CN114790241A - 抗tigit抗体及其应用 - Google Patents
抗tigit抗体及其应用 Download PDFInfo
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- CN114790241A CN114790241A CN202110101941.4A CN202110101941A CN114790241A CN 114790241 A CN114790241 A CN 114790241A CN 202110101941 A CN202110101941 A CN 202110101941A CN 114790241 A CN114790241 A CN 114790241A
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Abstract
本申请提供了抗TIGIT(VSIG9、VSTM3、WUCAM)抗体及其用途。本申请还提供了抗TIGIT抗体的嵌合抗体和人源化抗体形式。本申请的抗TIGIT抗体能够与哺乳动物PVR特异性结合,优选地具有对人和/或灵长类动物TIGIT蛋白的高亲和性、在一定浓度下可阻断TIGIT与其配体的结合、调节受体活性、刺激T细胞的活化、抑制Treg功能,从而更好的发挥效应T细胞作用等效果。本申请的抗TIGIT抗体可用于治疗TIGIT相关疾病。
Description
技术领域
本申请涉及免疫学领域,更具体地,本申请涉及抗TIGIT的抗体及其应用。
背景技术
免疫系统识别并清除癌症细胞的概念最早是在100多年前提出的,在不同类型癌症病人血液中可以检测到T细胞对癌症相关抗原的反应性。在有效的抗肿瘤免疫过程中,T细胞作为核心的执行者,首先被T细胞受体(T cell receptor,TCR)介导的抗原识别信号活化,同时众多的共刺激信号和共抑制信号精细调节T细胞反应的强度和质量,这些抑制信号即为免疫检查点。
免疫系统进化出了多种机制用来阻止免疫细胞的有害激活。其中一种机制就是T细胞共刺激和共抑制信号之间的平衡。B7-1(CD80)/B7-2(CD86)-CTLA-4通路是T细胞活化最具特征性的抑制通路。另一条抑制通路涉及程序性死亡-1(PD-1),通过与PD-L1(B7-H1)和PD-L2(B7-DC)相互作用负向调节T细胞活化。T细胞活化的第三个共抑制分子B细胞和T细胞弱化子(BTLA)是与CTLA-4和PD-1相似的细胞表面分子。由于这些抑制性复合受体抑制T细胞增殖和细胞因子产生,因此被认为在维持免疫稳态和耐受过程中发挥重要作用。大量证据表明共刺激分子在预防自身免疫性疾病过程中起关键作用,因为这些分子缺失或者功能突变加速基因自身免疫性和多态性与人自身免疫性疾病遗传易感性相关联。
在生理情况下,共刺激分子与免疫检查点分子保持平衡,从而最大程度减少对于周围正常组织的损伤,维持对自身组织的耐受、避免自身免疫反应。而肿瘤细胞可以通过此机制,异常上调共抑制分子及其相关配体,抑制T细胞活化,从而逃避免疫杀伤。针对免疫检查点的阻断是增强T细胞活化的有效策略之一,也是近些年抗肿瘤药物开发的热门靶点。到目前为止,已有3个免疫检查点抑制剂在美国获批,用于治疗多种癌症类型,靶点分别是CTLA-4和PD-1/PD-L1。
2008年,Xin Yu等(2009)运用基因芯片扫描的检索策略,对活化的人类T细胞进行了测序,并对一些具有免疫调节样结构域的蛋白质分子进行了进一步的研究,发现了一个在T细胞和NK上表达的新分子,该分子具有免疫球蛋白样结构域、跨膜区和免疫受体蛋白酪氨酸抑制基序(ITIM),因此命名为TIGIT(T cell immunoglobulin and ITIM domain)。
阻断型免疫检查点分子,主要指T细胞活化的共抑制信号分子-T细胞共抑制受体,研究表明TIGIT、CTLA-4和PD-1在T细胞活化过程中发挥免疫抑制作用,从而抑制T细胞对肿瘤细胞的免疫杀伤功能;而针对这三个靶点的阻断性单克隆抗体可以解除这种免疫抑制,恢复T细胞抗肿瘤免疫功能。
TIGIT基因位于人类第16号染色体,编码由244个氨基酸组成的I型跨膜蛋白。人TIGIT分子具有长141个氨基酸的胞膜外区,该区域具有1个免疫球蛋白V样结构域;长23个氨基酸的跨膜区;和长80个氨基酸的较短的胞质区,该区域具有1个PDZ结合结构域和1个ITIM模体。人TIGIT分子的结构如图13所示。TIGIT(又称VSIG9、VSTM3、WUCAM)是免疫受球蛋白脊髓灰质炎病毒受体家族CD28家族样受体的一员,在T细胞和自然杀伤(NK)细胞亚群中表达,但一般情况下,其表达水平很低,而当这些细胞活化后,其蛋白水平会上调。比如在肿瘤微环境中,肿瘤浸润淋巴细胞中的TIGIT经常处于高表达水平,TIGIT可与免疫细胞、非免疫细胞以及肿瘤细胞中的受体CD155(poliovirus receptor-PVR)、CD112(PVRL2,nectin-2)、CD113(PVRL3,Nectin-3)结合,结合后导致T细胞活化,T细胞和自然杀伤细胞的细胞毒性受到抑制。
具体的TIGIT可通过三种不同的作用机制抑制淋巴细胞:1)TIGIT可以在结合PVR后通过其细胞内尾部的ITIM和/或ITT基序发出信号,从而抑制NK、CD8+T等细胞对肿瘤细胞的杀伤;2)TIGIT可通过与PVR结合诱导相邻树突细胞或肿瘤细胞中的PVR信号传导,从而释放IL-10、TGF-β等细胞因子,促使Treg细胞激活从而抑制T细胞活性;3)TIGIT可以通过以更高的亲和力结合PVR或破坏CD226同型二聚化来抑制CD226信号传导。
因此,本领域内仍存在开发TIGIT靶向抗体的需求。
发明内容
为解决上述技术问题,本申请提供了一种抗TIGIT抗体及其应用。具体而言,本申请提供了以下技术方案。
在第一方面,本申请提供了特异性结合TIGIT的抗体或其抗原结合部分,其包含重链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3序列中的任意一项或多项,其中所述HCDR1序列为GFTFSNYW(SEQ ID NO:1),所述HCDR2序列为IRLKSNNYAT(SEQ ID NO:2),所述HCDR3序列为ARLYYGNYFDY(SEQ ID NO:3)或TRLYYGNYFDY(SEQ ID NO:4)。
在一些实施方案中,所述抗体或其抗原结合部分还包含轻链可变区,所述轻链可变区包含LCDR1、LCDR2和LCDR3序列中的任意一项或多项,其中所述LCDR1序列为ENTYSY(SEQ ID NO:5),所述LCDR2序列为NAK(SEQ ID NO:6),所述LCDR3序列为QHHYAFSYT(SEQ IDNO:7)。
在一些实施方案中,所述抗体为鼠源抗体。优选地,所述重链可变区的氨基酸序列如SEQ ID NO:8所示,和/或所述轻链可变区的氨基酸序列如SEQ ID NO:9所示。
在一些实施方案中,所述抗体为嵌合抗体。优选地,所述重链的氨基酸序列如SEQID NO:10所示,和/或所述轻链的氨基酸序列如SEQ ID NO:11所示。
在一些实施方案中,所述抗体为人源化抗体。优选地,所述重链可变区的氨基酸序列如SEQ ID NO:12或者SEQ ID NO:13所示,和/或所述轻链可变区的氨基酸序列如SEQ IDNO:14、SEQ ID NO:15或者SEQ ID NO:16所示。
在一些实施方案中,所述特异性结合TIGIT的抗体或其抗原结合部分能特异性结合灵长类TIGIT。
在一些实施方案中,所述特异性结合TIGIT的抗体为单克隆抗体。
在一些实施方案中,所述特异性结合TIGIT的抗体或其抗原结合部分以1×10-9至1×10-10M的KD特异性结合TIGIT分子。
在一些实施方案中,所述特异性结合TIGIT的抗体或其抗原结合部分具有TIGIT抑制剂功能。
在一些实施方案中,所述特异性结合TIGIT的抗体或其抗原结合部分能够刺激T细胞的活化及增殖。
在第二方面,本申请提供了药物组合物,其包含第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分以及药学上可接受的载体。
在一些实施方案中,所述药物组合物还包含一种或多种其他活性成分。在一些实施方案中,所述活性成分为化疗剂、PD-1结合拮抗剂等。
在第三方面,本申请提供了核酸分子,其编码第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分。
在第四方面,本申请提供了表达载体,其包含第三方面所述的核酸分子。
在第五方面,本申请提供了宿主细胞,其包含第三方面所述的核酸分子或第四方面所述的表达载体。
在第六方面,本申请提供了疫苗,其包含第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分,以及任选的免疫佐剂。
在第七方面,本申请提供了第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分、第二方面所述的药物组合物、第三方面所述的核酸分子、第四方面所述的表达载体、第五方面所述的宿主细胞或第六方面所述的疫苗在制备用于抑制Treg功能、杀死表达TIGIT的细胞、引发T细胞介导的反应、提高效应T细胞的功能、提高记忆T细胞的功能、和/或有效抑制肿瘤生长的药物中的用途。
在第八方面,本申请提供了第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分、第二方面所述的药物组合物、第三方面所述的核酸分子、第四方面所述的表达载体、第五方面所述的宿主细胞或第六方面所述的疫苗在制备用于预防和/或治疗TIGIT相关的疾病,例如肿瘤的药物中的用途。
在一些实施方案中,所述肿瘤选自结肠癌、黑色素瘤、间皮质瘤、肾细胞癌、淋巴瘤、晚期实体瘤以及上述的转移瘤。
