WO2016058148A1 - 抗butyrophilin-3人源化抗体及其使用 - Google Patents

抗butyrophilin-3人源化抗体及其使用 Download PDF

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WO2016058148A1
WO2016058148A1 PCT/CN2014/088685 CN2014088685W WO2016058148A1 WO 2016058148 A1 WO2016058148 A1 WO 2016058148A1 CN 2014088685 W CN2014088685 W CN 2014088685W WO 2016058148 A1 WO2016058148 A1 WO 2016058148A1
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butyrophilin
cancer
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fragment
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李小彦
钮晓音
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李小彦
钮晓音
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans

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  • the invention belongs to the field of medical biotechnology and humanized antibody research.
  • the present invention relates to a humanized antibody molecule having a specific recognition of an antigenic determinant of human butyrophilin-3 (potentin-3) and a composition comprising the same and a fragment thereof.
  • the invention also relates to the use of a humanized anti-butyrophilin-3 antibody for the treatment of various diseases.
  • the human butyrophilin-3 (pastilin-3) gene family is located at the extension of the MHC class I molecular cluster on chromosome 6, originally called the MHC-related gene.
  • the Butyrophilin-3 family contains three members: BTN3A1, BTN3A2, BTN3A3.
  • the Butyrophilin-3 gene is deleted in mice.
  • Butyrophilin-3 protein is a single transmembrane protein whose extracellular domain belongs to the immunoglobulin supergene family and contains an N-terminal IgV-like domain and a near-membrane IgC-like domain.
  • the extracellular regions of BTN3A1, BTN3A2 and BTN3A3 are highly homologous in amino acid composition, and the homology of the IgV-like domain is 99-100%. Therefore, the anti-butyrophilin-3 antibody against the IgV-like domain usually recognizes both BTN3A1, BTN3A2 and BTN3A3, so it is an anti-BTN3A1 humanized antibody, an anti-BTN3A2 humanized antibody and an anti-BTN3A3 humanized antibody.
  • General name is an anti-BTN3A1 humanized antibody, an anti-BTN3A2 humanized antibody and an anti-BTN3A3 humanized antibody.
  • BTN3A1 is expressed on the surface of various human tumor cell membranes, such as non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, pancreatic adenocarcinoma, breast cancer, ovarian cancer, cervical cancer, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma , erythroleukemia, myeloma cells, synovial sarcoma, chondrosarcoma, etc.
  • tumor cell membranes such as non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, pancreatic adenocarcinoma, breast cancer, ovarian cancer, cervical cancer, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma , erythroleukemia, myeloma cells, synovial sarcoma, chondrosarcoma, etc.
  • Antibodies against BTN3A1 on the surface of tumor cell membranes are capable of inhibiting the growth of tumor cells and inducing depolymerization of tumor cells. Therefore, the development of a humanized anti-butyrophilin-3 antibody can effectively treat a variety of tumors.
  • the present invention is based on a obtained parental anti-human butyrophilin-3 murine monoclonal antibody 6D9 which specifically binds to human butyrophilin-3 protein, and the CDR region sequence is determined by cloning, identification and gene structure analysis.
  • the corresponding humanized antibody and its eukaryotic expression vector were obtained, and a cell line expressing and secreting the anti-human butyrophilin 3 humanized antibody was obtained, and the humanized antibody was purified.
  • the present invention develops a humanized antibody against the IgV-like domain of butyrophilin-3 protein, named For Xylizumab (reinforcement of mAb), Xylizumab was found to recognize three proteins, BTN3A1, BTN3A2 and BTN3A3, whose binding epitopes are located in the butyrophilin 3 protein IgV-like domain.
  • Xylizumab inhibits the growth of 20 human tumor cell lines that cover epithelial-derived cancer cells such as non-small cell lung cancer cell lines (Calu-1), hepatocellular carcinoma cell lines (Huh7, HepG2), and gastric cancer cell lines ( MGC80-3), pancreatic adenocarcinoma cell line (PANC-1, BxPC-3, CFPAC-1), breast cancer cell line (SKBR3), ovarian cancer cell line (SKOV3), cervical cancer cell line (HeLa); blood system Tumors, such as acute myeloid leukemia cell line (HL-60, NB4), chronic myeloid leukemia cell line (K-562), multiple myeloma cell line (U266, KM3), erythroleukemia cell line (HEL); Sarcomas, such as myeloma cell line (U-2 OS, MNNG/HOS), synovial sarcoma cell line (SW982), chondrosarcoma cell line (SW1353).
