CN112154155A - 抗tigit抗体及其用途 - Google Patents
抗tigit抗体及其用途 Download PDFInfo
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- CN112154155A CN112154155A CN201980016227.6A CN201980016227A CN112154155A CN 112154155 A CN112154155 A CN 112154155A CN 201980016227 A CN201980016227 A CN 201980016227A CN 112154155 A CN112154155 A CN 112154155A
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Abstract
本文公开了特异性地结合肿瘤免疫抑制剂TIGIT(T细胞免疫球蛋白和基于免疫受体酪氨酸的抑制基序[ITIM]结构域)的新型抗体或其抗原结合片段、编码所述抗体或其抗原结合片段的核酸、包括所述核酸的载体和宿主细胞、用于产生所述抗体或其抗原结合片段的方法、含有所述抗体或其抗原结合片段作为活性成分的药物组合物、以及所述药物组合物的用途。与TIGIT特异性地结合的所述抗体或其抗原结合片段和含有所述抗体或其抗原结合片段作为活性成分的所述药物组合物优选用于癌症或肿瘤的治疗。
Description
技术领域
本发明涉及特异性地结合肿瘤免疫抑制剂TIGIT(T细胞免疫球蛋白和基于免疫受体酪氨酸的抑制基序[ITIM]结构域)的新型抗体或其抗原结合片段、编码所述抗体或其抗原结合片段的核酸、包括所述核酸的载体和宿主细胞、用于产生所述抗体或其抗原结合片段的方法、含有所述抗体或其抗原结合片段作为活性成分的药物组合物、以及所述药物组合物的用途。
优选将所述特异性地结合TIGIT的抗体或其抗原结合片段和含有所述抗体或其抗原结合片段作为活性成分的药物组合物用于治疗癌症或肿瘤,但本发明不限于此。
背景技术
人免疫***的功能是通过攻击从外部进入的病原体或病毒(抗原)以及异常细胞(如癌细胞)来保护人体。即,人免疫***的主要功能是区分体内的正常细胞与外部侵袭者、异常细胞(如癌细胞),并且确定是否攻击所述细胞。人免疫***中可以区分癌细胞的代表性免疫细胞是T细胞,并且尽管癌细胞会在体内生长,但健康的人可以通过免疫应答有效杀伤癌细胞。因此,癌症的进展意味着免疫***异常。
人免疫***具有免疫检测***以抑制由T细胞过度增殖引起的超免疫应答。这样的免疫检测***被称为“免疫检查点”,并且免疫检查点中涉及的蛋白质被称为“免疫检查点蛋白”。
本质上,免疫检查点的功能是抑制因T细胞的超激活和/或过度增殖引起的超免疫应答,但是癌细胞滥用免疫检查点来防止T细胞攻击癌细胞,最终导致癌症的进展。
在本领域中已知,可以使用这种免疫检查点的抑制剂来治疗如癌症的疾病。当前,靶向免疫检查点蛋白的抗体药物是可商购获得的,并且各种免疫检查点抑制剂正在开发中。
第一个开发的免疫检查点抑制剂型治疗剂是伊匹单抗(ipilimumab),其是对免疫检查点受体CTLA-4(细胞毒性T淋巴细胞相关抗原-4)具有特异性的单克隆抗体,并且显示对转移性恶性黑色素瘤有效。随后,已经开发了对PD-1(程序性细胞死亡-1)和作为PD-1的配体的PD-L1(程序性死亡配体-1)具有特异性的单克隆抗体。其代表性例子包括纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、阿维鲁单抗(avelumab)、阿特珠单抗(atezolizumab)和德瓦鲁单抗(durvalumab)。PD-1或PD-L1抑制剂在恶性黑色素瘤以及多种肿瘤中有效。
TIGIT(T细胞免疫球蛋白和基于免疫受体酪氨酸的抑制基序[ITIM]结构域)是主要在激活的T细胞和NK(自然杀伤)细胞中表达的受体,并且在广义地上包括在免疫检查点蛋白中。
