CN115340604A - Tim-3全人源单克隆抗体及其应用 - Google Patents
Tim-3全人源单克隆抗体及其应用 Download PDFInfo
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- CN115340604A CN115340604A CN202210432917.3A CN202210432917A CN115340604A CN 115340604 A CN115340604 A CN 115340604A CN 202210432917 A CN202210432917 A CN 202210432917A CN 115340604 A CN115340604 A CN 115340604A
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Abstract
本发明提供了一种高特异结合人的TIM‑3的全人源单克隆抗体,及其抗原结合片段,以及其双特异性抗体等。本发明的抗体可以用于癌症的诊断和治疗。
Description
技术领域
本发明属于生物技术领域,具体涉及特异性结合人TIM-3的全人源单克隆抗体、抗原结合片段和嵌合抗原受体,以及构建该抗体、抗原结合片段和嵌合抗原受体所需的核酸、质粒、宿主细胞,相应的药用组合物及其应用。
背景技术
T细胞免疫球蛋白黏蛋白分子3(T cell immunoglobulinand mucin-domain-containing molecule 3,TIM-3),最初在分泌IFN-γ的T辅助细胞(Th1)表面上被发现,随后也被证实在T调控细胞(Treg)、树突状细胞(DCs)、单核细胞、NK细胞上有表达(Claytonet al.,J.Immunol.,192(2):782-791(2014);Jones et al.,J.Exp.Med.,205:2763-2779(2008))。目前已知的TIM-3的受体包括半乳糖凝集素9(Galectin-9,Gal-9)、磷脂酰丝氨酸(PtdSer),高迁移率族蛋白1(HMGB1)和癌胚抗原细胞粘附分子1(CEACAM1)。
TIM-3可从多方面调节免疫系统的功能,尤其是针对肿瘤浸润性淋巴细胞(TILs)的调控,抑制TIM-3的活性可以逆转肿瘤导致的T细胞衰竭(Fourcade J,et al.,J ExpMed.2010;207(2175–2186)。TIM-3在Treg表面上调表达,TIM-3不仅表达于免疫细胞,在黑色素瘤、卵巢癌等肿瘤细胞中也有过表达,并直接促进肿瘤的增长。因此,通过抑制TIM-3的活性(如TIM-3抗体)以提高T细胞在肿瘤微环境中的响应,有望成为治疗肿瘤的新方法(see,e.g.,Ngiow et a1.,Cancer Res.,71(21):1-5(2011);Guo et a1.,Journal ofTranslational Medicine,11:215(2013);and Ngiow et a1.,Cancer Res.,71(21):6567-6571(2011))。
尽管目前已有专利报道了有关TIM-3的抗体,如WO2011159877、WO2013006490、WO2015117002、WO2016144803、WO2016161270、US20150218274,但就国内外而言,仅有少数TIM-3抗体处于临床研究阶段。目前急需新的全人源单克隆抗体调控TIM-3以及表达TIM-3细胞的功能。因此,有必要进一步开发具有更高活性、高亲和力和高稳定性的TIM-3的抗体,以进行TIM-3相关疾病的治疗研究和应用。
发明内容
本发明的发明人利用噬菌体展示技术和哺乳动物细胞展示技术,通过筛选得到了具有高特异性、高亲和力和高稳定性的抗TIM-3全人源单克隆抗体。
在第一方面,本发明提供了一种TIM-3结合分子,其包括特异性结合TIM-3的全人源免疫球蛋白。
在另一方面中,本发明涉及编码TIM-3结合分子的核酸分子以及含有所述核酸分子的表达载体和宿主细胞。
此外,本发明还公开了编码这些全克隆抗体和抗原结合片段的核酸。在一些实施方案中,公开了包含这些核酸的载体,及包含这些载体的宿主细胞。在进一步的实施方案中,公开了包含这些全克隆抗体,抗原结合片段,双特异性抗体,免疫偶联物,融合蛋白,核酸,和载体的药用组合物。在其它实施方案中,这些全克隆抗体,抗原结合片段,双特异性抗体,免疫偶联物,融合蛋白,核酸,和载体被用来诊断或治疗自身免疫疾病、慢性病毒感染和肿瘤等疾病。
本发明公开了特异于TIM-3的新型全人源单克隆抗体。利用此抗体CDR区或部分或全基因,可在原核和真核细胞及任何表达系统中改造和生产不同形式的基因工程抗体,可在临床上诊断或治疗自身免疫疾病、慢性病毒感染和肿瘤等疾病。
本发明公开了特异性结合人的TIM-3的全人源单克隆抗体,及其轻链可变区和/或重链可变区的CDR区。在一些实施方式中,单克隆抗体或抗原结合片段的轻链可变区的氨基酸序列和/或重链可变区的氨基酸序列,包含至少一个轻链和/或重链可变区的CDR区。本发明还公开了这些单克隆抗体的抗原结合片段,双特异性抗体,嵌合抗原受体CAR,抗体偶联物,相应的核酸、质粒和宿主细胞,相应的药用组合物,以及在癌症的诊断和治疗中的用途。
本发明提供了一种单克隆抗体,或抗原结合片段,包含具有轻链互补决定区LCDR1、LCDR2和LCDR3的轻链可变区和具有重链互补决定区HCDR1、HCDR2和HCDR3的重链可变区,其特征在于,其中,所述的LCDR1含有SEQ ID NO:1,2,3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列,
其中,所述的HCDR1含有SEQ ID NO:6,7,8,9,10,11的氨基酸序列,所述的HCDR2含有SEQ ID NO:12,13,14,15,16,17,18的氨基酸序列,所述的HCDR3含有SEQ ID NO:19,20,21,22,23,24,25的氨基酸序列。
本发明一种单克隆抗体,或抗原结合片段,其中,
(1)所述的LCDR1含有SEQ ID NO:1的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:6的氨基酸序列,所述的HCDR2含有SEQ ID NO:12的氨基酸序列,所述的HCDR3含有SEQ ID NO:19的氨基酸序列;或
(2)所述的LCDR1含有SEQ ID NO:1的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:7的氨基酸序列,所述的HCDR2含有SEQ ID NO:13的氨基酸序列,所述的HCDR3含有SEQ ID NO:20的氨基酸序列;或
(3)所述的LCDR1含有SEQ ID NO:2的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:6的氨基酸序列,所述的HCDR2含有SEQ ID NO:12的氨基酸序列,所述的HCDR3含有SEQ ID NO:19的氨基酸序列;或
(4)所述的LCDR1含有SEQ ID NO:1的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的基酸序列;