  • Xylizumab is able to induce apoptosis in certain tumor cells, a phenomenon that is particularly pronounced in HL-60 cells, and Xylizumab is able to completely inhibit the growth of HL-60.
  • Xylizumab-mediated tumor growth inhibition is the intracellular delivery of growth inhibition signals by binding of antibodies to BTN3A1 on the cell membrane.
  • Xylizumab exerts an inhibitory effect at a normal concentration of 10 ug/ml, and it induces intracellular tubulin depolymerization when the concentration in the culture system is increased to 500 ug/ml.
  • Xylizumab can slow the growth of transplanted liver cancer HepG2 and transplant osteosarcoma MNNG/HOS and prolong the survival of nude mice.
  • this antibody is capable of inhibiting the formation of cell clones of bone marrow-derived primary acute myeloid leukemia M3 and M4, indicating that the antibody is capable of treating certain primary hematological tumors.
  • BTN3A1 Since BTN3A1 is widely expressed in almost all types of tumor cell lines, BTN3A1 can serve as a common target for different types of tumors. Xylizumab mediates the depolymerization of intracellular microtubules by binding to BTN3A1 on the cell membrane. This discovery has enriched our understanding of antibody function and expanded the range of antibodies. With this new function of antibodies, the polymerization of microtubules can be dynamically and reversibly regulated, and immunotherapy based on this antibody will also have broad application prospects.
  • the present invention mainly relates to the following aspects:
  • the present invention relates to an anti-human butyrophilin-3 humanized antibody, wherein the humanized antibody comprises a light chain comprising three light chain variable regions and a heavy chain comprising three heavy chain variable regions Composition, wherein the amino acid sequences of the three light chain variable region CDRs are QSLSDN (SEQ ID NO: 1), FAS (SEQ ID NO: 2) and QQSHSWPYT (SEQ ID NO: 3), the amino acid sequences of the heavy chain variable region CDRs are GFTFSSYA (SEQ ID NO: 4), ISSGGNYS (SEQ ID NO: 5), and ARHGPDDFTSWVDY (SEQ ID NO: 6).
  • QSLSDN SEQ ID NO: 1
  • FAS SEQ ID NO: 2
  • QQSHSWPYT SEQ ID NO: 3
  • the amino acid sequences of the heavy chain variable region CDRs are GFTFSSYA (SEQ ID NO: 4), ISSGGNYS (SEQ ID NO: 5), and ARHGPDDFTSWV
  • the binding specificity and affinity of an antibody are mainly determined by the CDR sequence, and the amino acid sequence of the non-CDR region can be easily changed according to the mature and well-known existing techniques to obtain a similar biological activity. body.
  • the monoclonal antibody variants of the present invention having CDR sequences identical to those of the above CDR sequences, which have identical CDR sequences as the humanized antibodies of the present invention, have similar biological activities.
  • the invention relates to a fragment of an anti-human butyrophilin-3 humanized antibody, wherein the fragment is selected from the group consisting of F(ab') 2 , Fab', Fab, Fv, scFv and antibody minimal recognition units.
  • the fragment comprises the CDRs of the three light chain variable regions and the CDRs of the three heavy chain variable regions, the light chain variable region CDR amino acid sequences of which are QSLSDN (SEQ ID NO: 1), FAS (SEQ ID NO: 2) and QQSHSWPYT (SEQ ID NO: 3) and the heavy chain variable region CDR sequences are GFTFSSYA (SEQ ID NO: 4), ISSGGNYS (SEQ ID NO: 5), and ARHGPDDFTSWVDY (SEQ ID NO: 6).