在第九方面,本申请提供了检测试剂或者试剂盒,其包含第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分。
在第十方面,本申请提供了预防和/或治疗TIGIT相关的疾病,例如肿瘤的方法,其包括给予有需要的个体第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分、第二方面所述的药物组合物、第三方面所述的核酸分子、第四方面所述的表达载体、第五方面所述的宿主细胞或第六方面所述的疫苗。
在一些实施方案中,所述方法还包括联合施用其他的治疗剂,例如化疗剂、PD-1结合拮抗剂等。
本申请的特异性结合TIGIT的抗体或其抗原结合部分能够与TIGIT特异性结合,并且具有以下的一种或多种效应:具有TIGIT抑制剂功能,刺激T细胞的增殖活化,诱导TIGIT介导的抗肿瘤免疫应答,和/或抑制肿瘤生长等。
附图的简要说明
图1显示了本申请的鼠源抗TIGIT抗体(杂交瘤18A12分泌的抗体)阻断PVR与人TIGIT结合的能力。
图2显示了本申请的鼠源抗TIGIT抗体(杂交瘤18A12分泌的抗体)与食蟹猴TIGIT的结合亲和力。
图3显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)与人TIGIT-结合的亲和力。
图4显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)及抗PD-1抗体在B-hTIGIT小鼠体内抑制MC38结肠癌模型的药效实验。其中A:各组小鼠肿瘤体积变化图;B:小鼠体重随给药时间的变化;C、D和E:三组的具体抑瘤数据,F:小鼠处死后对肿瘤的拍照;G:计算的瘤重/体重数据。
图5显示了本申请的6种抗TIGIT人源化抗体(IgG1亚型)与人TIGIT-结合的亲和力,其通过流式细胞术检测。
图6显示了本申请的6种抗TIGIT人源化抗体(IgG1亚型)与食蟹猴TIGIT-结合的亲和力,其通过流式细胞术检测。
图7显示了本申请的6种抗TIGIT人源化抗体(IgG1亚型)阻断PVR与人TIGIT结合的能力,其通过流式细胞术检测。
图8显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)在MC38模型中的药效学实验结果。其中A:小鼠肿瘤体积变化图;B:小鼠体重变化图;C和D:两组小鼠肿瘤体积变化图;E和F:解剖小鼠后瘤脾展示图;G和H:脾重比与瘤重比分析图(N.S表示生理盐水溶剂对照组)。
图9显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)在CT26模型中的药效学实验结果:给药后小鼠瘤体积及体重变化趋势图(N.S表示生理盐水溶剂对照组)。
图10显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)在CT26模型中的药效学实验结果:给药后各组小鼠个体肿瘤生长趋势图。
图11显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)在CT26模型中的药效学实验结果:肿瘤体积达到人道终点处死小鼠后,各组小鼠的肿瘤和脾脏解剖图。
图12显示了本申请的嵌合抗TIGIT抗体(IgG1亚型)在CT26模型中的药效学实验结果:肿瘤体积达到人道终点处死小鼠后,各组小鼠的肿瘤和脾脏称重后经计算分析得到的瘤重比及脾重比分析图。
图13显示了人TIGIT分子的结构示意图,其中信号肽:第1-21位氨基酸;胞外段为第22-141位氨基酸(其中IgV区:第22-124位氨基酸);跨膜区:第142-162位氨基酸;胞内段:第163-244位氨基酸(其中ITIM基序:第229-234位氨基酸,如图中黑色框标注)。
发明的详细描述
提供以下定义和方法以更好地界定本申请以及在本申请实践中指导本领域普通技术人员。除非另作说明,本申请的术语按照相关领域普通技术人员的常规用法理解。
定义
为容易理解本申请,首先定义本文中使用的某些术语。
如本文所用的,术语“抗体”指包含四条多肽链,即通过双硫键互连的两条重链(H)及两条轻链(L)的免疫球蛋白分子,以及其多聚体(例如IgM)。重链包含重链可变区(缩写为VH)及重链恒定区(缩写为CH)。重链恒定区包含三个域,即CH1、CH2及CH3。轻链包含轻链可变区(缩写为VL)及轻链恒定区(缩写为CL)。轻链恒定区包含一个域(CL1)。VH及VL区可进一步细分成称为互补决定区(CDR)的高变区,其中穿插有称为构架区(FR)的保守区。在一些实施方案中,从N-末端至C-末端,轻链与重链可变结构域均包含FR1、CDR1、FR2、CDR2、FR3、CDR3与FR4。
如本文所用的,术语抗体的“抗原结合部分”是指负责结合抗原的完整抗体分子的一部分或区段。抗原结合部分可以包含重链可变区(VH)、轻链可变区(VL)或上述两者。抗体的抗原结合部分可使用任何适合的标准技术从完整抗体分子制备,所述标准技术包括蛋白水解消化或重组遗传工程化技术等。抗原结合部分的非限制性实例包括:Fab片段、F(ab')2片段、Fd片段、Fv片段、单链Fv(scFv)分子、单域抗体、dAb片段及由模拟抗体高变区的氨基酸残基组成的最小识别单元(例如分离的CDR)。术语“抗原结合部分”也包括其它工程化的分子,如双抗体、三抗体、四抗体及微型抗体等。例如,本文中所述的Fd片段指由VH与CH1结构域组成的抗体片段;Fv片段由抗体的单臂中VL与VH结构域组成;dAb片段(Ward et al.,Nature 1989;341:544-546)由VH结构域组成。
本领域技术人员公知,互补决定区(CDR,通常有CDR1、CDR2及CDR3)是可变区中对抗体的亲和力和特异性影响最大的区域。VH或VL的CDR序列有两种常见的定义方式,即Kabat定义和Chothia定义,例如参见Kabat et al.,“Sequences of Proteins ofImmunological Interest”,National Institutes of Health,Bethesda,MD.(1991);Al-Lazikani et al.,J Mol Biol 273:927-948(1997);以及Martin et al.,Proc.Natl.Acad.Sci.USA 86:9268-9272(1989)。对于给定抗体的可变区序列,可以根据Kabat定义或者Chothia定义来确定VH和VL序列中CDR区序列。在本申请的实施方案中,利用Kabat定义CDR序列。在本文中,重链可变区的CDR1、CDR2及CDR3分别简称为HCDR1、HCDR2及HCDR3;轻链可变区的CDR1、CDR2及CDR3分别简称为LCDR1、LCDR2及LCDR3。
对于给定抗体的可变区序列,可以通过多种方式分析可变区序列中CDR区序列,例如可以利用在线软件Abysis确定(http://www.abysis.org/)。
如本文所用的,术语“特异性结合”,是指两个分子之间的非随机结合反应,例如抗体与抗原表位的结合,例如抗体以比其对非特异性抗原的亲和性大至少两倍的亲和性结合于特异性抗原的能力。然而,应了解,抗体能够特异性结合于两种或更多种与其序列相关的抗原。例如,本发明的抗体可特异性结合于人类与非人类(例如小鼠或非人类灵长动物)的TIGIT。
如本文所用的,术语“单克隆抗体”指由基本同质的抗体群体获得的抗体,即,除了可能在少量个体中存在自然发生的突变以外,组成群体的各个抗体是相同的。本文所述单克隆抗体特别包括“嵌合”抗体,其中重链和/或轻链的一部分与来源于具体物种或属于具体抗体类或亚类的抗体中的对应序列相同或同源,而重链和/或轻链的余下部分与来源于另一物种或属于另一抗体类或亚类的抗体中的对应序列相同或同源,并且还包括这样的抗体的片段,只要它们能表现出所期望的生物学活性(参见,美国专利号4,816,567;和Morrison et al.,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。
如本文所用的,术语“鼠源化抗体”是指其中所有恒定结构域序列均为小鼠序列的任何抗体。此类抗体可通过杂交瘤产生。
如本文所用的,术语“嵌合抗体”是指包含来自两种或更多种不同抗体的区段的抗体。在一些实施方案中,一个或多个CDR衍生自小鼠抗TIGIT抗体。在另一些实施方案中,所有CDR均衍生自小鼠抗TIGIT抗体。在一些实施方案中,在嵌合抗体中组合来自一种以上小鼠抗TIGIT抗体的CDR。例如,嵌合抗体可包含来自第一种小鼠抗TIGIT抗体中轻链的CDR1、来自第二种小鼠抗TIGIT抗体中轻链的CDR2、与来自第三种小鼠抗TIGIT抗体中轻链的CDR3,以及来自重链的CDR可衍生自一种或多种其它抗TIGIT抗体。此外,框架区可来自相同抗TIGIT抗体或来自一个或多个不同的个体。在一些实施方案中,本文所述的嵌合抗体包含鼠源抗体的可变区(包括重链可变区VH和/或轻链可变区VL)和人抗体的恒定区。
如本文所用的,术语“人源化抗体”是指CDR移植抗体,具体是指将其他物种例如小鼠的CDR区序列移植到人的抗体可变区框架中产生的抗体。目的是克服嵌合抗体由于携带大量其他物种例如小鼠的蛋白成分从而在人体中诱导强烈的免疫副反应。
如本文所用的,术语“核酸分子”可以指DNA分子及RNA分子,其可以是单链或双链的。核酸分子也可以为cDNA。
如本文所用的,术语“TIGIT相关疾病”包括与TIGIT信号通路相关的疾病和/或症状。示例性TIGIT相关疾病或病症包括肿瘤,例如结肠癌、黑色素瘤、间皮质瘤、肾细胞癌、淋巴瘤、晚期实体瘤以及上述的转移瘤。
如本文所用的,术语“EC50”是指半数最大效应浓度(concentration for 50%ofmaximal effect,EC50),指能引起50%最大效应的浓度。