所述的HCDR1含有SEQ ID NO:8的氨基酸序列,所述的HCDR2含有SEQ ID NO:14的氨基酸序列,所述的HCDR3含有SEQ ID NO:21的氨基酸序列;或
(5)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:6的氨基酸序列,所述的HCDR2含有SEQ ID NO:15的氨基酸序列,所述的HCDR3含有SEQ ID NO:22的氨基酸序列;或
(6)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:9的氨基酸序列,所述的HCDR2含有SEQ ID NO:16的氨基酸序列,所述的HCDR3含有SEQ ID NO:23的氨基酸序列;或
(7)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:10的氨基酸序列,所述的HCDR2含有SEQ ID NO:17的氨基酸序列,所述的HCDR3含有SEQ ID NO:24的氨基酸序列;或
(8)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:11的氨基酸序列,所述的HCDR2含有SEQ ID NO:18的氨基酸序列,所述的HCDR3含有SEQ ID NO:25的氨基酸序列。
本发明的单克隆抗体,或抗原结合片段其中:
轻链可变区的氨基酸序列与SEQ ID NO:26具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:27具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:28具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:29具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:30具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:31具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:32具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:33具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:34具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:35具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:36具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:37具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:38具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:39具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:40具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:41具有至少90%的序列同一性。
本发明的单克隆抗体或抗原结合片段,其中所述的单克隆抗体或抗原结合片段特异性结合抗原TIM-3。
本发明的单克隆抗体或抗原结合片段,其中所述的单克隆抗体或抗原结合片段是全人源的。
本发明的单克隆抗体或抗原结合片段,其中所述的单克隆抗体为IgG。
本发明的单克隆抗体或抗原结合片段,其中所述的抗原结合片段是scFv,scFv-Fc,Fv,Fab、Fab’、F(ab)2或F(ab’)2。
除此之外,本发明还提供了一种双特异性抗体,含有本发明所述的单克隆抗体或抗原结合片段。
除此之外,本发明还提供了一种抗体-药物偶联物,含有本发明所述的单克隆抗体或抗原结合片段,或本发明所述的双特异性抗体,以及额外的一种效应分子偶联。
优选的,本发明所述的抗体-药物偶联物,其中的效应分子是可检测标记。
优选的,本发明所述的抗体-药物偶联物,其中的可检测标记是荧光标记,放射性标记,亲和素,生物素,或酶。
优选的,本发明所述的抗体-药物偶联物,其中的效应分子是毒素,免疫调节剂,抗血管,抗增殖,促凋亡或化疗剂。
优选的,本发明所述的抗体-药物偶联物,其中的毒素是抗生素,tubulin多聚抑制剂,蛋白合成抑制剂,蛋白酶抑制剂,磷酸化酶抑制剂,烷基化,拓扑异构酶抑制剂,或酶。
除此之外,本发明还提供了一种核酸分子,其可以编码本发明所述的单克隆抗体或抗原结合片段。
优选的,本发明所述的核酸分子,可操作地连接至启动子。
除此之外,本发明还提供了一种重组表达载体,所述的重组表达载体包含有本发明所述的核酸分子。
除此之外,本发明还提供了一种质粒,含有本发明所述的核酸分子。
优选的,本发明所述的质粒是一种病毒质粒。
除此之外,本发明还提供了一种宿主细胞,含有本发明所述的质粒。
除此之外,本发明还提供了一种在生物样品中检测TIM-3表达的方法,包含:将所述的生物样品与本发明所述的单克隆抗体或抗原结合片段接触,检测免疫复合物的存在与否,其中免疫复合物的存在表示生物样品中存在TIM-3。
优选的,本发明所述单克隆抗体或抗原结合片段是全人源的。所述全人源是指抗体或其抗原结合片段在本文中被定义为是非嵌合的(例如,非“人源化的”)并且不来自(无论是整体还是部分)非人物种。全人源抗体或其抗原结合片段可源自人,或者可以为合成的人抗体。全人源抗体或其抗原结合片段的另一个实例是从人来源的抗体序列的文库(例如,基于采自人天然来源的抗体的这种文库)中分离的核酸所编码的人抗体。人抗体的实例包括记载于Nat.Biotechnol.2000,18(8):853-856中的抗体。
优选的,本发明所述单克隆抗体为IgG。IgG还可进一步分为亚类(同种型),例如IgGl、IgG2、IgG3和IgG4。不同类的免疫球蛋白的亚基结构和三维构型是公知的。本文使用的抗体为通常已知的抗体和其功能片段。
优选的,本发明所述抗原结合片段是F(ab)2、Fab和scFv。
F(ab)2片段是“二价”的。“二价”是指所述抗体和F(ab')2片段具有两个抗原结合位点。相反,Fab、Fv、和scFv片段是单价的,仅具有一个抗原结合位点。
F(ab)2是通过用蛋白酶木瓜蛋白酶(切割H链的224位的氨基酸残基)处理IgG抗体分子所获得的片段中的具有约50,000的分子量并具有抗原结合活性的抗体片段,其中N端侧的约一半和整个L链通过二硫键结合在一起(C.A.K Borrebaeck,editor(1995)AntibodyEngineering(Breakthroughs in Molecular Biology),Oxford University Press;R.Kontermann&S.Duebel,editors(2001)Antibody Engineering(Springer LaboratoryManual),Springer Verlag)。
Fab是通过切割上述F(ab')2的铰链区的二硫键而获得的分子量为约50,000并具有抗原结合活性的抗体片段。本发明的Fab可以通过用还原剂例如二硫苏糖醇处理F(ab)2来生产。
