comprising: VL CDR1 having a sequence of 0, 243, or 246 amino acids; (2) SEQ ID NOs: 238, 241, 244, if or VL CDR2 having an amino acid sequence of 247; and / or (3) SEQ ID NOs: 239, 242, 245, or has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a sequence of 248 amino acids; do. The molecule can be an antibody. the antibody is a monoclonal antibody can. The antibody can be a humanized antibody.

[0401] In some embodiments, the molecules provided herein have (a)(1) SEQ ID NOS: 253, 256 , 259, or 262 amino acid sequences; (2) SEQ ID NOs: 254, 257, 260, or has a 263 amino acid sequence; and / or (3) SEQ ID NOs: 255, 258, 261, or 26 a heavy chain variable (VH) region comprising: a VH CDR3 having an amino acid sequence of 4; and (b) (1) SEQ ID NO: 265, 2 VL CDR1 having a sequence of 68, 271, or 274 amino acids; (2) SEQ ID NOs: 266, 269, 272, if or VL CDR2 having a sequence of 275 amino acids; and / or (3) SEQ ID NOs: 267, 270, 273, or has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a sequence of 276 amino acids; do. The molecule can be an antibody. the antibody is a monoclonal antibody can. The antibody can be a humanized antibody.

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

[0403] In some embodiments, the molecules provided herein have (a)(1) SEQ ID NOs: 309, 312 , 315, or 318 amino acid sequences; (2) SEQ ID NOs: 310, 313, 316, or has a 319 amino acid sequence; and / or (3) SEQ ID NOs: 311, 314, 317, or 32 a heavy chain variable (VH) region comprising: a VH CDR3 having an amino acid sequence of 0; and (b) (1) SEQ ID NOs:321,3 VL CDR1 having a sequence of 24, 327, or 330 amino acids; (2) SEQ ID NOs: 322, 325, 328, if or VL CDR2 having an amino acid sequence of 331; and / or (3) SEQ ID NOs: 323, 326, 329, or has an antigen-binding fragment with a light chain variable (VL) region comprising: a VL CDR3 with a sequence of 332 amino acids; do. The molecule can be an antibody. the antibody is a monoclonal antibody can. The antibody can be a humanized antibody.

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

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

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

[0407] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO: 16; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 17; and (3) SEQ ID NO: a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 18; and (b)(1) SEQ ID NO:28 (2) VL CDR2 having the amino acid sequence of SEQ ID NO:29; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO: 30; have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0408] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:35. (2) VH CDR2 having the amino acid sequence of SEQ ID NO:36; and (3) SEQ ID NO:36. a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 37; and (b) (1) SEQ ID NO: 47 (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 48; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO:49 have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0409] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:38. (2) VH CDR2 having the amino acid sequence of SEQ ID NO:39; and (3) SEQ ID NO:39. a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 40; and (b)(1) SEQ ID NO:50 (2) VL CDR2 having the amino acid sequence of SEQ ID NO:51; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO:52 have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0410] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:41. (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 42; and (3) SEQ ID NO: a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 43; and (b) (1) SEQ ID NO: 53 (2) VL CDR2 having the amino acid sequence of SEQ ID NO:54; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO: 55; have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0411] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:44. (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 45; and (3) SEQ ID NO: a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 46; and (b) (1) SEQ ID NO: 56 (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 57; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO: 58 have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0412] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:63. (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 64; and (3) SEQ ID NO: a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 65; and (b) (1) SEQ ID NO: 75 (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 76; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO: 77; have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0413] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:66. (2) VH CDR2 having the amino acid sequence of SEQ ID NO:67; and (3) SEQ ID NO. a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 68; and (b) (1) SEQ ID NO: 78 (2) VL CDR2 having the amino acid sequence of SEQ ID NO: 79; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO:80 have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0414] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:69. (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 70; and (3) SEQ ID NO: a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 71; and (b) (1) SEQ ID NO: 81 (2) VL CDR2 having the amino acid sequence of SEQ ID NO:82; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO:83 have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

[0415] In some embodiments, the molecules provided herein are (a)(1) amino acids of SEQ ID NO:72. (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 73; and (3) SEQ ID NO: a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of No. 74; and (b) (1) SEQ ID NO: 84 (2) VL CDR2 having the amino acid sequence of SEQ ID NO:85; and (3) VL CDR3 having the amino acid sequence of SEQ ID NO:86 have a piece. The molecule can be an antibody. the antibody is a monoclonal antibody be able to. The antibody can be a humanized antibody.