如本文所用的,术语“免疫反应”指脊椎动物内针对外来作用剂的生物反应,该反应保护生物体抵抗此类作用剂及由其引起的疾病。免疫反应系由免疫系统的细胞(例如,T淋巴细胞、B淋巴细胞、自然杀伤(NK)细胞、巨噬细胞、嗜酸性粒细胞、肥大细胞、树突细胞或嗜中性粒细胞)及由此类细胞中的任一者或由肝脏产生的可溶性大分子(包括抗体、细胞因子及补体)的作用介导,其导致选择性靶向、结合、损害、破坏和/或自脊椎动物身体消除侵入病原体、经病原体感染的细胞或组织、癌性或其他异常细胞或在自体免疫或病理炎症的情形下正常人类细胞或组织。免疫反应包括T细胞(例如效应T细胞)或Th细胞(例如CD4+或CD8+T细胞)的活化或抑制或Treg细胞的抑制。
如本文所用的,术语“癌症”指以体内异常细胞不受控生长为特点的一大类疾病。失调的细胞分裂可形成侵袭相邻组织且可经由淋巴系统或血流转移至身体的远处部分的恶性肿瘤或细胞。
如本文所用的,术语“治疗”指对受试者实施的任何类型的介入或方法或向其施用活性剂,其中目的是逆转、缓和、改善、抑制或缓解或预防症状、并发症、病况或与疾病相关的进展、发展、严重程度或复发。
如本文所用的,术语“预防”指对未患疾病的受试者施用,以防止疾病发生或使其影响(若存在)最小化。
具体实施方式
本发明人筛选得到了一株杂交瘤细胞,其上清中的抗体能够与人或猴的TIGIT结合,且可阻断人PVR与TIGIT的结合。
本发明人还通过基因工程手段从鼠源抗TIGIT抗体制备了嵌合抗体和人源化抗体形式,这些抗体形式同样能够与人或猴的TIGIT结合,且可阻断人PVR与TIGIT的结合,从而有效地诱导TIGIT介导的免疫应答,并起到预防或治疗TIGIT相关疾病的作用。
本申请还提供了编码该抗体或其抗原结合片段的核酸分子、包含所述核酸分子的表达载体、包含所述核酸分子或表达载体的宿主细胞、制备和纯化该抗体的方法以及所述抗体或其抗原结合片段的医学和生物学应用,例如预防或治疗TIGIT相关疾病或病症。本申请还涵盖使用所述抗体或其抗原结合片段来检测TIGIT及调节TIGIT活性的方法以及相关检测试剂或试剂盒。
可用于抗体方法中的合适的技术包括基于TIGIT的亲和纯化、非变性凝胶纯化、HPLC或RP-HPLC、在蛋白A柱上纯化、或这些技术的任何组合。可使用ELISA测定法测定TIGIT抗体同种型,例如可使用鼠Ig吸附的抗人Ig鉴定人Ig。
可通过本领域已知的多种标准的蛋白纯化或重组表达技术中的任何一种来产生适于产生抗体的TIGIT。适于产生免疫应答的TIGIT的形式包括TIGIT子序列(例如免疫原性片段)。另外的TIGIT的形式包括TIGIT表达细胞、含有TIGIT的制品或细胞提取物或级分、部分纯化的TIGIT。
在第一方面,本申请提供了特异性结合TIGIT的抗体或其抗原结合部分,其包含重链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3序列中的任意一项或多项,其中所述HCDR1序列为GFTFSNYW(SEQ ID NO:1),所述HCDR2序列为IRLKSNNYAT(SEQ ID NO:2),所述HCDR3序列为ARLYYGNYFDY(SEQ ID NO:3)或TRLYYGNYFDY(SEQ ID NO:4)。
在优选的实施方案中,本文所述的抗体或其抗原结合部分的重链可变区包含SEQID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2和SEQ ID NO:3或SEQ ID NO:4所示的HCDR3序列。
在一些实施方案中,本文所述的抗体或其抗原结合部分还包含轻链可变区,所述轻链可变区包含LCDR1、LCDR2和LCDR3序列中的任意一项或多项,其中所述LCDR1序列为ENTYSY(SEQ ID NO:5),所述LCDR2序列为NAK(SEQ ID NO:6),所述LCDR3序列为QHHYAFSYT(SEQ ID NO:7)。
在优选的实施方案中,本文所述的抗体或其抗原结合部分的轻链可变区包含SEQID NO:5所示的LCDR1、SEQ ID NO:6所示的LCDR2和SEQ ID NO:7所示的LCDR3序列。
在优选的实施方案中,本文所述的抗体或其抗原结合部分包含重链可变区和轻链可变区,其中所述重链可变区包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2和SEQ ID NO:3或SEQ ID NO:4所示的HCDR3序列,并且所述轻链可变区包含SEQ ID NO:5所示的LCDR1、SEQ ID NO:6所示的LCDR2和SEQ ID NO:7所示的LCDR3序列。
在一些更具体的实施方案中,本文公开的抗体可以为抗TIGIT单克隆抗体。抗TIGIT抗体类型与亚型可由本领域已知的任何方式确定。通常,抗体类型与亚型可使用特异于特定抗体类型与亚型的抗体确定。可使用ELISA测定法测定抗TIGIT抗体同种型,例如可使用鼠Ig吸附的抗人Ig鉴定人Ig。
在一些实施方案中,本文所述的抗体为鼠源抗体,优选地,所述重链可变区的氨基酸序列如SEQ ID NO:8所示,和/或所述轻链可变区的氨基酸序列如SEQ ID NO:9所示。
在优选的实施方案中,本文所述的鼠源抗体包含SEQ ID NO:8所示的重链可变区和SEQ ID NO:9所示的轻链可变区。
在一些实施方案中,本文所述的抗体为嵌合抗体。本文所述的嵌合抗体包含鼠源抗体的可变区(包括重链可变区VH和/或轻链可变区VL)和人抗体的恒定区。
在优选的实施方案中,本文所述的嵌合抗体包含鼠源抗体的可变区(包括重链可变区和轻链可变区)和人抗体的恒定区。
优选地,所述嵌合抗体包含SEQ ID NO:10所示的重链,和/或SEQ ID NO:11所示的轻链。
在优选的实施方案中,本文所述的嵌合抗体包含SEQ ID NO:10所示的重链和SEQID NO:11所示的轻链。
在一些实施方案中,本文所述的抗体为人源化抗体。本文所述的人源化抗体包含鼠源抗体的CDR区(包括HCDR1、HCDR2和HCDR3中的任意一项或多项和/或LCDR1、LCDR2和LCDR3中的任意一项或多项)、人抗体可变区的框架区(包括FR1、FR2、FR3和FR4中的任意一项或多项),以及任选地人抗体的恒定区。
在优选的实施方案中,本文所述的人源化抗体包含鼠源抗体的CDR区(包括HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3)、人抗体可变区的框架区(包括FR1、FR2、FR3和FR4),以及任选地人抗体的恒定区。
优选地,所述重链可变区的氨基酸序列如SEQ ID NO:12或SEQ ID NO:13所示,和/或所述轻链可变区的氨基酸序列如SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16所示。
在优选的实施方案中,本文所述的人源化抗体包含SEQ ID NO:12或SEQ ID NO:13所示的重链可变区,和SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16所示的轻链可变区。
本文所述的抗体还可以包含鼠或人抗体恒定区。鼠抗体恒定区包括鼠IgG1、IgG2a、IgG2b或IgG3的重链恒定区以及κ或λ型轻链恒定区等。人抗体恒定区包括人IgG1、IgG2、IgG3或IgG4的重链恒定区以及κ或λ型轻链恒定区等。
在一些实施方案中,本文所述的TIGIT为灵长类TIGIT。优选地,本文所述的灵长类TIGIT选自人TIGIT或猴TIGIT。
在一些实施方案中,本文所述的抗原结合部分选自:Fab片段、Fab’片段、F(ab’)2片段、Fv片段、scFv片段、Fd片段或单域抗体。
本文所用的术语“Fab片段”包含轻链以及重链的CH1和可变区。Fab分子的重链不能与另一个重链分子形成二硫键。
本文所用的术语“Fab’片段”含有轻链以及重链的部分或片段,所述部分或片段含有VH结构域和CH1结构域以及在CH1和CH2结构域之间的区域,使得在2个Fab’片段的两条重链之间可以形成链间二硫键,以形成F(ab’)2分子。
本文所用的术语“F(ab’)2片段”含有两条轻链和两条重链,所述重链含有在CH1和CH2结构域之间的恒定区的一部分,使得在两条重链之间形成链间二硫键。F(ab’)2片段因而由两个Fab’片段组成,而两个Fab’片段通过两条重链之间的二硫键连接在一起。
本文所用的术语“Fv片段”包含来自重链和轻链的可变区,但是缺少恒定区。
本文所用的术语“单链Fv”或“scFv”,是指包含抗体的VH结构域和VL结构域的抗体片段,其中这些结构域以单一多肽链形式存在。通常,Fv多肽还包含VH结构域和VL结构域之间的多肽接头,所述接头使scFv能够形成期望的结构以进行抗原结合。
本文所用的术语“单域抗体”指包含一个重链可变区(VHH)和两个常规的CH2与CH3区的抗原结合部分。最初是在羊驼外周血液中发现的一种天然缺失轻链的抗体,该抗体虽然只包含一个重链可变区(VHH)和两个常规的CH2与CH3区,但却不像人工改造的单链抗体片段(scFv)那样容易相互沾粘,甚至聚集成块。更重要的是单独克隆并表达出来的VHH结构具有与原重链抗体相当的结构稳定性以及与抗原的结合活性,是已知的可结合目标抗原的最小单位。VHH晶体分子量只有15KDa,因此也被称作纳米抗体(Nanobody,Nb)
在第二方面,本申请提供了药物组合物,其包含第一方面所述的抗体或其抗原结合部分以及药学上可接受的载体。