“单链Fv”或“scFv”意指包含通过接头连接的抗体重链可变结构域(或区域;VH)和抗体轻链可变结构域(或区域;VL)的分子。此类scFv分子可具有一般结构:H2-VL-接头-VH-COOH或H2-VH-接头-VL-COOH。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成,例如使用1-4个重复的变体。
本发明还提供了能够结合TIM-3的抗体或抗原结合片段,其是双特异性抗体或双特异性抗原结合片段。在一些实施方式中,所述双特异性抗体或双特异性抗原结合片段可以被分离。术语“双特异性”是指抗原结合分子能够特异性结合至少两个不同的抗原决定簇。在一些实施方式中,所述双特异性抗体和双特异性抗原结合片段包含根据本发明的抗原结合片段。在一些实施方式中,所述双特异性抗体和双特异性抗原结合片段包含能够与TIM-3结合的抗原结合片段,其中能够与TIM-3结合的抗原结合片段包含根据本发明的抗原结合片段。在一些实施方式中,所述双特异性抗体和双特异性抗原结合片段包含能够与TIM-3结合的抗原结合片段,和能够与另一靶蛋白结合的抗原结合片段。在一些实施方式中,所述双特异性抗体或抗原结合片段包含能够结合TIM-3的抗原结合分子和能够结合TIM-3以外的抗原结合分子。在一些实施方式中,TIM-3以外的抗原是免疫细胞表面分子。在一些实施方式中,TIM-3以外的抗原是癌细胞抗原。在一些实施方式中,TIM-3以外的抗原是受体分子,例如细胞表面受体。
本发明提供了一种细胞,其特征在于,表达本发明所述的任一嵌合抗原受体。所述细胞是抗原特异性T细胞(例如病毒特异性T细胞)、抗原特异性CD4 T细胞、抗原特异性CD8T细胞、效应记忆CD4 T细胞、效应记忆CD8 T细胞、中央记忆CD4 T细胞、中央记忆性CD8 T细胞、细胞毒性CD8+T细胞(即CTL)、NK细胞或抗原特异性NK细胞。
本发明提供了编码所述单克隆抗体或抗原结合片段或双特异性抗体或嵌合抗原受体的核酸。本发明提供了包含所述核酸的质粒,任选地,可操作地连接调控序列,如启动子、增强子等。本发明提供了包含该质粒的宿主细胞,以及用于生产和任选地回收该单克隆抗体或抗原结合片段或双特异性抗体或嵌合抗原受体的方法。本发明所述宿主细胞可以是任何原核细胞或真核细胞,包括但不限于细菌细胞(例如大肠杆菌、枯草杆菌)、昆虫细胞(例如利用杆状病毒表达系统)、酵母或哺乳动物细胞(例如CHO或BHK细胞系)。其它合适的宿主细胞为本领域技术人员所知。
本发明提供了一种药用组合物,由有效预防或治疗剂量的本发明的单克隆抗体或抗原结合片段或双特异性抗体或嵌合抗原受体或其核酸分子、质粒或表达该嵌合抗原受体的细胞,和生理学上或药学上可接受的载体、赋形剂或稳定剂混合制备而成,所述组合物包括但不限于冻干剂型、水溶液剂型、脂质体或胶囊剂型等。本发明的单克隆抗体或抗原结合片段或双特异性抗体或嵌合抗原受体或其核酸分子、质粒或表达该嵌合抗原受体的细胞的浓度可从约0.1%变化为100%(重量)。
本发明提供了上述药物组合物的用途,所述用途为用于制备抗肿瘤的药物。
优选的,所述肿瘤为实体瘤。
本发明提供了一种诊断、预防或治疗疾病的方法,包括向受试者施用本发明所述的单克隆抗体或抗原结合片段或双特异性抗体或嵌合抗原受体或其核酸分子、质粒或表达该嵌合抗原受体的细胞、以及药用组合物。
优选的,本发明所述疾病为癌症,包括但不限于淋巴瘤、胚细胞瘤、肉瘤(包括脂肉瘤)、神经内分泌肿瘤、间皮瘤、神经鞘瘤、脑膜瘤、腺瘤、黑素瘤以及非白血性白血病或淋巴恶性肿瘤。上述癌症更具体的实例包括鳞状细胞癌(如,鳞状上皮细胞癌)、肺癌、小细胞肺癌、非小细胞肺癌、肺腺癌以及肺鳞状细胞癌、腹膜癌、肝细胞癌、胃癌、胃肠癌、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、睾丸癌、食道癌、胆管肿瘤,头癌、颈癌、骨髓基质瘤、破骨细胞瘤、多发性骨髓瘤、溶骨性癌(osteolytic bone cancers)、中枢神经系统肿瘤、脑肿瘤(神经胶质瘤、成神经细胞瘤、星细胞瘤、成神经管细胞瘤、室管膜细胞瘤和视网膜成神经细胞瘤)、鼻咽癌、基底细胞癌、胆管癌、卡波氏肉瘤、原发性肝癌或子宫内膜癌、以及血管系统肿瘤(血管肉瘤和hemagiopericytoma)、血液瘤、何杰金氏淋巴瘤、非何杰金淋巴瘤(Burkitt’s淋巴瘤、小淋巴细胞淋巴瘤/慢性淋巴细胞性白血病、蕈样肉芽肿病、外套细胞淋巴瘤、滤泡性淋巴瘤、弥漫性巨大B细胞淋巴瘤、边缘区淋巴瘤、毛细胞性白血病以及淋巴浆细胞性白血病)、淋巴细胞前体细胞肿瘤、B细胞急性成淋巴细胞性非白血性白血病/淋巴瘤、T细胞急性成淋巴细胞性非白血性白血病/淋巴瘤、胸腺瘤、成熟T和NK细胞肿瘤、外周T细胞非白血性白血病、成熟T细胞非白血性白血病/T细胞淋巴瘤、大颗粒状淋巴细胞性白血病、朗罕氏细胞组织细胞增多症、急性骨髓性粒细胞性白血病的骨髓瘤,成熟的急性骨髓性白血病(AML)、分化的急性骨髓性白血病、急性前髓细胞性白血病、急性骨髓单核细胞性白血病、急性单核细胞性白血病、脊髓发育不良综合征、慢性骨髓增生病,慢性髓细胞性白血病、血液恶性肿瘤诸如多发性骨髓瘤(MM)、骨髓增生异常综合征(MDS)和急性骨髓性白血病(AML)。
本发明的单克隆抗体或抗原结合片段或双特异性抗体或嵌合抗原受体或其核酸分子、质粒或表达该嵌合抗原受体的细胞、以及药用组合物可以通过各种不同的给药途径给予人或动物受试者,所述给药途径通常取决于待治疗的疾病本身的特征。一般而言,可利用医学上可接受的任何给药模式来实施本发明的方法,所述给药模式包括经口、直肠、局部、眼内、脑池内、脑室内、气管内、鼻内滴入、透皮、皮下、鞘内、肌内、腹腔、腹膜内、颅内输注或者静脉输注。
本发明描述了抗体和抗体偶联药物,其与现存的抗体和抗体偶联药物的区别在于它们低至0.5nM的高亲和力。
本发明还描述了BM101-01的体外T细胞激活能力,其效果在于具有优异的T细胞激活能力,和较高IFN-γ释放水平,最终导致BM101-01在体内肿瘤实验中的更优异抗肿瘤活性。本发明的这些和其他目的在本文中更加详细地描述。
附图说明
图1.非还原SDS-PAGE凝胶电泳检测纯化的BM101-01蛋白。
图2.利用ELISA检测抗TIM-3单抗和无关对照IgG1与TIM-3-ECD-hFc蛋白的结合能力。
图3.利用BLI检测BM101-01和BM101-99与TIM-3-ECD-hFc蛋白的结合亲和力。
图4.利用BLI竞争结合实验分析TIM-3单抗的结合表位。
图5.FACS检测BM101-01与表达TIM-3-ECD的CHO的细胞结合能力。
图6.利用ELISA检测抗TIM-3单抗和PBMC共孵育后IFN-γ的分泌水平。
图7.TIM-3单抗在Raji淋巴瘤异种移植小鼠模型中抑制肿瘤生长。
图8.通过SEC-HPLC检测TIM-3单抗样品稳定性。
发明详述
为了能更彻底地理解发明,以下列出一些定义。上述定义意在包含语法等同成分。