  • QSLSDN SEQ ID NO: 1
  • FAS SEQ ID NO: 2
  • QQSHSWPYT SEQ ID NO: 3
  • the heavy chain variable region CDR sequences are GFTFSSYA (SEQ ID NO: 4), ISSGGNYS (SEQ ID NO: 5), and ARHGPDDFTSWVDY (SEQ ID NO: 6).
  • the present invention relates to a method of treating a disease, wherein the disease is selected from the group consisting of a tumor such as osteosarcoma, chondrosarcoma, synovial sarcoma, medullary thyroid carcinoma (MTC), colorectal cancer , hepatocellular carcinoma, liver cancer, gastric cancer, esophageal cancer, lung cancer, non-small cell lung cancer, breast cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, urinary tract Cancer, prostate cancer, hematological tumor, lymphatic system tumor, thymoma, melanoma, etc.; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, systemic vasculitis, self Immune liver disease, pemphigus, scleroderma, dermatomyositis, mixed connective tissue disease
  • a tumor
  • Figure 1.a demonstrates that the anti-butyrophilin-3 humanized antibody Xylizumab recognizes purified BTN3A1, BTN3A2 and BTN3A3 from CHO cells by ELISA. b using ELISA method It was confirmed that the antigenic determinant recognized by the anti-butyrophilin-3 humanized antibody Xylizumab is located in the Ig V domain of the butyrophilin-3 protein. Since the Ig V structure of butyrophilin-3 protein is highly homologous, Xylizumab recognizes both BTN3A1, BTN3A2 and BTN3A3.
  • Xylizumab inhibits the growth of transplanted hepatocellular carcinoma HepG2 in nude mice.
  • Xylizumab inhibits the growth of MNNG/HOS in transplanted osteosarcoma in nude mice.

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Abstract

提供了一种抗butyrophilin-3人源化抗体或其片段，其包含了轻链可变区CDR序列QSLSDN（SEQ ID NO：1）、FAS（SEQ ID NO：2）和QQSHSWPYT（SEQ ID NO：3）及重链可变区CDR序列GFTFSSYA（SEQ ID NO：4）、ISSGGNYS（SEQ ID NO：5）和ARHGPDDFTSWVDY（SEQ ID NO：6）。

Description