药学上可接受的载体或稀释剂包括盐水、水性缓冲溶液、溶剂和/或分散介质。这种载体和稀释剂的使用是本领域熟知的。可用作药学上可接受的载体的材料的一些非限制性实例包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、甲基纤维素、乙基纤维素、微晶纤维素和乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)润滑剂,例如硬脂酸镁、十二烷基硫酸钠和滑石;(8)赋形剂,例如可可脂和栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇和聚乙二醇(PEG);(12)酯,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液;(19)乙基酒精;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酸酐;(22)填充剂,例如多肽和氨基酸;(23)血清组分,例如血清白蛋白、HDL和LDL;(22)C2-C12醇类,例如乙醇;以及(23)药物制剂中所用的其他无毒的相容物质。湿润剂、着色剂、脱模剂、包衣剂、甜味剂、调味剂、芳香剂、防腐剂和抗氧化剂也可以存在于药物制剂中。
在一些实施方案中,本文所述的药物组合物还包含一种或多种其他活性成分,例如用于治疗TIGIT相关疾病如肿瘤的药剂,如化疗剂和/或PD-1结合拮抗剂。
在第三方面,本申请提供了核酸分子,其编码第一方面所述的抗体或其抗原结合部分。
在优选的实施方案中,本文所述的核酸可以是适合在宿主细胞中表达的密码子优化的核酸。例如根据密码子的简并性,其仍然编码同样的蛋白质。根据所用宿主细胞进行密码子优化的方法是本领域技术人员公知的。
在第四方面,本申请提供了表达载体,其包含第三方面所述的核酸分子。
可以使用任何合适的表达载体。例如,原核克隆载体包括来自大肠杆菌的质粒,如colEl、pCRl、pBR322、pMB9、pUC、pKSM和RP4。原核载体还包括噬菌体DNA如M13和其它丝状单链DNA噬菌体的衍生物。可用于酵母的载体的实例是2μ质粒。用于在哺乳动物细胞中表达的合适载体包括以下众所周知的衍生物:SV-40、腺病毒、逆转录病毒衍生的DNA序列以及衍生自功能性哺乳动物载体(如上述那些)和功能性质粒和噬菌体DNA的组合的穿梭载体。
另外的真核表达载体为本领域已知的(例如,P J.Southern&P.Berg,J.Mol.Appl.Genet,1:327-341(1982);Subramani等人,Mol.Cell.Biol,1:854-864(1981);Kaufinann&Sharp,"Amplification And Expression of Sequences Cotransfected witha Modular Dihydrofolate Reductase Complementary DNA Gene,"J.Mol.Biol,159:601-621(1982);Kaufhiann&Sharp,Mol.Cell.Biol,159:601-664(1982);Scahill等人,"Expression And Characterization Of The Product Of A Human Immune InterferonDNA Gene In Chinese Hamster Ovary Cells,"Proc.Nat'l Acad.Sci USA,80:4654-4659(1983);Urlaub&Chasin,Proc.Nat'l Acad.Sci USA,77:4216-4220,(1980),将其全部通过引用并入本文)。
可用于本申请的表达载体含有至少一个表达控制序列,其与待表达的DNA序列或片段可操作连接。将控制序列插入载体中以控制和调节克隆的DNA序列的表达。有用的表达控制序列的实例是lac系统,trp系统,tac系统,trc系统,噬菌体λ的主要操纵子和启动子区,fd外壳蛋白的控制区,酵母的糖酵解启动子,例如3-磷酸甘油酸激酶的启动子,酵母酸性磷酸酶的启动子,例如Pho5,酵母α-交配因子的启动子,以及来源于多瘤病毒、腺病毒、逆转录病毒和猿猴病毒的启动子,例如SV40的早期和晚期启动子和已知控制原核或真核细胞及其病毒或其组合的基因表达的其它序列。
在第五方面,本申请提供了宿主细胞,其包含三方面所述的核酸分子或第四方面所述的表达载体。
在一些实施方案中,本文所述的宿主细胞为哺乳动物细胞。哺乳动物细胞可以包括但不限于CHO细胞、NS0细胞、SP2/0细胞、HEK293细胞、COS细胞和PER.C6细胞。本领域技术人员能够根据需要选择适合的宿主细胞。
本文公开的抗TIGIT单克隆抗体的制备方法可包括:在表达条件下培养宿主细胞,从而表达抗TIGIT单克隆抗体;分离和纯化表达的抗TIGIT单克隆抗体。利用上述方法,可以获得粗抗TIGIT单克隆抗体。然后通过纯化方法,包括基于TIGIT的亲和纯化、非变性凝胶纯化、HPLC或RP-HPLC、分子排阻、在蛋白A柱上纯化、或这些技术的任何组合,将抗TIGIT单克隆抗体纯化为基本均一的物质,例如在SDS-PAGE电泳上为单一条带。
在第六方面,本申请提供了疫苗,其包含第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分,以及任选的免疫佐剂。
一般来说,该疫苗被制备成可注射的,例如制备成液态的溶液或者悬浮液,或者适于在注射前再悬浮于液体中的固体形式。该制备物也可以是乳化的。活性的免疫原性组分通常与药学上可接受的并且与所述活性成分相容的赋形剂混合。合适的赋形剂为如水、盐水、葡萄糖、甘油、乙醇等或者其组合。除此之外,疫苗也可以按照需要含有少量的辅料,如润湿剂或者乳化剂,pH缓冲剂或者提高所述疫苗的效果的佐剂。
将疫苗以与其剂型相容的方式给予,并且施用量是治疗上有效的和能产生免疫性的。所施用的量取决于所治疗的受试者,包括例如个体的免疫系统产生免疫应答的能力、给药途径等,具体的量由医师判断。对于初次给予和加强注射而言,适用的治疗方案也是可以变化的。在一些实施方案中,疫苗经静脉内递送,或者直接地递送到肿瘤或者感染的位点,或者其他的疫苗给药的传统方法。
在第七方面,本申请提供了第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分、第二方面所述的药物组合物、第三方面所述的核酸分子、第四方面所述的表达载体、第五方面所述的宿主细胞或第六方面所述的疫苗在制备用于抑制Treg功能、杀死表达TIGIT的细胞、引发T细胞介导的反应、提高效应T细胞的功能、提高记忆T细胞的功能、和/或有效抑制肿瘤生长的药物中的用途。
在第八方面,本申请提供了第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分、第二方面所述的药物组合物、第三方面所述的核酸分子、第四方面所述的表达载体、第五方面所述的宿主细胞或第六方面所述的疫苗在制备用于预防和/或治疗TIGIT相关疾病的药物中的用途。
在第九方面,本申请提供了预防和/或治疗TIGIT相关的疾病,例如肿瘤的方法,其包括给予有需要的个体第一方面所述的特异性结合TIGIT的抗体或其抗原结合部分、第二方面所述的药物组合物、第三方面所述的核酸分子、第四方面所述的表达载体、第五方面所述的宿主细胞或第六方面所述的疫苗。
在一些实施方案中,所述方法还包括施用预防和/或治疗TIGIT相关疾病如肿瘤的第二药剂,如化疗剂和/或PD-1结合拮抗剂。
本文使用的术语“个体”是指哺乳动物,包括但不限于灵长类动物、牛、马、猪、绵羊、山羊、狗、猫以及诸如大鼠和小鼠的啮齿类动物。优选地,哺乳动物为非人类的灵长类或者人类。特别优选的哺乳动物是人。本文使用的“个体”和“受试者”可以互换使用。
“治疗”既指治疗性处理,也指预防性或防止性的措施,其目的就是预防或减缓(减轻)目标病理状态或病症。需要治疗的个体包括那些已经存在所述病症的个体,还包括那些将发展为该病症的或欲对其病症进行预防的个体。因此,本文中欲被治疗的个体已经被诊断为患有该病症或倾向于或易患该病症。
本文中所用的“治疗有效量”可以根据具体情况而定,本领域普通技术人员根据实际所需药量可以很容易地掌握,如可根据患者体重、年龄和病症情况来确定。
在第七或第八方面的实施方案中,所述TIGIT相关疾病为肿瘤。
在一些实施方案中,本文所述的肿瘤为原发性癌症或转移性癌症。在具体的实施方案中,肿瘤选自肺癌例如非小细胞肺癌、结直肠癌、膀胱癌、造血系统癌症例如白血病、乳腺癌、胃癌、食管癌、B淋巴细胞型非霍奇金淋巴瘤、霍奇金淋巴瘤、间变大细胞淋巴瘤、头颈癌例如头颈部鳞状细胞癌、恶性胶质瘤、肾癌、黑色素瘤、前列腺癌、骨癌、骨巨细胞瘤、胰腺癌、卵巢癌、肉瘤、肝癌、皮肤鳞癌、甲状腺癌、宫颈癌、鼻咽癌、子宫内膜癌,或上述肿瘤的转移癌。
在任一方面的实施方案中,本文所述的方法、用途和药物组合物还可包括向个体施用第二药剂和/或治疗,例如作为联合疗法的一部分。第二药剂和/或治疗的非限制性实例可包括放射疗法、手术、吉西他滨、西司他丁、紫杉醇、卡铂、硼替佐米、AMG479、伏立诺他、利妥昔单抗、替莫唑胺、雷帕霉素、苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤(6-thioguanine);巯基嘌呤;甲氨蝶呤;铂类似物,诸如顺铂、奥沙利铂和卡铂;长春碱;长春地辛;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺肖林(novantrone);替尼泊苷;依达曲沙(edatrexate);正定霉素(daunomycin);氨基蝶呤;希罗达(xeloda);降低细胞增殖的PKC-α、Raf、H-Ras、EGFR(例如,埃罗替尼)和VEGF-A的抑制剂以及上述任何的药学上可接受的盐、酸或衍生物。
在第九方面,本申请提供了检测试剂或试剂盒,其包含第一方面所述的抗体或其抗原结合部分。
本文所述的抗体或其抗原结合部分可与可检测部分结合。示例性的可检测部分包括但不限于放射性同位素例如碘125、碘-131、铯-137、铱192和钴60、辣根过氧化物酶、异硫氰酸荧光素、生物素、碱性磷酸酶、化学发光剂如鲁米诺类等。本领域技术人员可以根据需要选择适合的可检测部分与本申请的抗体或其抗原结合部分结合,从而实现不同的检测目的。