本文中“抗体”意指由基本上为公认的免疫球蛋白基因的全部或部分所编码的一种或多种多肽组成的蛋白质。所述公认的免疫球蛋白基因,例如在人中,包括kappa(κ)、lambda(λ)和重链基因座,其中包含了无数的可变区基因,以及分别编码IgM、IgD、IgG、IgE和IgA同种型的恒定区基因mu(μ)、delta(δ)、gamma(γ)、epsilon(ε)、alpha(α)。本文中的抗体意指包括全长抗体和抗体片段,以及来自任意生物体的天然抗体,工程抗体,或为试验、治疗目的或其它如下所进一步规定的目的而重组产生的抗体。术语“抗体”包括抗体片段,为本领域所公知,诸如Fab、Fab’、F(ab’)2、Fv,scFv或抗体的抗原结合的其它亚序列,或通过修饰完整抗体或使用重组DNA技术重新合成的那些抗体而产生的抗体片段。术语“抗体”包括单克隆以及多克隆抗体。抗体可以是拮抗剂、激动剂、中和性抗体、或抑制性抗体、或刺激性抗体。本发明的抗体可以是非人抗体,嵌合抗体,人源化抗体或完全人抗体。
本文使用的术语“单克隆抗体”是指获自基本上同质的抗体群体的抗体,即,所述包含单一抗体的群体除了可能以极少量存在的可能突变(例如天然突变)之外是相同的。因此,所述术语“单克隆”表明所述抗体的性质,即不是不相关(discrete)抗体的混合物。与通常包括针对不同决定簇(表位)的不同抗体的多克隆抗体制剂相反,单克隆抗体制剂的每个单克隆抗体均针对抗原上的单独一个决定簇。除了其特异性之外,单克隆抗体制剂的优点在于它们通常不会被其他免疫球蛋白污染。所述术语“单克隆”不应被理解为需要通过任何特定的方法产生所述抗体。所述术语单克隆抗体具体地包括全人源抗体。(refCN201280067865-抗FGFR2的抗体及其用途-审定授权)
用于本文时术语“互补决定区”(CDR,例如CDR1、CDR2和CDR3)是指抗体可变区的氨基酸残基,互补决定区的存在对于抗原结合来说是必需的。抗体的“抗原结合区”通常存在于抗体的一个或多个高变区中,例如CDR1、CDR2和CDR3的CDR区域。每个互补决定区可包含来自如Kabat所定义的“互补决定区”的氨基酸残基,例如,轻链可变区中的残基24-34(L1)、50-56(L2)和89-97(L3)和重链可变区中的26-33(H1)、51-57(H2)和96-105(H3)(Kabat etal.,Sequences of Proteins of Immulological Interest,5th Ed.Public HealthService,National Institutes of Health,1991)。
本文中使用的“抗原”意指可以在动物体内刺激抗体产生或T细胞反应的化合物、组合物或物质,包括注射或吸收到动物体内的组合物,可以是蛋白质、糖类、脂质或其它病原体。
抗体/免疫球蛋白的“功能片段”或“抗原结合片段”在本文中被定义为保留抗原结合区的抗体/免疫球蛋白的片段(例如IgG的可变区)。抗体的“抗原结合区”通常存在于抗体的一个或多个高变区中,例如CDR1、-2和/或–3区;然而,可变“框架”区也可以在抗原结合中起重要作用,例如通过提供CDR的支架。优选地,所述“抗原结合区”至少包括可变轻链(VL)的氨基酸残基4-103和可变重链(VH)的氨基酸残基5-109,更优选VL的氨基酸残基3-107和VH的氨基酸残基4-111,并且特别优选完整的VL和VH链(VL的氨基酸第1-109位和VH的氨基酸第1-113位;编号根据WO97/08320进行)。本发明中使用的优选的免疫球蛋白类为IgG。
本文中使用的“氨基酸”意指20种天然存在的氨基酸之一或任一非天然类似物,它们可位于具体规定的位置。本文中“蛋白质”意指至少两个共价连接的氨基酸,其包括蛋白质、多肽、寡肽和肽。蛋白质可由天然存在的氨基酸和肽键构成,或由合成的肽模拟物结构构成,该肽模拟物即“类似物”。因此本文中使用的“氨基酸”或“肽残基”意指天然存在和合成的氨基酸。举例来说,对于本发明目的而言,高苯基丙氨酸、瓜氨酸和降亮氨酸被认为是用于本发明目的的氨基酸。“氨基酸”也包括诸如脯氨酸和羟脯氨酸的亚氨基酸残基。侧链可以是(R)或(S)构型。在优选的实施方案中,氨基酸以(S)或L-构型存在。如果使用非天然存在的侧链,可使用非氨基酸取代,例如以阻止或延迟体内降解。
本文中使用的“相同性”意指核苷酸或氨基酸序列之间的相似性,或者称为序列同一性。序列同一性通常根据百分比同一性(或相似性或同源性)来衡量;百分比越高,两个序列越相似。当使用标准方法比对时,同源物或变体将具有相对高程度的序列同一性。用于比较的序列比对方法是本领域熟知的。各种程序和对准算法描述于:Smith and Waterman,Adv Appl.Math.,2:482,1981;Needlema and Wunsch,J.Mol.Biol.48:443,1970;Pearsonand Lipman,Proc.Natl.Acad.Sci.U.S.A.85:2444,1988;Higgins and Sharp,Gene 73:237-244,1988;Higgins and Sharp,CABIOS 5:151-153,1989;Corpet等,Nucleic AcidsResearch 16:10881-10890,1988;和Altschul等,Nature Genet.,1994,6:119-129。
可从若干来源获得NCBI基本局部比对搜索工具(BLAST TM)(Altschul等,J.Mol.Biol.,215:403-410,1990。),包括国家生物技术信息中心(NCBI,Bethesda,Md.)和在因特网上有关用于序列分析程序blastp,blastn,blastx,tblastn和tblastx。
本文所使用的“核酸”意指由核苷酸单元(核糖核苷酸,脱氧核糖核苷酸,相关的天然存在的结构变体及其合成的非天然存在的类似物)通过磷酸二酯键组成的聚合物。因此,该术语包括核苷酸聚合物,其中核苷酸和它们之间的键包括非天然存在的合成类似物,例如但不限于硫代磷酸酯,氨基磷酸酯,甲基磷酸酯,手性甲基磷酸酯,2'-O-甲基核糖核苷酸,肽核酸(PNA)等。例如,可以使用自动DNA合成仪合成这些多核苷酸。术语“寡核苷酸”通常是指短多核苷酸,通常不大于约50个核苷酸。应当理解,当核苷酸序列由DNA序列(即A,T,G,C)表示时,这也包括其中“U”取代“T”的RNA序列(即A,U,G,C)。
本文使用常规符号来描述核苷酸序列:单链核苷酸序列的左手末端5'末端;双链核苷酸序列的左手方向称5'方向。向新生RNA转录物添加5'至3'核苷酸的方向称为转录方向。具有与mRNA相同序列的DNA链被称为编码链。
本文中所使用的“编码”意指多核苷酸中特定核苷酸序列的固有特性,例如基因,cDNA或mRNA,用作在具有确定的核苷酸序列的生物过程中合成其他聚合物和大分子的模板,或确定的氨基酸序列和由此产生的生物学特性。因此,如果由该基因产生的mRNA的转录和翻译在细胞或其他生物系统中产生蛋白质,则基因编码蛋白质。编码链(其核苷酸序列与mRNA序列相同并且通常在序列表中提供)和非编码链(用作转录模板,基因或cDNA)可以被称为编码蛋白质。或该基因或cDNA的其他产物。除非另有说明,否则“编码氨基酸序列的核苷酸序列”包括彼此简并形式且编码相同氨基酸序列的所有核苷酸序列。编码蛋白质和RNA的核苷酸序列可包括内含子。
本文中使用的“质粒”意指在天然质粒的基础上为适应实验室操作而进行人工构建的质粒。可将核酸分子导入宿主细胞,从而产生转化的宿主细胞。载体可包括允许其在宿主细胞中复制的核酸序列,例如复制起点,还可以包括一种或多种选择标记基因和本领域已知的其他遗传元件。
本文所使用的“宿主细胞”也称为受体细胞,是指在转化和转导(感染)中接受外源基因的宿主细胞。