抗butyrophilin-3人源化抗体及其使用 技术领域
本发明属于医学生物技术和人源化抗体研究领域。本发明涉及对人butyrophilin-3(嗜乳脂蛋-3)的抗原决定簇具有特异性识别的人源化抗体分子和包含所述抗体分子及其片段的组合物。本发明还涉及人源化抗butyrophilin-3抗体在治疗各种疾病中的用途。
背景技术
人的butyrophilin-3(嗜乳脂蛋-3)基因家族位于6号染色体MHC I类分子基因簇的延伸端，最初称为MHC相关基因。Butyrophilin-3家族包含三个成员：BTN3A1，BTN3A2，BTN3A3。Butyrophilin-3基因在小鼠上缺失。Butyrophilin-3蛋白是单次穿膜蛋白，其胞外区结构属于免疫球蛋白超基因家族，包含有一个N端的IgV样结构域，和一个近膜端的IgC样结构域。BTN3A1，BTN3A2和BTN3A3的胞外区氨基酸组成上高度同源，其中IgV样结构域的同源性达99-100％。因此，针对IgV样结构域的抗butyrophilin-3抗体通常能同时识别BTN3A1，BTN3A2和BTN3A3，因此它是抗-BTN3A1人源化抗体、抗-BTN3A2人源化抗体和抗-BTN3A3人源化抗体的总称。
BTN3A1表达于人类各种肿瘤细胞膜表面，如非小细胞肺癌、肝细胞肝癌、胃癌、胰腺腺癌、乳腺癌、卵巢癌、宫颈癌、急性原髓样白血病、慢性髓样白血病、多发性骨髓瘤、红白血病、骨髓瘤细胞、滑膜肉瘤、软骨肉瘤等。
针对肿瘤细胞膜表面BTN3A1的抗体能够抑制肿瘤细胞的生长和诱导肿瘤细胞微管蛋白的解聚。因此开发一种人源化抗butyrophilin-3抗体能够有效地治疗多种肿瘤。
发明内容
本发明是基于所获得的一株具有与人butyrophilin-3蛋白特异性结合的亲本抗人butyrophilin-3鼠单克隆抗体6D9，通过克隆、鉴定与基因结构的分析，确定了其CDR区序列，构建了相应的人源化抗体及其真核细胞表达载体，并获得了表达并分泌该抗人butyrophilin 3人源化抗体的细胞株，生产纯化了该人源化抗体。
本发明研发了针对butyrophilin-3蛋白IgV样结构域的人源化抗体，命名 为Xylizumab(再力助单抗)，发现Xylizumab能够识别BTN3A1，BTN3A2和BTN3A3三个蛋白，其结合的表位位于butyrophilin 3蛋白IgV样结构域。
Xylizumab能够抑制20种人类肿瘤细胞系的生长，这些细胞系覆盖了上皮来源的癌症细胞如非小细胞肺癌细胞系(Calu-1)、肝细胞肝癌细胞系(Huh7,HepG2)、胃癌细胞系(MGC80-3)、胰腺腺癌细胞系(PANC-1,BxPC-3,CFPAC-1)、乳腺癌细胞系(SKBR3)、卵巢癌细胞系(SKOV3)、宫颈癌细胞系(HeLa)；血液系统肿瘤，如急性原髓样白血病细胞系(HL-60,NB4)、慢性髓样白血病细胞系(K-562)、多发性骨髓瘤细胞系(U266，KM3)、红白血病细胞系(HEL)；肉瘤，如骨髓瘤细胞系(U-2 OS,MNNG/HOS)、滑膜肉瘤细胞系(SW982)、软骨肉瘤细胞系(SW1353)。但它对正常细胞系HFL1没有表现出抑制作用。Xylizumab能够诱导某些肿瘤细胞凋亡，这种现象对于HL-60细胞特别明显，并且Xylizumab能够完全抑制HL-60的生长。
Xylizumab介导的肿瘤生长抑制是通过抗体与细胞膜上的BTN3A1结合后，来向胞内传递生长抑制信号的。Xylizumab在正常浓度10ug/ml的水平下就能发挥抑制效应，当培养体系中浓度增加至500ug/ml的时候，它能诱导细胞内微管蛋白解聚。
动物实验显示Xylizumab能够减缓移植性肝癌HepG2和移植性骨肉瘤MNNG/HOS的生长，延长裸鼠的生存期。
另外，这个抗体能够抑制骨髓来源的原代急性髓性白血病M3和M4的细胞克隆形成，这说明该抗体能够治疗某些原代血液系统肿瘤。
由于BTN3A1广泛表达于几乎所有类型肿瘤细胞系中，所以BTN3A1能够做为不同类型肿瘤的共同靶标。Xylizumab能够通过与细胞膜上的BTN3A1结合来介导胞内微管解聚，这项功能的发现丰富了我们对抗体功能的认识，也拓展了抗体的应用范围。利用抗体的这一新功能，可以动态可逆地调节微管的聚合，并且以这个抗体为基础的免疫治疗也会具有广阔的应用前景。
因此，本发明主要涉及了以下几个方面：