本说明书和权利要求书中,词语“包括”、“包含”和“含有”意指“包括但不限于”,且并非意图排除其他部分、添加物、组分、或步骤。
应该理解,在本申请的特定方面、实施方案或实施例中描述的特征、特性、组分或步骤,可适用于本文所描述的任何其他的方面、实施方案或实施例,除非与之矛盾。
本发明公开了特异性结合哺乳动物(人、灵长类动物等)TIGIT的抗体,本发明提供此类蛋白质在治疗、筛选和检测等方面的应用,如在癌症治疗中的用途。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明的范围内。本领域技术人员能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明。
为了使本领域的技术人员更好地理解本发明的技术方案,下面结合实施例对本发明作进一步的详细说明。
实施例
以下实施例用于说明本申请,但不用来限制本申请的范围。在不背离本申请精神和实质的情况下,对本申请方法、步骤或条件所作的修改或替换,均属于本申请的范围。
若未特别指明,实施例中所用的化学试剂均为常规市售试剂,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例不包括对传统方法的详细描述,如那些用于构建载体和质粒的方法,将编码蛋白的基因插入到载体和质粒的方法或将质粒引入宿主细胞的方法。这样的方法对于本领域具有普通技术的人员来说是众所周知的,并且在许多出版物中都有所描述,例如参见Sambrook,J.,Fritsch,EF.and Maniais,T.(1989)Molecular Cloning:A LaboratoryManual,2nd edition,Cold spring Harbor Laboratory Press。
实施例1.产生抗TIGIT抗体的杂交瘤的制备
制备方法如下:
1.取6-8周大的Balb/c小鼠,经腹膜内接种TIGIT-His蛋白(100μg/剂/只)。TIGIT-His蛋白由本申请人构建表达,其包含TIGIT序列(mRNA:NM_173799.3)的胞外区M1-120P和位于该胞外区的C末端的His标签,通过SDS-PAGE验证其分子量在15kDa。2周免疫一次,共免疫3次。进行融合前为小鼠连续3天注射TIGIT-His蛋白。
2.进行融合前2天,取普通昆明鼠(KM)腹腔内巨噬细胞作为滋养层,接种于96孔板中。
3.取来自经免疫接种的小鼠的脾与淋巴结的淋巴细胞与非分泌性骨髓瘤SP2/0细胞系融合,将融合后的细胞加入到提前铺有滋养层的96孔板中,对融合的细胞进行HAT选择(Galfre and Milstein,Methods Enzymol 1981;73:3-46)。
4.回收一组均分泌抗TIGIT特异性抗体的杂交瘤细胞。初次筛选是利用酶联免疫分析法(ELISA)确定杂交瘤分泌的抗TIGIT抗体的滴度。
实施例2.人TIGIT(hTIGIT)、猴TIGIT(Cyno-TIGIT)和人PVR(hPVR)高表达细胞株的构建
通过稳定细胞株构建平台构建人TIGIT(hTIGIT)、猴TIGIT(CynoTIGIT)和人PVR(hPVR)高表达细胞株,具体步骤如下:
质粒pEnter-hTIGIT-嘌呤霉素、pEnter-Cyno-TIGIT-嘌呤霉素和pEnter-hPVR-嘌呤霉素的构建:分别以hTIGIT cDNA(其编码的氨基酸序列如SEQ ID NO:17所示)、Cyno-TIGIT cDNA(其编码的氨基酸序列如SEQ ID NO:18所示)和hPVR cDNA(其编码的氨基酸序列如SEQ ID NO:19所示)为模板,用引物进行扩增,对扩增产物进行电泳和凝胶回收;将pEnter质粒用KpnI/HindIII酶切,胶回收大片段7450bp;将上述所得的三种小片段分别连接入胶回收的用KpnI/HindIII酶切的pEnter质粒大片段,挑阳性克隆送测序,测序正确的质粒分别命名为pEnter-hTIGIT-嘌呤霉素、pEnter-Cyno-TIGIT-嘌呤霉素和pEnter-hPVR-嘌呤霉素。
将293T细胞(协和细胞库)接种于三个T25培养瓶,每个培养瓶接种的细胞数为2×106。第二天将293T细胞培养液更换为4mL Opti-MEM(Thermofisher ScientificCat31985070)。将分别克隆有人TIGIT(hTIGIT)、猴TIGIT(Cyno-TIGIT)和人PVR(hPVR)的质粒pEnter-hTIGIT-嘌呤霉素、pEnter-Cyno-TIGIT-嘌呤霉素和pEnter-hPVR-嘌呤霉素各5μg分别加入到Opti-MEM中,终体积为500μL,另准备500μL Opti-MEM,并在其中加入7μL转染试剂PEI(3μg/mL),将二者混匀并室温静置20min后,加入到上述培养好的4ml 293T细胞中。第三天将细胞培养液更换为5mL DMEM高糖培养基。第四天加入2μg/mL嘌呤霉素进行筛选。2-3天后细胞大量死亡,更换新鲜培养基至细胞稳定生长后,进行单克隆筛选,扩增培养并冻存保种。
本申请构建的稳定表达目的基因的细胞株分别命名为293T-hTIGIT细胞、293T-Cyno-TIGIT细胞和293T-hPVR细胞。所用蛋白序列源自公开发表的数据库,各蛋白质的序列如下:
SEQ ID NO:17:人TIGIT,NP_776160.2,具有Ig和ITIM域亚型的T细胞免疫受体,[智人(Homo sapiens)]
MRWCLLLIWAQGLRQAPLASGMMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLLGAMAATLVVICTAVIVVVALTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCGEQRGEDCAELHDYFNVLSYRSLGNCSFFTETG
SEQ ID NO:18:食蟹猴TIGIT,XP_014985302.2,具有Ig和ITIM域亚型的T细胞免疫受体,[食蟹猴(Macaca fascicularis,Crab-eating macaque,Cynomolgus monkey)]
MRWCLFLIWAQGLRQAPLASGMMTGTIETTGNISAKKGGSVILQCHLSSTMAQVTQVNWEQHDHSLLAIRNAELGWHIYPAFKDRVAPGPGLGLTLQSLTMNDTGEYFCTYHTYPDGTYRGRIFLEVLESSVAEHSARFQIPLLGAMAMMLVVICIAVIVVVVLARKKKSLRIHSVESGLQRKSTGQEEQIPSAPSPPGSCVQAEAAPAGLCGEQQGDDCAELHDYFNVLSYRSLGSCSFFTETG
SEQ ID NO:19:人PVR,NP_006496.4,脊髓灰质炎受体,[智人(Homo sapiens)]
MARAMAAAWPLLLVALLVLSWPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAVFHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVDIWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPGFLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNNWYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICNVTNALGARQAELTVQVKEGPPSEHSGMSRNAIIFLVLGILVFLILLGIGIYFYWSKCSREVLWHCHLCPSSTEHASASANGHVSYSAVSRENSSSQDPQTEGTR
实施例3.杂交瘤分泌的抗体的流式细胞术筛选
方法一:筛选阻断型克隆
收集293T-hPVR细胞,用FACS缓冲液洗涤一次,以2-5×105个细胞/50μL/孔加入到流式管中,然后每孔加入50μL杂交瘤上清及500ng/10μl的TIGIT-hFc蛋白(即人TIGIT胞外区与人IgG1Fc的融合蛋白,由本申请发明人设计),并以BMS的抗TIGIT抗体作为对照,之后孵育0.5小时。
每孔加入2ml FACS缓冲液洗涤两次,分别加入APC羊抗小鼠IgG Fc二抗(Biolegend,Cat405308)及抗人IgG Fc二抗(Biolegend,Cat409306),孵育1小时后上流式细胞仪检测。
结果如表1及图1所示。获得6个候选单克隆抗体:13H3、16F5、18A6、18A12、19F3和20D8。阻断率:Geom.Mean(TIGIT-hFc-样品)/Geom.MeanTIGIT-hFc*100%。
表1.抗TIGIT的阻断型杂交瘤克隆复筛结果
杂交瘤克隆号 | Geom.Mean | 阻断率% |
TIGIT-hFc | 11792 | - |
13H3 | 1579 | 88.6 |
16F5 | 1603 | 26.9 |
18A6 | 1709 | 41.0 |
18A12 | 2762 | 80.9 |
19F3 | 2667 | 86.6 |
20D8 | 2042 | 89.2 |
BMS | 5372 | 54.3 |
方法二:筛选食蟹猴TIGIT高亲和克隆
收集293T-Cyno-TIGIT细胞,用FACS缓冲液洗涤一次,以2-5×105个细胞/50μL/孔加入到流式管中,然后各孔各自加入50μL上述6个杂交瘤上清,之后孵育0.5小时。
每孔加入2ml FACS缓冲液洗涤两次,分别加入APC羊抗小鼠IgG Fc二抗(Biolegend,Cat405308),孵育1小时后上流式细胞仪检测。
结果如表2及图2所示:
表2.抗食蟹猴TIGIT的高亲和杂交瘤克隆筛选
杂交瘤克隆号 | Geom.Mean |
293T-Cyno-TIGIT | 826 |