本文中使用的“药学可接受载体”意指常规的药学上可接受的载体。Remington'sPharmaceutical Sciences,EWMartin,Mack Publishing Co.,Easton,Pa.,第15版(1975),描述了适用于药物递送一种或多种治疗化合物或分子(例如一种或多种抗体)的组合物和制剂,以及另外的药剂。
本文中所使用的“诊断”疾病是指在给病人做检查之后判定病人的病症及其发展情况。“预防”疾病是指抑制疾病的完全发展。“治疗”是指在其开始发展后改善疾病或病理状况的体征或症状的治疗性干预。
本文中“施用”意指选择合适的途径将所述物质引入受试者。例如,如果所选择的途径是静脉内的,则通过将所述物质引入受试者的静脉来施用组合物。
本文中“有效预防/治疗剂量”意指足以在用该药剂治疗的受试者中达到所需效果的一定量的特定药剂。精确的剂量将依赖于治疗的目的,并可为本领域技术人员通过使用公知技术所确定。剂量范围可为0.01-100mg/kg体重或更大,例如0.1、1、10或50mg/kg体重,优选1-10mg/kg。如本领域所公知,对于抗体或Fc融合体降解、全身性或局部性递药和新蛋白酶合成速率,以及年龄、体重、大致健康状况、性别、饮食、给药时间、药物相互作用以及病症的严重程度而言,调整可以是必需的,并可由本领域那些技术人员通过常规的实验方法来确定。此类试剂包括本文所述的单体Fc结构域分子。在一个非限制性实例中,这可以是用于预防,治疗或改善HIV感染的HIV特异性单体Fc结构域(或HIV特异性CH3结构域分子)的量。理想地,治疗有效量的抗体是足以预防,治疗或改善感染或疾病的量,例如由受试者中的HIV感染引起而不会在受试者中引起显着的细胞毒性作用。用于预防,改善和/或治疗受试者的治疗有效量的药剂将取决于所治疗的受试者,痛苦的类型和严重程度,以及治疗组合物的施用方式。
本文中的“癌症”为实体瘤或血源性癌。本发明所述的实体瘤是肉瘤或癌,例如纤维肉瘤,粘液肉瘤,脂肪肉瘤,软骨肉瘤,成骨肉瘤,或另一种肉瘤,滑膜瘤,间皮瘤,尤文氏瘤,平滑肌肉瘤,横纹肌肉瘤,结肠癌,淋巴恶性肿瘤,胰腺癌,乳腺癌,肺癌,卵巢癌,前列腺癌,肝细胞癌,鳞状细胞癌,基底细胞癌,腺癌,汗腺癌,皮脂腺癌,乳头状癌,乳头状腺癌,髓样癌,支气管癌,肾细胞癌,肝细胞癌,胆管癌,绒毛膜癌,肾母细胞瘤,宫颈癌,睾丸肿瘤,膀胱癌或中枢神经系统肿瘤(如胶质瘤,星形细胞瘤,成神经管细胞瘤,颅咽管瘤,室管膜瘤,松果体,血管母细胞瘤,听神经瘤,少突神经胶质瘤,血管瘤,黑素瘤,神经母细胞瘤或视网膜母细胞瘤)。本发明所述的血源性癌症是白血病,如急性白血病(如急性淋巴细胞白血病,急性髓细胞白血病,急性髓性白血病和成髓细胞,早幼粒细胞,髓单核细胞,单核细胞和红白血病);慢性白血病(如慢性粒细胞性(粒细胞)白血病,慢性粒细胞白血病和慢性淋巴细胞白血病),真性红细胞增多症,淋巴瘤,霍奇金病,非霍奇金淋巴瘤(惰性和高级形式),多发性骨髓瘤,瓦尔登斯特伦巨球蛋白血症,重链性疾病,骨髓增生异常综合征,多毛细胞白血病或骨髓增生异常。
除非另外说明,否则本文使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常理解的含义相同的含义。除非上下文另有明确说明,否则单数术语“一”,“一个”和“该”包括复数指示物。还应理解,对于核酸或多肽给出的所有碱基大小或氨基酸大小,以及所有分子量或分子量值是近似的,并且提供用于描述。尽管与本文描述的那些类似或等同的方法和材料可用于本公开的实践或测试,但下文描述了合适的方法和材料。术语“包含”表示“包括”。本文提及的所有出版物、专利申请、专利和其他参考文献均通过引用整体并入。如果发生冲突,将以本说明书(包括术语解释)为准。另外,材料,方法和实施例仅是说明性的而不是限制性的。
具体实施方式
实施例中使用的标准的重组DNA技术和分子克隆技术是本领域所熟知的(Ausubel,F.M等人,Current Protocols in Molecular Biology,Greene PublishingAssoc.和Wiley-Interscience出版),适用于微生物生长的材料和方法是本领域熟知的。主要化学、生物试剂购自KAPA Biosystems,New England Biolabs,TransGen Biotech,Thermo Fisher Scientific,OMEGA bio-tek等。
下面结合具体实施例对本发明进行详细说明。
实施例1结合人TIM-3的单克隆抗体的产生
首先在利用40个健康志愿者的外周血单核细胞cDNA构建的大型噬菌体展示抗体文库中(Cell Host Microbe.2017.22(4):471-483.e5.),使用生物素标记的TIM-3-ECD-hFc蛋白进行筛选。TIM-3-ECD-hFc是通过将TIM-3抗原胞外区第22-200位氨基酸序列(Uniprot Accession#Q8TDQ0-1)构建到C端有avi-tag的pSecTag2B(购自Invitrogen),然后通过共转染Expi293(购自Thermo Fisher)并使用Protein G(购自GE Healthcare)纯化获得。生物素标记的TIM-3-ECD-hFc蛋白与1012个噬菌体展示的抗体在1.5ml离心管中室温孵育30min,之后加入与链亲和素包被的磁珠孵育1.5h(购自Invitrogen)。孵育结束后,将离心管固定于磁力架上,吸取离心管中溶液弃掉。之后使用含有0.05%tween-20的PBS溶液(0.05%PBST)洗涤磁珠,再使用100μl的PBS溶液重悬磁珠并将磁珠加入TG1大肠杆菌菌液,在37℃侵染2h,之后加入M13KO7 helpphage,在37℃侵染30min。离心,收集菌体,使用2YT培养基重悬,加入青霉素与卡那霉素,在30℃条件下震荡过夜培养。第二天离心菌液,收集上清,使用PEG8000溶液沉淀菌液上清中的噬菌体,即第一轮筛选过后获得的多克隆噬菌体并计数。共进行4轮筛选,每轮逐步减少TIM-3-ECD-hFc的使用量,即将第1,2,3,4轮的噬菌体用5μg,3μg,2μg,1μg的TIM-3-ECD-hFc蛋白孵育,每轮逐步增加磁珠的洗涤次数,即第1,2,3,4轮的分别使用0.05%PBST洗涤磁珠4,3,2,1次,以增加筛选压力。通过多克隆噬菌体ELISA检测抗TIM-3抗体的富集程度,即将第1,2,3,4轮的噬菌体与包被的TIM-3-ECD-hFc蛋白孵育,用抗M13噬菌体的HRP耦合抗体(Invitrogen)来检测噬菌体与TIM-3-ECD-hFc的结合。根据多克隆噬菌体ELISA结果,针对TIM-3-ECD-hFc的抗体在第3-4轮筛选后出现显著的富集。因此,选用第3-4轮筛选获得的噬菌体,感染TG1细胞(购自Thermo Fisher)并随机挑选384个克隆,37℃培养4h后加入1mM IPTG于30℃进行诱导表达过夜。取培养液进行单克隆噬菌体ELISA,使用5%BSA封闭1h,然后将每孔的培养液取50ul与包被的TIM-3-ECD-hFc蛋白孵育1.5h,用抗FLAG的HRP耦合抗体(购自SIGMA)来检测抗体与TIM-3-ECD-hFc的结合。阳性反应孔对应的单克隆送测序,经序列比对,鉴定出优选抗体的序列。