第一方面，本发明涉及一种抗人butyrophilin-3人源化抗体，其中所述人源化抗体由含有3个轻链可变区的轻链和含有3个重链可变区的重链组成，其中所述3个轻链可变区CDR的氨基酸序列为QSLSDN(SEQ ID NO：1)、FAS(SEQ ID  NO：2)和QQSHSWPYT(SEQ ID NO：3)，重链可变区CDR的氨基酸序列为GFTFSSYA(SEQ ID NO：4)、ISSGGNYS(SEQ ID NO：5)和ARHGPDDFTSWVDY(SEQ ID NO：6)。本领域公知，抗体的结合特异性及亲合力均主要由CDR序列决定，根据成熟、公知的现有各项技术可轻易地将非CDR区域的氨基酸序列改变而获得具有相类似的生物活性的变体。本发明涉及的具有与上述CDR序列完全相同的CDR序列的单克隆抗体变体，因其具有与本发明所述的人源化抗体完全相同的CDR序列，因此具有相类似的生物活性。
第二方面，本发明涉及抗人butyrophilin-3人源化抗体的片段，其中该片段选自由F(ab’)2、Fab’、Fab、Fv、scFv和抗体最小识别单位组成的组。并且该片段包含了3个轻链可变区的CDR和3个重链可变区的CDR，其轻链可变区CDR氨基酸序列为QSLSDN(SEQ ID NO：1)、FAS(SEQ ID NO：2)和QQSHSWPYT(SEQ ID NO：3)及重链可变区CDR序列为GFTFSSYA(SEQ ID NO：4)、ISSGGNYS(SEQ ID NO：5)和ARHGPDDFTSWVDY(SEQ ID NO：6)。
第三方面，本发明涉及一种治疗疾病的方法，其中所述疾病选自由以下组成的组：肿瘤，如：骨肉瘤、软骨肉瘤、滑膜肉瘤、甲状腺髓样癌(MTC)、结肠直肠癌、肝细胞癌、肝癌、胃癌、食道癌、肺癌、非小细胞肺癌、乳腺癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、头颈部癌、膀胱癌、尿路上皮癌、前列腺癌、血液系统肿瘤、淋巴系统肿瘤、胸腺瘤、黑素瘤等；自身免疫性疾病，如：类风湿性关节炎、系统性红斑狼疮、多发性硬化症、系统性血管炎、自身免疫性肝病、天疱疮、硬皮病、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、溃疡性结肠炎、Crohn氏病、银屑病、干燥性综合症、恶性贫血、新生儿溶血、自身免疫性溶血性贫血、特发性血小板减少性紫癜、胰岛素依赖型糖尿病、强直性脊柱炎、硬皮病、重症肌无力、结节性多动脉炎、Wegener肉芽肿病、亚急性细菌性心内膜炎等；免疫排斥性疾病，如宿主抗移植物反应、移植物抗宿主反应、输血相关性移植物抗宿主病、过敏性反应等。
附图说明
图1.a采用ELISA方法证实抗-butyrophilin-3人源化抗体Xylizumab识别从CHO细胞表达纯化的BTN3A1、BTN3A2和BTN3A3。b采用ELISA方法 证实抗-butyrophilin-3人源化抗体Xylizumab识别的抗原决定簇位于butyrophilin-3蛋白的Ig V结构域。由于butyrophilin-3蛋白的Ig V结构高度同源，因此Xylizumab能够同时识别BTN3A1、BTN3A2和BTN3A3。
图2.Xylizumab抑制裸鼠移植性肝细胞肝癌HepG2的生长。
图3.Xylizumab抑制裸鼠移植性骨肉瘤MNNG/HOS的生长。
图4.Xylizumab延长移植性肝细胞肝癌HepG2荷瘤裸鼠的生存期(log-rank test,Chi square＝14.36,P<0.001)。
图5.Xylizumab延长移植性骨肉瘤MNNG/HOS荷瘤裸鼠的生存期(log-rank test,Chi square＝12.67,P<0.001)。

Claims (14)

  1. 一种人源化抗体、单链抗体或其抗体片段及其组合物，其包括包含轻链可变区CDR(互补决定区)序列QSLSDN(SEQ ID NO：1)、FAS(SEQ ID NO：2)和QQSHSWPYT(SEQ ID NO：3)及重链可变区CDR序列GFTFSSYA(SEQ ID NO：4)、ISSGGNYS(SEQ ID NO：5)和ARHGPDDFTSWVDY(SEQ ID NO：6)。
  2. 根据权利要求1所述，其中抗-butyrophilin-3人源化抗体或其片段是裸抗体或其片段。