TIGIT与癌细胞表面上的配体(如CD155和CD112)结合以抑制免疫细胞的激活。已报道,靶向TIGIT的抗体诱导CD8+T细胞连同PD-1/PD-L1阻断抗体的激活,从而有效去除肿瘤或病毒。
迄今为止,已经报道了若干种抗TIGIT抗体(如US 9,713,641B、US 2016/0176963A、US 9,499,596B),但是对其具体机理的研究不足,并且还没有开发出具有实际上可用于治疗剂的功效的抗体。因此,对具有高功效的TIGIT特异性抗体还存在日益增加的需求。
因此,作为大力开发特异性地结合TIGIT的新型抗体的结果,本发明人发明了对癌细胞中过表达的TIGIT具有高亲和力的新型抗TIGIT抗体,并且鉴定了根据本发明的抗体或抗原结合片段作为高效的抗癌药物的潜在可能性,从而完成了本发明。
现有技术文献
美国专利号9,713,641(2017年7月25日)。
美国公开号2016/0176963(2016年6月23日)。
美国专利号9,499,596(2016年11月22日)。
发明内容
技术问题
因此,本发明的一个目的是提供特异性地结合TIGIT的新型抗TIGIT抗体或其抗原结合片段。
本发明的另一个目的是提供药物组合物,特别是用于免疫抗癌药物(免疫肿瘤药物)的药物组合物,所述药物组合物含有所述抗TIGIT抗体或其抗原结合片段作为活性成分。
本发明的另一个目的是提供用于治疗癌症或肿瘤的方法,所述方法包括给予所述抗TIGIT抗体或其抗原结合片段;所述抗TIGIT抗体或其抗原结合片段用于治疗癌症或肿瘤的用途;以及所述抗TIGIT抗体或其抗原结合片段用于制备用于治疗癌症或肿瘤的药物的用途。
本发明的另一个目的是提供用于治疗癌症或肿瘤的用于共给予的组合物,所述组合物含有所述抗TIGIT抗体或其抗原结合片段、和其他癌症治疗剂。
本发明的另一个目的是提供编码所述抗TIGIT抗体或其抗原结合片段的核酸、含有所述核酸的载体和宿主细胞、以及用于使用所述载体和宿主细胞产生抗TIGIT抗体或其抗原结合片段的方法。
问题的解决方案
根据本发明,上述和其他目的可以通过提供如下抗TIGIT抗体或其抗原结合片段来实现,所述抗TIGIT抗体或其抗原结合片段包括:重链可变区,所述重链可变区包括包含SEQ ID NO:1或2中所示的氨基酸序列的重链CDR1、包含SEQ ID NO:3或4中所示的氨基酸序列的重链CDR2、和包含SEQ ID NO:5或6中所示的氨基酸序列的重链CDR3;和轻链可变区,所述轻链可变区包括包含SEQ ID NO:7或8中所示的氨基酸序列的轻链CDR1、包含SEQ ID NO:9或10中所示的氨基酸序列的轻链CDR2、和包含SEQ ID NO:11或12中所示的氨基酸序列的轻链CDR3。
所述抗TIGIT抗体或其抗原结合片段可以包括包含SEQ ID NO:13或14中所示的氨基酸序列的重链可变区和包含SEQ ID NO:15或16中所示的氨基酸序列的轻链可变区。
附图说明
从以下详细描述结合附图将更清楚地理解本发明的上述和其他目的、特征和其他优点,在所述附图中:
图1示出了鉴定抗TIGIT抗体与人、小鼠和恒河猴TIGIT抗原的结合以便确定最初筛选的抗TIGIT抗体的物种交叉反应性的ELISA的结果;
图2是示出了鉴定抗TIGIT抗体与TIGIT、CD96、CD155、CD112、CD113和CD226的结合以便确定最初选择的抗TIGIT抗体的TIGIT超家族的特异性的ELISA的结果的图;
图3示出了使用荧光流式细胞仪进行测量以便鉴定最初选择的抗TIGIT抗体与细胞表面上表达的TIGIT抗原的结合的结果;
图4示出了使用荧光流式细胞仪测量抗TIGIT抗体与细胞表面上的TIGIT蛋白的结合程度的结果;
图5示出了鉴定通过用抗TIGIT抗体处理抑制TIGIT与CD155之间的结合的程度的阻断测定的结果;
图6示出了在过表达TIGIT的NK92细胞系和过表达PVR的HeLa细胞系的共培养物中,根据用抗TIGIT抗体的处理,从NK92细胞系分泌的IFN-g的量;