APC羊抗小鼠IgG Fc | 1918 |
13H3 | 2470 |
16F5 | 2049 |
18A6 | 1911 |
18A12 | 19972 |
19F3 | 5070 |
20D8 | 1966 |
通过以上两种方法,本实施例中得到了杂交瘤克隆18A12,其上清中的抗体既可有效阻断人TIGIT与PVR的结合,又可以高亲和力结合食蟹猴的TIGIT。对杂交瘤克隆18A12进行测序,得到其包含SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:4所示的重链CDR以及SEQ IDNO:5、SEQ ID NO:6和SEQ ID NO:7所示的轻链CDR)
实施例4.抗TIGIT嵌合抗体和293T-hTIGIT细胞的结合活性(FACS检测)
抗TIGIT嵌合抗体的制备
获取18A12杂交瘤细胞cDNA,用本实验室保存的抗体引物通过PCR扩增测序,最终获得鼠源抗TIGIT抗体编码VH1和VL1的基因序列。其中抗TIGIT抗体的VH1和VL1编码核酸序列通过全合成的方式构建成质粒pUC57 TIGIT 18A12-VH1、pUC57TIGIT 18A12-VL1(通用生物系统(安徽)有限公司),分别以pUC57 TIGIT 18A12-VH1、pUC57 TIGIT 18A12-VL1为模板,使用金牌Mix PCR试剂盒(TSINGKE公司),按照试剂盒的说明书,扩增抗TIGIT VH1和TIGIT VL1片段;同时以限制性内切酶SapI(NEB,R0569S)对载体质粒pQKX1和pQKX2进行酶切,将所得的PCR扩增产物和酶切载体以BM无缝克隆试剂盒(博迈德公司),按照试剂盒的说明书,进行重组连接以获得重链表达载体pQK TIGIT 18A12-H1和轻链表达载体pQK TIGIT18A12-L1。
将293Fv细胞(中国医学科学院基础医学研究所细胞资源中心)稀释到1.5×106个细胞/mL,终体积为200ml,37℃摇床培养24h。用转染体积10%的新鲜培养基稀释质粒pQKTIGIT 18A12-H1和pQK TIGIT 18A12-L1,按转染细胞体积计算,至浓度为1μg/mL。向稀释后质粒中按细胞体积的1/1000加入3mg/mL的PEI 200μl,立即涡旋震荡10秒,室温放置15分钟,将质粒/PEI混合物滴加到细胞培养基中,边滴加边轻轻摇动培养瓶,放入摇床培养,7天后收集培养上清,0.4μm的滤膜过滤后,使用Mab sure Lx 5ml纯化柱从培养上清中捕获抗体,流速设定为3ml/min,用5个柱体积的20mM PB+150mM Nacl,PH7.4平衡液平衡纯化柱,柱平衡稳定后上样,上样结束选择20mM PB+150mM Nacl,pH7.4淋洗,淋洗结束使用50mM柠檬酸pH3.0洗脱液进行洗脱,收集用1M Tris-Hcl,pH9.0中和洗脱的抗体(其重链和轻链的氨基酸序列分别如SEQ ID NO:10和SEQ ID NO:11所示)。
收集一个T75细胞培养瓶的293T-hTIGIT细胞,FACS缓冲液洗涤一次,用FACS缓冲液重悬计数,调整细胞浓度为2×106;稀释抗体(包括BMS TIGIT Ab和抗TIGIT嵌合抗体两种抗体,其中BMS TIGIT Ab作为对照),梯度稀释。取10μL稀释后的各抗体分别加入上述调整浓度后的细胞样品100μL,混匀,室温孵育1小时。
每孔加入2ml FACS缓冲液洗涤两次,加入APC抗人IgG Fc二抗(Biolegend,Cat409306),孵育1小时,上流式细胞仪检测,结果见表3和图3。图3结果表明抗TIGIT嵌合抗体和对照抗体BMS TIGIT Ab均与293T-hTIGIT特异性结合。
表3.抗TIGIT嵌合抗体与293T-hTIGIT结合活性
分组 | Geom.Mean |
APC抗人IgG Fc | 405 |
嵌合抗体1.7μg | 12194 |
嵌合抗体1.0μg | 10331 |
嵌合抗体0.5μg | 8786 |
实施例5.抗TIGIT嵌合抗体的动物体内药效实验
利用小鼠结肠癌细胞系MC38细胞在B-hTIGIT小鼠(南方模式)的皮下建立小鼠结肠癌模型,然后再给予抗TIGIT嵌合抗体及PD-1抗体(BE0033-2),考察单独用药及联合用药对小鼠肿瘤的抑瘤作用。
材料与方法:
通过右前肢背侧皮下注射5×105个MC38细胞建立小鼠结肠癌模型;待肿瘤体积在100~150mm3时,按照肿瘤体积分组:对照:生理盐水;PD-1组:1mg/kg;TIGIT组:10mg/kg;PD-1与TIGIT联合组:1+10mg/kg。然后通过腹腔注射单抗,每周注射两次,共6次。给药后密切观察小鼠体征变化,每次给药前测量一次肿瘤大小、称量一次体重并记录。
结果见图4,药效方面联合组的抑瘤效率明显好于对照组及单药组。实验终点解剖肿瘤,分析肿瘤大小,各组之间没有明显差异。相对抑瘤率TGI如表4所示。综上表明,PD-1与TIGIT联合组可有效抑制肿瘤生长。
表4.抗TIGIT嵌合抗体的抑瘤相对抑瘤率(TGI)
备注:D3表示给药后第3天,D7表示给药后第7天,依次类推。
实施例6.抗TIGIT人源化抗体和293T-hTIGIT细胞、293T-Cyno-TIGIT细胞和293T-hPVR的结合活性(FACS检测)
抗TIGIT人源化抗体的制备
抗TIGIT人源化抗体编码VH2和VL2核苷酸序列由本申请的发明设计。其中抗TIGIT人源化抗体VH2、VL2核苷酸序列通过全合成的方式构建成质粒pUC57 TIGIT VH2和pUC57TIGIT VL2(通用生物系统(安徽)有限公司),分别以pUC57 TIGIT VH2和pUC57 TIGIT VL2为模板,使用金牌Mix PCR试剂盒(TSINGKE公司),按照试剂盒的说明书,扩增抗TIGIT VH2和TIGIT VL2片段;同时以限制性内切酶SapI(NEB,R0569S)对载体质粒pQKX1和pQKX2进行酶切,将所得的PCR扩增产物和酶切载体以BM无缝克隆试剂盒(博迈德公司),按照试剂盒的说明书,进行重组连接以获得重链表达载体pQK 18A12 H2和轻链表达载体pQK 18A12 L2。
将293Fv细胞稀释到1.5×106个细胞/mL,终体积为200ml,37℃摇床培养24h。用转染体积10%的新鲜培养基稀释质粒pQK18A12 H2和pQK 18A12 L2,按转染细胞体积计算,至浓度为1μg/mL。向稀释后质粒中按细胞体积的1/1000加入3mg/mL的PEI200μl,立即涡旋震荡10秒,室温放置15分钟,将质粒/PEI混合物滴加到细胞培养基中,边滴加边轻轻摇动培养瓶,放入摇床培养,7天后收集培养上清,0.4μm的滤膜过滤后,使用Mab sure Lx5ml纯化柱从培养上清中捕获抗体,流速设定为3ml/min,用5个柱体积的20mM PB+150mM Nacl,PH7.4平衡液平衡纯化柱,柱平衡稳定后上样,上样结束选择20mM PB+150mM Nacl,PH7.4淋洗,淋洗结束使用50mM柠檬酸PH3.0洗脱液进行洗脱,收集用1M Tris-Hcl,PH9.0中和洗脱的抗体。共制备了6种抗TIGIT人源化抗体,将其分别编号为#1-#6。抗TIGIT人源化抗体#1-#6的重链可变区和轻链可变区如表5所示。
表5.抗TIGIT人源化抗体#1-#6的重链可变区和轻链可变区
抗TIGIT人源化抗体和293T-hTIGIT细胞的结合活性
收集位于T75细胞培养瓶的293T-hTIGIT细胞,FACS缓冲液洗涤一次,用FACS缓冲液重悬计数,调整细胞浓度为2×106;稀释抗体(包括BMS TIGIT Ab和六种抗TIGIT人源化抗体,其中BMS TIGIT Ab作为对照)。取10μL稀释后的各抗体分别加入上述调整浓度后的细胞样品100μL,混匀,室温孵育1小时。
每孔加入2ml的FACS缓冲液洗涤两次,加入APC羊抗人IgG Fc二抗(Biolegend,Cat409306),孵育1小时,上流式细胞仪检测,结果见图5。图5结果表明抗TIGIT人源化抗体和对照抗体BMS TIGIT Ab均与293T-hTIGIT细胞特异性结合。
抗TIGIT人源化抗体和293T-Cyno-TIGIT细胞的结合活性
收集位于T75细胞培养瓶的293T-Cyno-TIGIT细胞,FACS缓冲液洗涤一次,用FACS缓冲液重悬计数,调整细胞浓度为2×106;稀释抗体(包括BMS TIGIT Ab和六种抗TIGIT人源化抗体,其中BMS TIGIT Ab作为对照)。取10μL稀释后的各抗体分别加入上述调整浓度后的细胞样品100μL,混匀,室温孵育1小时。
每孔加入2ml的FACS缓冲液洗涤两次,加入APC羊抗人IgG Fc二抗(Biolegend,Cat409306),孵育1小时,上流式细胞仪检测,结果见图6。图6结果表明对照抗体BMS TIGITAb与293T-Cyno-TIGIT细胞的亲和力比TIGIT人源化抗体强很多。
抗TIGIT人源化抗体和293T-hPVR细胞的结合活性
收集位于T75细胞培养瓶的293T-hPVR细胞,FACS缓冲液洗涤一次,用FACS缓冲液重悬计数,调整细胞浓度为2×106;稀释抗体(包括BMS TIGIT Ab和六种抗TIGIT人源化抗体,其中BMS TIGIT Ab作为对照)。取10μL稀释后的各抗体及500ng的TIGIT-hFc分别加入上述调整浓度后的细胞样品100μL,混匀,室温孵育1小时。
每孔加入2ml的FACS缓冲液洗涤两次,加入APC羊抗人IgG Fc二抗(Biolegend,Cat409306),孵育1小时,上流式细胞仪检测,结果见图7。图7结果表明对照抗体BMS TIGITAb与TIGIT人源化抗体都有较强的阻断能力。
实施例7.抗TIGIT人源化抗体的动物体内药效实验
MC38模型
利用小鼠结肠癌细胞系MC38在B-hTIGIT小鼠(南方模式)的皮下建立小鼠结肠癌模型,然后再给予#2抗TIGIT人源化抗体及抗PD-1抗体(BE0033-2),考察单独用药及联合用药对小鼠肿瘤的抑瘤作用。