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

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

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

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

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

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

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

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

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

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

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

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

[0428] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO: 197 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 198; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 199; VL CDR1 having the amino acid sequence of SEQ ID NO:209; (2) VL CD having the amino acid sequence of SEQ ID NO:210 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:211: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0429] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:200 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 201; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 202; VL CDR1 having the amino acid sequence of SEQ ID NO:212; (2) VL CD having the amino acid sequence of SEQ ID NO:213 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:214: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0430] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:203; (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 204; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 205; VL CDR1 having the amino acid sequence of SEQ ID NO:215; (2) VL CD having the amino acid sequence of SEQ ID NO:216 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:217: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

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

[0432] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:225 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 226; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 227; VL CDR1 having the amino acid sequence of SEQ ID NO:237; (2) VL CD having the amino acid sequence of SEQ ID NO:238 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:239: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

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

[0434] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:231 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 232; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 233; VL CDR1 having the amino acid sequence of SEQ ID NO:243; (2) VL CD having the amino acid sequence of SEQ ID NO:244 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:245: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0435] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:234 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 235; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 236; VL CDR1 having the amino acid sequence of SEQ ID NO:246; (2) VL CD having the amino acid sequence of SEQ ID NO:247 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:248: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0436] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:253 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 254; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 255; VL CDR1 having the amino acid sequence of SEQ ID NO:265; (2) VL CD having the amino acid sequence of SEQ ID NO:266 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:267: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0437] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:256 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 257; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 258; VL CDR1 having the amino acid sequence of SEQ ID NO:268; (2) VL CD having the amino acid sequence of SEQ ID NO:269 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:270: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0438] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:259 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 260; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 261; VL CDR1 having the amino acid sequence of SEQ ID NO:271; (2) VL CD having the amino acid sequence of SEQ ID NO:272 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:273: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

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

[0440] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:281 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 282; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 283; VL CDR1 having the amino acid sequence of SEQ ID NO:293; (2) VL CD having the amino acid sequence of SEQ ID NO:294 R2; and / or (3) a light chain variable (VL) region comprising: a VL CDR3 having the amino acid sequence of SEQ ID NO:295; has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0441] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:284 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 285; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO:286; VL CDR1 having the amino acid sequence of SEQ ID NO:296; (2) VL CD having the amino acid sequence of SEQ ID NO:297 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:298: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0442] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:287 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 288; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 289; VL CDR1 having the amino acid sequence of SEQ ID NO:299; (2) VL CD having the amino acid sequence of SEQ ID NO:300 R2; and / or (3) a light chain variable (VL) region comprising: a VL CDR3 having the amino acid sequence of SEQ ID NO:301; has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

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

[0444] In some embodiments, the molecules provided herein comprise (a)(1) the address of SEQ ID NO:309 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 310; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO:311; VL CDR1 having the amino acid sequence of SEQ ID NO:321; (2) VL CD having the amino acid sequence of SEQ ID NO:322 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:323: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0445] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:312 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 313; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO:314; VL CDR1 having the amino acid sequence of SEQ ID NO:324; (2) VL CD having the amino acid sequence of SEQ ID NO:325 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:326: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

[0446] In some embodiments, the molecules provided herein have (a)(1) the address of SEQ ID NO:315 (2) VH CDR2 having the amino acid sequence of SEQ ID NO: 316; and / or ( 3) a heavy chain variable (VH) region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 317; VL CDR1 having the amino acid sequence of SEQ ID NO:327; (2) VL CD having the amino acid sequence of SEQ ID NO:328 R2; and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO:329: a light chain variable (VL) region comprising: has an antigen-binding fragment with The molecule can be an antibody. The antibody is a monochrome can be an internal antibody. The antibody can be a humanized antibody.