图7示出了在共培养过表达TIGIT的NK92细胞系和过表达PVR的HeLa细胞系的条件下,使用荧光流式细胞仪测量用抗TIGIT抗体处理的NK92细胞系中NKG2D表达的结果;
图8是示出了在评价根据一个实施方案的抗TIGIT抗体的体内功效的测试的最后一天的肿瘤体积并示出了指示在CT26肿瘤模型中的功效的结果的图;并且
图9是示出了在评价根据一个实施方案的抗TIGIT抗体在单独给予和与抗PD-L1抗体组合给予时在每种体内剂量下的功效的测试的最后一天的肿瘤体积并且示出了指示在CT26肿瘤模型中的功效的结果的图。
具体实施方式
除非另外定义,否则本文所用的全部技术和科学术语具有与本发明所属领域的技术人员所理解的意义相同的意义。一般而言,本文所用术语在本领域中是公知的并且常常使用。
一方面,本发明涉及抗TIGIT抗体或其抗原结合片段,所述抗TIGIT抗体或其抗原结合片段包括:
重链可变区,所述重链可变区包括:
重链CDR1,其包含SEQ ID NO:1或2中所示的氨基酸序列;
重链CDR2,其包含SEQ ID NO:3或4中所示的氨基酸序列;以及
重链CDR3,其包含SEQ ID NO:5或6中所示的氨基酸序列;以及
轻链可变区,所述轻链可变区包括:
轻链CDR1,其包含SEQ ID NO:7或8中所示的氨基酸序列;
轻链CDR2,其包含SEQ ID NO:9或10中所示的氨基酸序列;以及
轻链CDR3,其包含SEQ ID NO:11或12中所示的氨基酸序列。
此外,根据本发明的抗TIGIT抗体或其抗原结合片段包括:包含SEQ ID NO:13或14中所示的氨基酸序列的重链可变区;和包含SEQ ID NO:15或16中所示的氨基酸序列的轻链可变区。
优选地,根据本发明的抗TIGIT抗体或其抗原结合片段包括:
(1)重链可变区,其包括包含SEQ ID NO:1中所示的氨基酸序列的重链CDR1;包含SEQ ID NO:3中所示的氨基酸序列的重链CDR2;和包含SEQ ID NO:5中所示的氨基酸序列的重链CDR3;以及
轻链可变区,其包括包含SEQ ID NO:7中所示的氨基酸序列的轻链CDR1;包含SEQID NO:9中所示的氨基酸序列的轻链CDR2;和包含SEQ ID NO:11中所示的氨基酸序列的轻链CDR3;或
(2)重链可变区,其包括包含SEQ ID NO:2中所示的氨基酸序列的重链CDR1;包含SEQ ID NO:4中所示的氨基酸序列的重链CDR2;和包含SEQ ID NO:6中所示的氨基酸序列的重链CDR3;以及
轻链可变区,其包括包含SEQ ID NO:8中所示的氨基酸序列的轻链CDR1;包含SEQID NO:10中所示的氨基酸序列的轻链CDR2;和包含SEQ ID NO:12中所示的氨基酸序列的轻链CDR3;或
(3)重链可变区,其包含SEQ ID NO:13中所示的氨基酸序列;以及
轻链可变区,其包含SEQ ID NO:15中所示的氨基酸序列;或
(4)重链可变区,其包含SEQ ID NO:14中所示的氨基酸序列;以及
轻链可变区,其包含SEQ ID NO:16中所示的氨基酸序列。
在免疫细胞(如T细胞、NK细胞和树突细胞)表面上表达的TIGIT与癌细胞表面上的PVR(脊髓灰质炎病毒受体,CD155)结合以抑制免疫细胞的活性。根据本发明的抗TIGIT抗体或其抗原结合片段特异性地结合TIGIT的CD155结合位点,并且抑制通过TIGIT/CD155相互作用进行的信号传递以诱导免疫细胞的激活并抑制肿瘤细胞的生长。CD155在各种哺乳动物(如人、猴、小鼠和大鼠)的细胞表面上表达,并且通过结合TIGIT来传递抑制免疫细胞激活的信号。
即,根据本发明的抗TIGIT抗体或其抗原结合片段抑制通过TIGIT/CD155相互作用进行的信号传递,以抵消癌细胞对免疫细胞的抑制信号,从而诱导免疫应答的重新激活以有效攻击癌细胞并由此提供抗癌作用。最终,所述抗TIGIT抗体或其抗原结合片段可用于靶向TIGIT的免疫抗癌疗法,即肿瘤免疫抑制剂。具体地,根据本发明的抗TIGIT抗体或其抗原结合片段在患有癌症的受试者中降低或抑制TIGIT的表达或活性,并且诱导T细胞或NK细胞的持续抗癌应答,从而提供治疗癌症的作用。