材料与方法:
以MC38细胞为靶细胞,5e5/只的细胞量接种于B-hTIGIT小鼠右前肢皮下,待种瘤体积长到80-100mm3时,对小鼠进行量瘤、分组、给药。然后一周两次量瘤给药,记录小鼠的体重及肿瘤的长宽数据,瘤体积计算方式为:V=L*W2/2。当肿瘤长到伦理终点(2000mm3)时,对小鼠进行CO2处死,测量小鼠的瘤重、脾重和体重,并拍照。计算瘤重/体重的比例。
肿瘤体积变化如图8A所示,充分显示了联合用药的抑瘤效果,与对照组相比,抗体组具有一定的抑瘤效果且两组间具有显著性统计差异(p<0.05)。由表6可以看出,联合给药组的相对抑瘤率最高,可以达到80%。虽然给药组小鼠的体重较对照组轻(图8B),但差异并未进一步增大,说明药物对小鼠体重的影响很小,与对照组相比无显著性统计差异(p>0.05)。
另外,实验结束时,对小鼠进行解剖,测量小鼠肿瘤组织及脾脏组织的体重占比。与对照组相比,给药组肿瘤的体重占比降低,具有显著性统计学差异(p<0.05);与对照组相比,给药组脾脏的体重占比降低,具有显著性统计学差异(p<0.05),结合瘤重指数推断其与荷瘤大小呈正相关。
表6.抑瘤实验联合组的相对肿瘤抑制率(TGI%)
备注:D3表示给药后第3天,D7表示给药后第7天,依次类推。PD1+TIGIT表示抗PD-1抗体+抗TIGIT人源化抗体联合给药。
CT26模型
利用小鼠结肠癌细胞系CT26在BALB/C-hTIGIT小鼠(集萃药康)的皮下建立小鼠结肠癌模型,然后再给予#2抗TIGIT人源化抗体及抗PD-1抗体(BE0033-2),考察单独用药及联合用药对小鼠肿瘤的抑瘤作用。
以CT26细胞为靶细胞,5e5/只的细胞量接种于B-hTIGIT小鼠右前肢皮下,待种瘤体积长到80-100mm3时,对小鼠进行量瘤、分组、给药。然后一周两次量瘤给药,记录小鼠的重量及肿瘤的长宽数据,瘤体积计算方式为:V=L*W2/2。当肿瘤长到伦理终点(2000mm3)时,对小鼠进行CO2处死,测量小鼠的瘤重、脾重和体重,并拍照。计算瘤重/体重的比例。
以CT26肿瘤模型进行的抗TIGIT人源化抗体的抑瘤实验结果如图9A所示,PD1+TIGIT联合给药组的抑瘤效果要好于PD-1及TIGIT单药组,且各组之间分别具有显著性统计差异(p<0.05)。各组小鼠体重无明显差别,无显著性差异(p>0.05)。
实验结束时,对小鼠进行解剖,测量小鼠肿瘤组织及脾脏组织的体重占比,如图11。与对照组相比,给药组肿瘤的体重占比降低,无显著性统计学差异(p>0.05);与对照组相比,给药组脾脏的体重占比差异明显,具统计学差异(p<0.05)。统计相对肿瘤抑瘤率TGI(%)结果如表7所示,随着给药时间的进展,给药组的TGI逐渐增大。
表7.抑瘤实验联合组相对肿瘤抑制率(TGI%)
备注:D3表示给药后第3天,D7表示给药后第7天,依次类推。PD1表示单独给予抗PD-1抗体;TIGIT表示单独给予抗TIGIT人源化抗体;PD1+TIGIT表示抗PD-1抗体+抗TIGIT人源化抗体联合给药。
可以理解,尽管本申请以上述具体形式描述了所涉及的发明,但这些发明并不局限于这些具体形式描述的特定内容。对本领域的技术人员显而易见的是,在不偏离本申请所描述的发明精神的前提下,还可对其中所涉及的发明包含的技术特征进行各种等同变化,这些变化都应该属于所述发明的范围之内。
序列表
<110> 北京免疫方舟医药科技有限公司
<120> 抗TIGIT抗体及其应用
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Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
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Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
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Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
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Gly Thr Leu Val Thr Val Ser Ser
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Ala Phe Ser Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 16
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
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Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Thr Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
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Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Ala Phe Ser Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 17
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Arg Trp Cys Leu Leu Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala
1 5 10 15
Pro Leu Ala Ser Gly Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn
20 25 30
Ile Ser Ala Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser
35 40 45
Ser Thr Thr Ala Gln Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln
50 55 60
Leu Leu Ala Ile Cys Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser
65 70 75 80
Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln
85 90 95
Ser Leu Thr Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr
100 105 110
Tyr Pro Asp Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu
115 120 125
Ser Ser Val Ala Glu His Gly Ala Arg Phe Gln Ile Pro Leu Leu Gly
130 135 140
Ala Met Ala Ala Thr Leu Val Val Ile Cys Thr Ala Val Ile Val Val
145 150 155 160
Val Ala Leu Thr Arg Lys Lys Lys Ala Leu Arg Ile His Ser Val Glu
165 170 175
Gly Asp Leu Arg Arg Lys Ser Ala Gly Gln Glu Glu Trp Ser Pro Ser
180 185 190
Ala Pro Ser Pro Pro Gly Ser Cys Val Gln Ala Glu Ala Ala Pro Ala
195 200 205
Gly Leu Cys Gly Glu Gln Arg Gly Glu Asp Cys Ala Glu Leu His Asp
210 215 220
Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Gly Asn Cys Ser Phe Phe
225 230 235 240
Thr Glu Thr Gly
<210> 18
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Met Arg Trp Cys Leu Phe Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala
1 5 10 15
Pro Leu Ala Ser Gly Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn
20 25 30
Ile Ser Ala Lys Lys Gly Gly Ser Val Ile Leu Gln Cys His Leu Ser
35 40 45
Ser Thr Met Ala Gln Val Thr Gln Val Asn Trp Glu Gln His Asp His
50 55 60
Ser Leu Leu Ala Ile Arg Asn Ala Glu Leu Gly Trp His Ile Tyr Pro
65 70 75 80
Ala Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu
85 90 95