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

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

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

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

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

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

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

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

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

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

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

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

[0459] In some embodiments, the molecules provided herein are mouse A monoclonal antibody or a humanized antibody version thereof. A humanized STC703 antibody is described herein can have the VH region, the VL region, or both the VH and VL regions of STC703 described in be. The humanized STC703 antibody comprises the six CDR regions of STC703 described herein (VH CDR1, VH CDR 2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized STC703 antibody can also have less than 6 CDR regions of STC703. In some embodiments, the STC703 antibodies containing 1, 2, 3, 4 or 5 CDR regions of STC703 (VH CDR1, VH CDR2 , VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0460] In some embodiments, the molecules provided herein are mouse A monoclonal antibody or a humanized antibody version thereof. The humanized STC810 ​​antibody is herein can have the VH region, the VL region, or both the VH and VL regions of STC810 ​​described in be. The humanized STC810 ​​antibody comprises the six CDR regions of STC810 ​​described herein (VH CDR1, VH CDR 2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized STC810 ​​antibody can also have less than 6 CDR regions of STC810. In some embodiments, the STC810 ​​antibodies containing 1, 2, 3, 4 or 5 CDR regions of STC810 ​​(VH CDR1, VH CDR2 , VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0461] In some embodiments, the molecules provided herein are mouse A monoclonal antibody or a humanized antibody version thereof. The humanized STC820 antibody is herein can have the VH region, the VL region, or both the VH and VL regions of STC820 described in be. The humanized STC820 antibody comprises the six CDR regions of STC820 described herein (VH CDR1, VH CDR 2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized STC820 antibody can also have less than 6 CDR regions of STC820. In some embodiments, the STC820 antibodies containing 1, 2, 3, 4 or 5 CDR regions of STC820 (VH CDR1, VH CDR2 , VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0462] In some embodiments, the molecule provided herein is a mouse strain designated STC1011. monoclonal antibodies or humanized antibody versions thereof. The humanized STC1011 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC1012 described herein can be done. Humanized STC1011 antibodies have the six CDR regions of STC1011 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C1011 antibody can also have less than 6 CDR regions of STC1011. in some embodiments In humanized STC1011 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC1011 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0463] In some embodiments, the molecule provided herein is a mouse strain designated STC1012. monoclonal antibodies or humanized antibody versions thereof. The humanized STC1012 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC1012 described herein can be done. Humanized STC1012 antibodies have the six CDR regions of STC1012 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C1012 antibody can also have less than 6 CDR regions of STC1012. in some embodiments In humanized STC1012 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC1012 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0464] In some embodiments, the molecule provided herein is a mouse strain designated STC1029. monoclonal antibodies or humanized antibody versions thereof. The humanized STC1029 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC1029 described herein can be done. The humanized STC1029 antibody has the six CDR regions of STC1029 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C1029 antibody can also have less than 6 CDR regions of STC1029. in some embodiments In humanized STC1029 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC1029 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0465] In some embodiments, the molecule provided herein is a mouse strain designated STC2602. monoclonal antibodies or humanized antibody versions thereof. The humanized STC2602 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC2602 described herein can be done. The humanized STC2602 antibody has the six CDR regions of STC2602 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C2602 antibody can also have less than 6 CDR regions of STC2602. in some embodiments In humanized STC2602 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC2602 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0466] In some embodiments, the molecule provided herein is a mouse strain designated STC2714. monoclonal antibodies or humanized antibody versions thereof. The humanized STC2714 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC2714 described herein can be done. The humanized STC2714 antibody has the six CDR regions of STC2714 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST The C2714 antibody can also have less than 6 CDR regions of STC2602. in some embodiments In humanized STC2714 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC2714 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0467] In some embodiments, the molecule provided herein is a mouse strain designated STC2739. monoclonal antibodies or humanized antibody versions thereof. The humanized STC2739 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC2739 described herein can be done. The humanized STC2739 antibody has the six CDR regions of STC2739 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C2739 antibody can also have less than 6 CDR regions of STC2739. in some embodiments In humanized STC2739 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC2739 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0468] In some embodiments, the molecule provided herein is a mouse strain designated STC2778. monoclonal antibodies or humanized antibody versions thereof. The humanized STC2778 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC2778 described herein can be done. Humanized STC2778 antibodies have the six CDR regions of STC2778 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C2778 antibody can also have less than 6 CDR regions of STC2778. in some embodiments In humanized STC2778 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC2778 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0469] In some embodiments, the molecule provided herein is a mouse strain designated STC2781. monoclonal antibodies or humanized antibody versions thereof. The humanized STC2781 antibody is Having the VH region, the VL region, or both the VH region and the VL region of STC2781 described herein can be done. The humanized STC2781 antibody has the six CDR regions of STC2781 described herein (VH CDR1 , VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3). Humanized ST A C2781 antibody can also have less than 6 CDR regions of STC2781. in some embodiments In humanized STC2781 antibodies, 1, 2, 3, 4, or 5 CDR regions of STC2781 (VH CD R1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0470] For example, site-directed mutagenesis and PCR-mediated mutagenesis to generate amino acid substitutions Antigen-binding fragments or fragments provided herein can be isolated using standard techniques known to those of skill in the art, including can introduce mutations into the nucleotide sequence encoding the antibody. one embodiment , the derivative has fewer than 25 amino acid substitutions, less than 20 amino acid substitutions, compared to the parent molecule <15 amino acid substitutions; <10 amino acid substitutions; <5 amino acid substitutions; <4 amino acid substitutions; no acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions. specific implementation in which derivatives are conservative amino acid substitutions made at one or more predicted non-essential amino acid residues. have exchanges. A "conservative amino acid substitution" is one in which the amino acid residues have side chains with similar charges is a substitution that replaces an amino acid residue with amino acids with similarly charged side chains Families of residues have been defined in the art. These families include basic side chains (e.g. lysine, arginine, histidine), amino acids with acidic side chains Acids (e.g. aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g. glycine, asparagine, glutamine, serine, threonine, tyrosine, cis tein), amino acids with non-polar side chains (e.g. alanine, valine, leucine, isolei syn, proline, phenylalanine, methionine, tryptophan), with β-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains. acids (eg tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations are made to all or part of the coding sequence, for example by saturation mutagenesis. can be introduced randomly along the route and the resulting mutants screened for biological activity. Leaning can be performed to identify mutants that retain activity. After mutagenesis , can express the encoded protein and determine the activity of the protein can do.