充当根据本发明的抗TIGIT抗体或其抗原结合片段的抗原的TIGIT蛋白与免疫细胞活性的抑制密切相关,是存在于免疫细胞表面上的膜蛋白,并且用作免疫细胞的亚抑制受体。TIGIT可以源自哺乳动物,如包括人和猴的灵长类动物,以及包括小鼠和大鼠的啮齿动物。
如本文所用,术语“TIGIT”是由细胞天然表达的TIGIT的任何变体、亚型或物种同源物的通用名称,优选是人TIGIT,但是本发明不限于此并且包括其他动物的TIGIT等。
根据本发明的抗TIGIT抗体优选地特异性结合人TIGIT(hTIGIT;SEQ ID NO:21;NCBI登录号NP_776160)的CD155结合位点或CD155结合-抑制位点,但本发明不限于此。
根据本发明的抗TIGIT抗体或其抗原结合片段的重链CDR和轻链CDR的氨基酸序列和可变区序列如表1至表4中所示。
[表1]
根据本发明的抗TIGIT抗体的重链CDR的氨基酸序列
[表2]
根据本发明的抗TIGIT抗体的轻链CDR的氨基酸序列
[表3]
根据本发明的抗TIGIT抗体的重链可变区的氨基酸序列(CDR区带下划线)
[表4]
根据本发明的抗TIGIT抗体的轻链可变区的氨基酸序列(CDR区带下划线)
同时,根据本发明的抗TIGIT抗体或其抗原结合片段包括具有与以下中的每一个的80%或更高、优选90%或更高、更优选99%或更高的序列同一性的重链可变区:包含SEQID NO:1或2中所示的氨基酸序列的重链CDR1;包含SEQ ID NO:3或4中所示的氨基酸序列的重链CDR2;和包含SEQ ID NO:5或6中所示的氨基酸序列的重链CDR3,并且具有与根据本发明的TIGIT相同的特征的抗体或其抗原结合片段也落入根据本发明的抗TIGIT抗体或其抗原结合片段的范围内。
根据本发明的抗TIGIT抗体或其抗原结合片段包括具有与包含SEQ ID NO:13或14中所示的氨基酸序列的重链可变区的80%或更高、优选90%或更高、更优选99%或更高的序列同一性的重链可变区,并且具有与根据本发明的TIGIT相同的特征的抗体或其抗原结合片段也落入根据本发明的抗TIGIT抗体或其抗原结合片段的范围内。
此外,根据本发明的抗TIGIT抗体或其抗原结合片段包括具有与以下中的每一个的80%或更高、优选90%或更高、更优选99%或更高的序列同一性的轻链可变区:包括包含SEQ ID NO:7或8中所示的氨基酸序列的轻链CDR1;包含SEQ ID NO:9或10中所示的氨基酸序列的轻链CDR2;和包含SEQ ID NO:11或12中所示的氨基酸序列的轻链CDR3的轻链可变区,并且具有与根据本发明的TIGIT相同的特征的抗体或其抗原结合片段也落入根据本发明的抗TIGIT抗体或其抗原结合片段的范围内。
另外,所述抗TIGIT抗体或其抗原结合片段包括具有与包含SEQ ID NO:15或16中所示的氨基酸序列的轻链可变区中的每一个的80%或更高、优选90%或更高、更优选99%或更高的序列同一性的轻链可变区,并且具有与根据本发明的TIGIT相同的特征的抗体或其抗原结合片段也落入根据本发明的抗TIGIT抗体或其抗原结合片段的范围内。
此外,根据本发明的抗TIGIT抗体或其抗原结合片段还可以包括如下抗体或其抗原结合片段,其中所述抗TIGIT抗体或其抗原结合片段的氨基酸序列的一部分通过保守取代被取代。
如本文所用,术语“保守取代”是指多肽的修饰,所述修饰包括用具有相似的生物或生化特性但不会引起所述多肽的生物或生化功能损失的一个或多个氨基酸取代一个或多个氨基酸。术语“保守氨基酸取代”是指用具有相似侧链的氨基酸残基置换氨基酸残基的取代。具有相似侧链的氨基酸残基的种类是本领域中已定义且熟知的。此类种类包括具有碱性侧链的氨基酸(例如赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(例如天冬氨酸、谷氨酸)、具有不带电荷的极性侧链的氨基酸(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、具有非极性侧链的氨基酸(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、具有β-分支侧链的氨基酸(例如苏氨酸、缬氨酸、异亮氨酸)以及具有芳香族侧链的氨基酸(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。认为根据本发明的抗体具有保守氨基酸取代并且仍然保留活性。