接下来设计引物将噬菌体库筛到阳性克隆PCR扩增,得到抗体重链可变区(VH)和轻链全长基因,经酶切后插入哺乳动物细胞抗体表面展示载体,转染FCHO细胞构建稳转细胞株作为筛选的阳性对照。另外构建人TIM-3胞外区Fc融合蛋白表达载体,瞬时转染293悬浮细胞表达蛋白,经FITC标记后作为筛选抗体库的抗原。将阳性对照Vh片段和本公司构建的LC基因库酶切后插入抗体细胞表面展示载体构建轻链置换基因库,同样,将阳性对照LC片段和本公司构建的Vh基因库酶切后插入抗体细胞表面展示载体构建重链置换基因库,分别抽提两个基因库质粒,稳转FCHO细胞构建抗体哺乳动物细胞展示库。将FITC标记的人TIM-3ECD-Fc融合蛋白作为抗原,梯度稀释后与PE标记的小鼠抗人IgG抗体(双染TIM-3阳性对照细胞,FACS分析,计算相对亲和力(RBA)并作出拟合曲线,找到最优的筛选抗体库所用抗原浓度(即IC50),以该浓度抗原和PE双染抗体库细胞,流式细胞仪分选亲和力高于或等于对照的单克隆。单克隆长满96孔板后取一部分细胞同样双染FACS分析双阳性克隆,挑取亲和力较高的扩增细胞提取genomic DNA后PCR扩增目的基因一部分测序,去除重复克隆及与阳性对照序列一致的克隆,即得到CDR区突变克隆,将突变克隆PCR产物酶切后插入抗体可溶表达载体,挑选单克隆抽质粒小量瞬转293贴壁细胞,取上清与细胞表面表达抗原稳转细胞结合FACS分析,选择阳性克隆测序,去除重复克隆及与阳性对照序列一致的克隆,即得到目的克隆,大提质粒顺转Expi293细胞,表达纯化全长抗体后ELISA鉴定亲和力,得到目的抗体。
实施例2利用ELISA检测抗TIM-3单抗与TIM-3-ECD-hFc蛋白的结合能力
利用PCR从实施例1中获得的抗TIM-3抗体的质粒和BM101-99(从专利UnitedStates Application US20180057591 A1获得序列)中分别扩增出重链和轻链的可变区,然后分别构建到真核表达载体pTT5(购自上海柯雷生物科技有限公司)中,将重链与轻链的表达质粒瞬时共转染Expi293细胞表达抗体蛋白,(购自Thermo Fisher)并使用Protein G(购自GE Healthcare)纯化(具体方法见文献EMI.2017.6(10):e89.)如非还原SDS-PAGE凝胶所示(图1),BM101-01抗体在非还原条件下显示的条带为~150kDa,与抗体的理论分子量相一致。
通过ELISA确定BM101-01抗体与TIM-3-ECD-hFc蛋白的结合。简而言之,平板用2μg/ml的TIM-3-ECD-hFc蛋白在4℃包被过夜。经3%milk-PBS封闭和0.5%PBST洗涤后,加入不同浓度的抗TIM-3抗体和IgG1同型对照抗体,并在洗涤后于室温孵育1.5h。然后洗涤平板,随后与HRP标记的山羊抗人Fab抗体(购自Thermo Fisher)一起孵育45min。洗涤后,加入ABTS底物(购自Invitrogen)显色。使用酶标仪读取405nm处的吸光度。结果显示在图2中,根据ELISA结果,BMB101-01与TIM-3-ECD-hFc蛋白结合力最强,而同型对照抗体不能与TIM-3-ECD-hFc蛋白结合。
实施例3利用BLI检测BM101-01与TIM-3-ECD-hFc蛋白的结合亲和力
使用BLI技术对抗体BM101-01与TIM-3-ECD-hFc的结合动力学进行检测,BLI实验在Octet-Red96(Pall ForteBio)仪器上进行,使用氨基偶联传感器(AR2G biosensor),固定TIM-3-ECD-hFc,抗体溶液作为分析样品。步骤如下:将TIM-3-ECD-hFc蛋白用10mM乙酸钠(pH5.0)稀释至30μg/ml,然后固化到激活的AR2G传感器上,与0.02%PBST溶液配置的多种浓度的抗体进行结合,在0.02%PBST溶液中进行解离,其中空白对照孔中不加入抗体。应用ForteBio Data analysis8.1软件对数据进行分析。以对应的空白对照孔作为对照扣减背景,各浓度的曲线按照1:1结合模式进行拟合,得到动力学分析结果,报告中显示抗体与各抗原结合的平衡常数(KD)值以及结合速率常数(kon)和解离速率常数(koff)。结果显示在图3中,根据实验结果BM101-01与TIM-3蛋白结合的KD为5.47E-10M。
实施例4利用BLI竞争结合实验分析TIM-3单抗的结合表位
使用BLI技术对抗体(BM101-01、BM101-06、BM101-08和BM101-99)与TIM-3-ECD-hFc的结合表位进行检测,BLI实验在Octet-Red96(Pall ForteBio)仪器上进行,使用氨基偶联传感器(AR2G biosensor),固定TIM-3-ECD-hFc,抗体溶液作为分析样品。步骤如下:将TIM-3-ECD-hFc蛋白用10mM乙酸钠(pH 5.0)稀释至30μg/ml,然后固化到激活的AR2G传感器上,分别用100nM BM101-99在running buffer(0.02%PBST)中进行结合,随后在实验dissociation阶段加入另一种抗体及running buffer中一样100nM抗体的混合溶液,测定结合曲线。程序设定为:Association,300s;dissociation,300s,温度设定为37℃。应用ForteBio Data analysis 8.1软件对数据进行分析。图4的BLI结果显示,BM101-01和BM101-06均与BM101-99存在竞争关系,说明这两个抗体在TIM-3蛋白的结合表位与BM101-99在TIM-3蛋白结合表位不同。
实施例5FACS检测BM101-01与表达TIM-3-ECD的FCHO的细胞结合能力
BM101-01Fab与过表达TIM-3的FCHO细胞的结合能力通过流式细胞术进行测定。具体而言,收集对数生长期的TIM-3过表达的FCHO细胞,将细胞离心后使用400μl 2%FBS-PBS溶液重悬,与100nM,20nM,4nM,0.8nM浓度的BM101-01在冰上孵育1.5h之后,然后用1000rpm离心5min后除去上清,加入抗人IgG-PE标记的抗体溶液重悬,4℃避光孵育30min,1000rpm4℃离心5min,去上清,加入200μl PBS洗涤细胞,在次离心去上清,重复洗涤步骤一次,最后使用PBS重悬细胞,上流式细胞仪检测样本的FITC信号。结果显示在图5中,显示BM101-01能与TIM-3过表达FCHO细胞相结合。
实施例6利用ELISA检测抗TIM-3单抗和PBMC共孵育后IFN-γ的分泌水平
通过密度梯度离心法收集人PBMCs,用磁珠从人PBMC分离出CD14+DC(树突状细胞),具体方法参考Miltenyi CD14 MicroBeads说明书。然后使用GM-CSF(50ng/ml)和IL-4(35ng/ml)在37℃,5%CO2培养条件下剌激细胞5天,再加入TNF-α(25ng/ml)和polyI:C(5ug/ml)在相同培养条件下培养2天诱导DC细胞成熟。将成熟的DC细胞和不同献血者的PBMC分离获得中的CD4+T细胞(使用Miltenyi CD4 MicroBeads分离获得)以1:10的比例混合培养,同时加入多种浓度的BM101-01,BM101-99或同型对照IgG1抗体。在37℃,5%CO2培养条件下培养5天。5天后通过定量ELISA方法检测上清中的IFN-γ浓度。结果显示在图6中,根据实验结果,BM101-01和BM101-99均有效剌激了IFN-γ的分泌,BM101-01显示出更强的剌激作用。
实施例7 TIM-3单抗在Raji淋巴瘤异种移植小鼠模型中抑制肿瘤生长