  3. 根据权利要求1所述，其中抗butyrophilin-3人源化抗体包含人抗体IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列。
  4. 根据权利要求1所述的组合物，其中所述组合物是药物组合物。
  5. 根据权利要求1所述的组合物，其中所述抗体片段选自由F(ab’)2、Fab’、Fab、Fv、scFv和抗体最小识别单位组成的组。
  6. 根据权利要求1所述，其中人源化抗-butyrophilin-3抗体与butyrophilin3A1(BTN3A1)，butyrophilin3A2(BTN3A2)，butyrophilin3A3(BTN3A3)结合。
  7. 根据权利要求6所述，抗-butyrophilin-3人源化抗体是抗-BTN3A1人源化抗体、抗-BTN3A2人源化抗体和抗-BTN3A3人源化抗体的总称。
  8. 根据权利要求1所述的组合物，其中所述抗-butyrophilin-3人源化抗体或其片段与至少一种诊断剂和/或治疗剂偶联以形成免疫偶联物。
  9. 根据权利要求8所述的组合物，其中所述治疗剂选自由以下组成的组：裸抗体、细胞毒素剂、药物、放射性核素、硼原子、免疫调节剂、光敏性治疗剂、免疫偶联物、寡核苷酸和激素。
  10. 权利要求8所述的组合物，其中所述诊断剂选自由以下组成的组：放射性核素、放射性造影剂、顺磁离子、金属、荧光标记物、化学发光标记物、超声造影剂和光敏剂。
  11. 一种递送诊断剂和/或治疗剂的方法，其包括给受试者使用抗-butyrophilin-3人源化抗体或其片段，其中所述抗-butyrophilin-3人源化抗体或其片段包含所述轻链可变区CDR序列QSLSDN(SEQ ID NO：1)、FAS(SEQ ID NO：2)和QQSHSWPYT(SEQ ID NO：3)及重链可变区CDR序列GFTFSSYA(SEQ ID NO：4)、ISSGGNYS(SEQ ID NO：5)和ARHGPDDFTSWVDY(SEQ ID NO： 6)，其中所述抗-butyrophilin-3人源化抗体或其片段与至少一种治疗剂和/或诊断剂偶联。
  12. 一种治疗疾病的方法，其包括给受试者使用抗-butyrophilin-3人源化抗体或其片段，其中所述抗-butyrophilin-3抗体或其片段包含所述轻链可变区CDR序列QSLSDN(SEQ ID NO：1)、FAS(SEQ ID NO：2)和QQSHSWPYT(SEQ ID NO：3)及重链可变区CDR序列GFTFSSYA(SEQ ID NO：4)、ISSGGNYS(SEQ ID NO：5)和ARHGPDDFTSWVDY(SEQ ID NO：6)。
  13. 根据权利要求12所述的方法，其中所述疾病选自由以下组成的组：骨肉瘤、软骨肉瘤、滑膜肉瘤、甲状腺髓样癌(MTC)、结肠直肠癌、肝细胞癌、肝癌、胃癌、食道癌、肺癌、非小细胞肺癌、乳腺癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、子宫内膜癌、头颈部癌、膀胱癌、尿路上皮癌、前列腺癌、血液系统肿瘤、淋巴系统肿瘤、胸腺瘤、黑素瘤、类风湿性关节炎、系统性红斑狼疮、多发性硬化症、系统性血管炎、自身免疫性肝病、天疱疮、硬皮病、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、溃疡性结肠炎、Crohn氏病、银屑病、干燥性综合症、恶性贫血、新生儿溶血、自身免疫性溶血性贫血、特发性血小板减少性紫癜、胰岛素依赖型糖尿病、强直性脊柱炎、硬皮病、重症肌无力、结节性多动脉炎、Wegener肉芽肿病、亚急性细菌性心内膜炎等、宿主抗移植物反应、移植物抗宿主反应、输血相关性移植物抗宿主病、过敏性反应。
  14. 一种促进细胞微管蛋白解聚的方法，其包括给受试物体或细胞使用抗-butyrophilin-3抗体或其片段，其中所述抗-butyrophilin-3抗体或其片段包含所述轻链可变区CDR序列QSLSDN(SEQ ID NO：1)、FAS(SEQ ID NO：2)和QQSHSWPYT(SEQ ID NO：3)及重链可变区CDR序列GFTFSSYA(SEQ ID NO：4)、ISSGGNYS(SEQ ID NO：5)和ARHGPDDFTSWVDY(SEQ ID NO：6)。
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