如本文所用,术语“TIGIT特异性抗体”是指与TIGIT结合以抑制TIGIT的生物活性的抗体,其与“抗TIGIT抗体”可互换使用。
如本文所用,术语“抗TIGIT抗体”包括多克隆抗体和单克隆抗体两者,优选是单克隆抗体并且可以具有全抗体。全抗体是具有两条全长轻链和两条全长重链,并包括恒定区的结构,其中每条轻链通过二硫键与相应的重链连接。
根据本发明的抗TIGIT抗体的全抗体包括IgA、IgD、IgE、IgM和IgG形式,并且IgG包括亚型IgG1、IgG2、IgG3和IgG4。
根据本发明的抗TIGIT抗体优选是从人抗体文库中筛选的完全人抗体,但是本发明不限于此。
如本文所用,术语抗TIGIT抗体的“抗原结合片段”是指具有能够结合抗TIGIT抗体的抗原即TIGIT的功能的片段,并且涵盖Fab、Fab'、F(ab')2、scFv、(scFv)2、scFv-Fc、Fv等,所述术语与“抗体片段”可互换使用。
Fab包括重链和轻链各自的可变区、轻链的恒定区以及重链的第一恒定区(CH1结构域),每个Fab具有抗原结合位点。Fab'与Fab的不同之处在于,其进一步具有铰链区,所述铰链区包括重链CH1结构域C末端的至少一个半胱氨酸残基。F(ab')2是通过Fab'铰链区中的半胱氨酸残基之间的二硫键形成的。
包括重链和轻链各自的可变区的Fv(可变片段)是具有亲本免疫球蛋白的原始特异性的最小抗体片段。双链Fv(dsFv,二硫键稳定的Fv)是通过经由二硫键将轻链的可变区与重链的可变区结合而形成。单链Fv(scFv)是其中重链和轻链各自的可变区经由肽接头共价连接的Fv。这些抗体片段可以通过用蛋白酶处理全抗体来获得(例如,Fab可以通过用木瓜蛋白酶对全抗体进行限制性裂解而获得,并且F(ab')2片段可以通过用胃蛋白酶对全抗体进行限制性切割而获得),并且优选通过遗传重组技术来构建(例如,通过使用一对引物通过PCR(聚合酶链反应)扩增作为模板的编码抗体重链或其可变区的DNA或编码轻链或其可变区的DNA,并且使用一对引物的组合进行扩增以将编码肽接头的DNA及其两个末端中的每一个连接至重链或其可变区和轻链或其可变区)。
另一方面,本发明涉及编码根据本发明的抗TIGIT抗体的核酸。如本文所用,核酸可以存在于细胞或细胞裂解物中,或者以部分纯化的形式或按基本上纯的形式存在。当通过包括例如碱/SDS处理、CsCl显带、柱色谱、琼脂糖凝胶电泳和本领域熟知的其他技术的标准技术从其他细胞组分或其他污染物(例如其他细胞的核酸或蛋白质)中纯化时,核酸可以是“分离的”或“基本上纯的”。本发明的核酸可以是例如DNA或RNA,并且可以包括或可以不包括内含子序列。
另一方面,本发明涉及含有核酸的载体。对于根据本发明的抗TIGIT抗体或其抗原结合片段的表达,通过标准分子生物学技术(例如,使用表达靶抗体的杂交瘤进行PCR扩增或cDNA克隆)获得编码部分或全长轻链或重链的DNA,并且可以将DNA“可操作地结合”至有待***表达载体中的转录和翻译控制序列。
如本文所用,术语“可操作地结合”可以指示,将编码抗体的基因连接到载体中,使得转录和翻译控制序列可以起到调节抗体基因的转录和翻译的预期功能。