在补充有10%胎牛血清、100U/ml青霉素和100μg/ml链霉素的RMPI 1640中,在37℃以及5%CO2的培养条件下,培养Raji肿瘤细胞。收获在指数生长期生长的细胞并计数以接种肿瘤。每只小鼠在皮下接种0.1ml PBS中的Raji肿瘤细胞(1x106),用于肿瘤形成。同时,1x107人PBMC通过尾静脉注射的方式移植至小鼠体内。当平均肿瘤体积达到60-70mm3时,将动物随机分组,然后通过腹膜内施用抗体或PBS处理,每周两次达三周。使用测径器以二维方式每周三次测量肿瘤大小,并使用公式:V=0.5axb2以mm3表示体积,其中a和b分别是肿瘤的长径和短径。结果显示在图7中。根据实验结果在Raji肿瘤模型中,BM101-01组或对照组相比肿瘤体积显著减少,指示BM101-01抗体具有优异的抗肿瘤作用。
实施例8通过SEC-HPLC检测BM101-01样品一定条件下的稳定性
将样品浓度控制在约10mg/ml,在pH 7.4的PBS体系中比较抗TIM-3抗体在-80℃反复冻融1-3次次后的稳定情况。利用TOSOH TSKgel SuperSW3000分离柱检测抗体的纯度和均一性。图8结果所示在-80℃反复冻融1-3次后,BM101-01仍然表现出良好的稳定性。
序列表
<110> 上海博奥明赛生物科技有限公司
复旦大学
<120> TIM-3全人源单克隆抗体及其应用
<141> 2022-04-22
<150> 202110448790X
<151> 2021-04-25
<160> 41
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<213> Artificial Sequence
<400> 33
Gln Val Gln Val Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Glu Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Ser Gly Ser Thr Asn Tyr Ala Gln Met Phe
50 55 60
His Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met His Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Pro His Ser Ser Ser Thr Leu Ser Asp Gly Phe
100 105 110
Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 34
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 34
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 125
<212> PRT
<213> Artificial Sequence
<400> 35
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Val Val Pro Ala Ala His Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 36
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 36
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 37
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Arg Tyr Ala Glu Lys Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Lys Ser Ser Pro Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Trp Asp Gly Ala Tyr Phe Phe Asp Tyr Gly Gly Gln Gly
100 105 110
Thr Leu Ala Thr Val Ser Ser
115
<210> 38
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 38
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 39
Gln Val His Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Gln Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
His Phe Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Phe Asn Pro Asn Thr Gly Gly Thr Ser Ser Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Gly Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Arg Leu Ala Val Pro Ala Ala Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 40
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 40
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 41
<211> 123
<212> PRT
<213> Artificial Sequence
<400> 41
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ala Gly Ile Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Ile
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Tyr Thr Ile Tyr Tyr Ala Asn Ser Val
50 55 60
Lys Gly Gln Phe Thr Leu Ser Arg Asp Asn Ala Asn Asn Ser Leu Asn
65 70 75 80
Leu Lys Met Asn Ser Leu Lys Ala Lys Asn Thr Val Val Tyr Tyr Cys
85 90 95
Ala Lys Arg Ser Arg Gly Ser Ser Ser Asp Pro Tyr Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
Claims (20)
1.一种单克隆抗体,或抗原结合片段,包含具有轻链互补决定区LCDR1、LCDR2和LCDR3的轻链可变区和具有重链互补决定区HCDR1、HCDR2和HCDR3的重链可变区,
其中,所述的LCDR1含有SEQ ID NO:1,2,3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列,