Gln Ser Leu Thr Met Asn Asp Thr Gly Glu Tyr Phe Cys Thr Tyr His
100 105 110
Thr Tyr Pro Asp Gly Thr Tyr Arg Gly Arg Ile Phe Leu Glu Val Leu
115 120 125
Glu Ser Ser Val Ala Glu His Ser Ala Arg Phe Gln Ile Pro Leu Leu
130 135 140
Gly Ala Met Ala Met Met Leu Val Val Ile Cys Ile Ala Val Ile Val
145 150 155 160
Val Val Val Leu Ala Arg Lys Lys Lys Ser Leu Arg Ile His Ser Val
165 170 175
Glu Ser Gly Leu Gln Arg Lys Ser Thr Gly Gln Glu Glu Gln Ile Pro
180 185 190
Ser Ala Pro Ser Pro Pro Gly Ser Cys Val Gln Ala Glu Ala Ala Pro
195 200 205
Ala Gly Leu Cys Gly Glu Gln Gln Gly Asp Asp Cys Ala Glu Leu His
210 215 220
Asp Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Gly Ser Cys Ser Phe
225 230 235 240
Phe Thr Glu Thr Gly
245
<210> 19
<211> 417
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Met Ala Arg Ala Met Ala Ala Ala Trp Pro Leu Leu Leu Val Ala Leu
1 5 10 15
Leu Val Leu Ser Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln
20 25 30
Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro
35 40 45
Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu
50 55 60
Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln
65 70 75 80
Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala
85 90 95
Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly
100 105 110
Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe
115 120 125
Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys
130 135 140
Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro
145 150 155 160
Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln
165 170 175
Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val
180 185 190
Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu
195 200 205
Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu
210 215 220
His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val
225 230 235 240
Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr
245 250 255
Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro
260 265 270
Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro
275 280 285
Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys
290 295 300
Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala
305 310 315 320
Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu
325 330 335
His Ser Gly Met Ser Arg Asn Ala Ile Ile Phe Leu Val Leu Gly Ile
340 345 350
Leu Val Phe Leu Ile Leu Leu Gly Ile Gly Ile Tyr Phe Tyr Trp Ser
355 360 365
Lys Cys Ser Arg Glu Val Leu Trp His Cys His Leu Cys Pro Ser Ser
370 375 380
Thr Glu His Ala Ser Ala Ser Ala Asn Gly His Val Ser Tyr Ser Ala
385 390 395 400
Val Ser Arg Glu Asn Ser Ser Ser Gln Asp Pro Gln Thr Glu Gly Thr
405 410 415
Arg
Claims (12)
1.特异性结合TIGIT的抗体或其抗原结合部分,其包含重链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3序列中的任意一项或多项,其中所述HCDR1序列为GFTFSNYW(SEQ IDNO:1),所述HCDR2序列为IRLKSNNYAT(SEQ ID NO:2),所述HCDR3序列为ARLYYGNYFDY(SEQID NO:3)或TRLYYGNYFDY(SEQ ID NO:4),优选地,所述抗原结合部分选自:Fab片段、Fab’片段、F(ab’)2片段、Fv片段、scFv片段、Fd片段或单域抗体。
2.如权利要求1所述的抗体或其抗原结合部分,其还包含轻链可变区,所述轻链可变区包含LCDR1、LCDR2和LCDR3序列中的任意一项或多项,其中所述LCDR1序列为ENTYSY(SEQ IDNO:5),所述LCDR2序列为NAK(SEQ ID NO:6),所述LCDR3序列为QHHYAFSYT(SEQ ID NO:7)。
3.如权利要求1或2所述的抗体或其抗原结合部分,其中所述抗体为鼠源抗体,任选地,所述重链可变区的氨基酸序列如SEQ ID NO:8所示,和/或所述轻链可变区的氨基酸序列如SEQ ID NO:9所示,任选地,其中所述抗体为嵌合抗体,任选地,所述嵌合抗体包含氨基酸序列如SEQ ID NO:10所示的重链,和/或氨基酸序列如SEQ ID NO:11所示的轻链,任选地,其中所述抗体为人源化抗体,任选地,所述重链可变区的氨基酸序列如SEQ ID NO:12或者SEQID NO:13所示,和/或所述轻链可变区的氨基酸序列如SEQ ID NO:14、SEQ ID NO:15或者SEQ ID NO:16所示。
4.如前述权利要求中的任一项所述的抗体或其抗原结合部分,所述抗体或其抗原结合部分特异性结合于灵长类TIGIT,优选地,所述灵长类TIGIT选自人TIGIT或猴TIGIT,任选地,所述抗体或其抗原结合部分以1×10-10至1×10-9M的KD特异性结合TIGIT分子,优选地,所述抗体具有PVR抑制剂功能,刺激T细胞的活化及增殖。
5.药物组合物,其包含权利要求1-4中任一项所述的抗体或其抗原结合部分以及药学上可接受的载体,
任选地,所述药物组合物还包含一种或多种其他活性成分,如化疗剂和/或PD-1结合拮抗剂。
6.疫苗,其包含权利要求1-4中任一项所述的抗体或其抗原结合部分,以及任选的免疫佐剂。
7.核酸分子,其编码权利要求1-4中任一项所述的抗体或其抗原结合部分。
8.表达载体,其包含权利要求7所述的核酸分子。
9.宿主细胞,其包含权利要求7所述的核酸分子或权利要求8所述的表达载体。
10.权利要求1-4中任一项所述的抗体或其抗原结合部分、权利要求5所述的药物组合物、权利要求6所述的疫苗、权利要求7所述的核酸分子、权利要求8所述的表达载体或权利要求9所述的宿主细胞在制备用于抑制Treg功能、阻断PVR与TIGIT结合、促进T细胞活化、引发T细胞介导的反应、提高效应T细胞的功能、提高记忆T细胞的功能、和/或抑制肿瘤生长的药物中的用途。
11.权利要求1-4中任一项所述的抗体或其抗原结合部分、权利要求5所述的药物组合物、权利要求6所述的疫苗、权利要求7所述的核酸分子、权利要求8所述的表达载体或权利要求9所述的宿主细胞在制备用于预防和/或治疗TIGIT相关的疾病的药物中的用途,任选地,所述疾病为肿瘤,任选地,所述肿瘤选自以下中的一种或多种:结肠癌、黑色素瘤、间皮质瘤、肾细胞癌、淋巴瘤、晚期实体瘤以及上述的转移瘤。
12.检测试剂或试剂盒,其包含权利要求1-4中任一项所述的抗体或其抗原结合部分。
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