[0471] In some embodiments, immunospecifically binds to BTN1A1 or glycosylated BTN1A1 Molecules provided herein having an antigen-binding fragment are the murine monoclonal antibody STC703, STC810, STC820, STC1011, STC1012, STC1029, STC2602, STC2714, STC2739, STC2778, or STC2781, or an antigen-binding fragment thereof, e.g. at least 35%, at least 40%, at least 45%, at least 50%, at least at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% It can have an amino acid sequence that is one. In one embodiment, provided herein Molecules containing 1, 223, 249, 251, 277, 279, 305, or 307 and at least 35% at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, have amino acid sequences that are at least 90%, at least 95%, or at least 99% identical be able to. In yet another embodiment, the molecules provided herein are represented in Tables 2a-2 above. VH CDR amino acid sequence and / or VL CDR amino acid sequence shown in any one of 12b and at least at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least VH CDRs that are both 85%, at least 90%, at least 95%, or at least 99% identical and / or can have a VL CDR amino acid sequence.

[0472] In some embodiments, molecules provided herein are treated under stringent conditions Bottom (e.g., 6x sodium chloride / sodium citrate (S SC) at about 45° C., followed by about 50-65 in 0.2×SSC / 0.1% SDS one or more washes at °C), under very stringent conditions (e.g. Hybridization at about 45° C. in 6×SSC for the nucleic acids that were obtained, followed by 0.1×SSC / 0.2 % SDS at about 68° C.) or other stringent high VH and / or VL domains shown in any one of Tables 2a-12b under hybridization conditions which hybridizes to the complement of a nucleotide sequence encoding any one of the amino acid sequence of the VH domain and / or of the VL domain encoded by the (eg Ausubel, F.M. et al. eds. 1989, The latest in molecular biology) Current Protocols in Molecular Biology, Volume I, Green Publishing As socialtes and John Wiley & Sons, New York, see pages 6.3.1-6.3.6 and 2.10.3) .

[0473] In another embodiment, the molecules provided herein are administered under stringent conditions (e.g. For example, hybridization to filter-bound DNA in 6×SSC at about 45° C. followed by one or more washes in 0.2 x SSC / 0.1% SDS at about 50-65°C), extremely stringent under gentle conditions (e.g., high temperature at about 45°C in 6 x SSC for filter-bound nucleic acids). hybridization, followed by one or more washes in 0.1×SSC / 0.2% SDS at about 68° C.), or under other stringent hybridization conditions known to those skilled in the art, Tables 2a-12b a nuk encoding any one of the VH CDRs and / or VL CDRs shown in any one of VH C encoded by a nucleotide sequence that hybridizes to th...

Claims

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

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