其中,所述的HCDR1含有SEQ ID NO:6,7,8,9,10,11的氨基酸序列,所述的HCDR2含有SEQ ID NO:12,14,15,16,17,18的氨基酸序列,所述的HCDR3含有SEQ ID NO:19,20,21,22,23,24,25的氨基酸序列。
2.如权利要求1所述的单克隆抗体,或抗原结合片段,其中,
(1)所述的LCDR1含有SEQ ID NO:1的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:6的氨基酸序列,所述的HCDR2含有SEQ ID NO:12的氨基酸序列,所述的HCDR3含有SEQ ID NO:19的氨基酸序列;或
(2)所述的LCDR1含有SEQ ID NO:1的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:7的氨基酸序列,所述的HCDR2含有SEQ ID NO:13的氨基酸序列,所述的HCDR3含有SEQ ID NO:20的氨基酸序列;或
(3)所述的LCDR1含有SEQ ID NO:2的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:6的氨基酸序列,所述的HCDR2含有SEQ ID NO:12的氨基酸序列,所述的HCDR3含有SEQ ID NO:19的氨基酸序列;或
(4)所述的LCDR1含有SEQ ID NO:1的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的基酸序列;
所述的HCDR1含有SEQ ID NO:8的氨基酸序列,所述的HCDR2含有SEQ ID NO:14的氨基酸序列,所述的HCDR3含有SEQ ID NO:21的氨基酸序列;或
(5)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:6的氨基酸序列,所述的HCDR2含有SEQ ID NO:15的氨基酸序列,所述的HCDR3含有SEQ ID NO:22的氨基酸序列;或
(6)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:9的氨基酸序列,所述的HCDR2含有SEQ ID NO:16的氨基酸序列,所述的HCDR3含有SEQ ID NO:23的氨基酸序列;或
(7)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:10的氨基酸序列,所述的HCDR2含有SEQ ID NO:17的氨基酸序列,所述的HCDR3含有SEQ ID NO:24的氨基酸序列;或
(8)所述的LCDR1含有SEQ ID NO:3的氨基酸序列,所述的LCDR2含有SEQ ID NO:4的氨基酸序列,所述的LCDR3含有SEQ ID NO:5的氨基酸序列;
所述的HCDR1含有SEQ ID NO:11的氨基酸序列,所述的HCDR2含有SEQ ID NO:18的氨基酸序列,所述的HCDR3含有SEQ ID NO:25的氨基酸序列。
3.如权利要求1或权利要求2所述的单克隆抗体或抗原结合片段,其中:
轻链可变区的氨基酸序列与SEQ ID NO:26具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:27具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:28具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:29具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:30具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:31具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:32具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:33具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:34具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:35具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:36具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:37具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:38具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:39具有至少90%的序列同一性;或
轻链可变区的氨基酸序列与SEQ ID NO:40具有至少90%的序列同一性,且重链可变区的氨基酸序列与SEQ ID NO:41具有至少90%的序列同一性。
4.如权利要求1至3任一项所述的单克隆抗体或抗原结合片段,其中单克隆抗体或抗原结合片段特异性结合抗原TIM-3。
5.如权利要求1-3中任一项所述的单克隆抗体或抗原结合片段,其中的单克隆抗体或抗原结合片段是全人源的。
6.如权利要求1-4中任一项所述的单克隆抗体,其中的单克隆抗体为IgG。
7.如权利要求1-4中任一项所述的抗原结合片段,其中抗原结合片段是scFv,scFv-Fc,Fv,Fab、Fab’、F(ab)2或F(ab’)2。
8.一种双特异性抗体,含有权利要求1-6中任一项所述的单克隆抗体或抗原结合片段。
9.一种抗体-药物偶联物,含有如权利要求1-6中任一项所述的单克隆抗体或抗原结合片段,或权利要求8所述的双特异性抗体,以及额外的一种效应分子偶联。
10.如权利要求9所述的抗体-药物偶联物,其中的效应分子是可检测标记。
11.如权利要求10所述的抗体-药物偶联物,其中的可检测标记是荧光标记,放射性标记,亲和素,生物素,或酶。
12.如权利要求9所述的抗体-药物偶联物,其中的效应分子是毒素,免疫调节剂,抗血管,抗增殖,促凋亡或化疗剂。
13.如权利要求12所述的抗体-药物偶联物,其中的毒素是抗生素,tubulin多聚抑制剂,蛋白合成抑制剂,蛋白酶抑制剂,磷酸化酶抑制剂,烷基化,拓扑异构酶抑制剂,或酶。
14.一种核酸分子,其编码权利要求1-6中任一项所述的单克隆抗体或抗原结合片段。
15.如权利要求13所述的核酸分子,可操作地连接至启动子。
16.一种重组表达载体,所述的重组表达载体包含有权利要求14所述的核酸分子。
17.一种质粒,含有权利要求13或权利要求14所述的核酸分子。
18.如权利要求15所述的质粒,其中质粒是一种病毒质粒。
19.一种宿主细胞,含有权利要求15或权利要求16所述的质粒。
20.一种在生物样品中检测TIM-3表达的方法,包含:将所述的生物样品与权利要求1-6重任一项所述的单克隆抗体或抗原结合片段接触,检测免疫复合物的存在与否,其中免疫复合物的存在表示生物样品中存在TIM-3。
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