选择与用于表达的宿主细胞相容的表达载体和表达控制序列。将抗体的轻链基因和抗体的重链基因***分开的载体中,或将两种基因***同一个表达载体中。通过标准方法将抗体***表达载体中(例如,将抗体基因片段与载体上的互补限制性酶位点连接,或在没有限制性酶位点时进行平端连接)。在一些情况下,重组表达载体可以编码促进宿主细胞分泌抗体链的信号肽。可以将抗体链基因克隆到载体中,使得信号肽根据框架附接至抗体链基因的氨基末端。信号肽可以是免疫球蛋白信号肽或异源信号肽(即,源自除了免疫球蛋白以外的蛋白质的信号肽)。此外,重组表达载体具有调节序列,所述调节序列控制抗体链基因在宿主细胞中的表达。“调节序列”可以包括控制抗体链基因的转录或翻译的启动子、增强子、和其他表达控制元件(例如,聚腺苷酸化信号)。本领域技术人员应理解,表达载体的设计可以通过根据多种因素选择不同的调节序列而改变,所述因素如待转化的宿主细胞的选择和蛋白质表达的水平。
另一方面,本发明涉及含有核酸或载体的宿主细胞。根据本发明的宿主细胞优选选自动物细胞、植物细胞、酵母、大肠杆菌(Escherichia coli)和昆虫细胞,但本发明不限于此。
更具体地,根据本发明的宿主细胞可以是原核细胞,如大肠杆菌、枯草芽孢杆菌(Bacillus subtilis)、链霉菌属物种(Streptomyces sp.)、假单胞菌属物种(Pseudomonassp.)、奇异变形杆菌(Proteus mirabilis)或葡萄球菌属物种(Staphylococcus sp.)。此外,宿主细胞可以选自真菌(如曲霉属物种(Aspergillus sp.))、酵母(如巴斯德毕赤酵母(Pichia pastoris)、酿酒酵母(Saccharomyces cerevisiae)、裂殖酵母属物种(Schizosaccharomyces sp.)、或粗糙脉孢菌(Neurospora crassa))和其他真核细胞(包括低等真核细胞、和源自昆虫的高等真核细胞)。
宿主细胞也可以源自植物或哺乳动物。优选地,宿主细胞选自猴肾细胞(COS7)、NSO细胞、SP2/0、中国仓鼠卵巢(CHO)细胞、W138、幼仓鼠肾(BHK)细胞、MDCK、骨髓瘤细胞系、HuT 78细胞和HEK293细胞,但本发明不限于此。特别优选地,使用CHO细胞。
核酸或载体被转化或转染到宿主细胞中。通常用于将外来核酸(DNA或RNA)引入原核或真核宿主细胞以进行“转化”或“转染”的各种技术包括电泳、磷酸钙沉淀、DEAE-葡聚糖转染、脂转染等。各种表达宿主/载体组合可以用于表达根据本发明的抗TIGIT抗体。用于真核宿主的合适的表达载体包括但不限于源自SV40、牛***瘤病毒、腺病毒、腺相关病毒、巨细胞病毒和逆转录病毒的表达调节序列。用于细菌宿主的表达载体包括源自大肠杆菌的细菌质粒(如pET、pRSET、pBluescript、pGEX2T、pUC载体、col E1、pCR1、pBR322、pMB9及其衍生物)、具有较宽宿主范围的质粒(如RP4)、可以由多种噬菌体λ衍生物(如λgt10、λgt11和NM989)例示的噬菌体DNA、以及其他DNA噬菌体(如M13和丝状单链的DNA噬菌体)。可用于酵母细胞的表达载体是2℃质粒及其衍生物。可用于昆虫细胞的载体是pVL941。
另一方面,本发明涉及用于产生根据本发明的抗TIGIT抗体或其抗原结合片段的方法,所述方法包括培养宿主细胞以表达根据本发明的抗TIGIT抗体或其抗原结合片段。
当将能够表达抗TIGIT抗体或其抗原结合片段的重组表达载体引入哺乳动物宿主细胞中时,可以通过以下方式产生抗体:孵育足够长的时间段以允许所述抗体在宿主细胞中表达,更优选地孵育足够长的时间段以允许所述抗体分泌到培养基中。
在一些情况下,可以将表达的抗体与宿主细胞分离并纯化至同质。抗体的分离或纯化可以通过通常用于蛋白质的分离和纯化方法(例如色谱法)进行。色谱法可以包括例如包括蛋白A柱和蛋白G柱的亲和色谱、离子交换色谱或疏水色谱。除色谱法之外,还可以通过过滤、超滤、盐析、透析等的组合来分离和纯化抗体。
另一方面,本发明涉及用于治疗癌症或肿瘤的药物组合物,所述药物组合物含有抗TIGIT抗体或其抗原结合片段作为活性成分。
另一方面,本发明涉及用于治疗癌症或肿瘤的方法,所述方法包括将抗TIGIT抗体或其抗原结合片段给予至需要预防或治疗的患者。
另一方面,本发明涉及抗TIGIT抗体或其抗原结合片段用于治疗癌症或肿瘤的用途。
另一方面,本发明涉及抗TIGIT抗体或其抗原结合片段用于制备用于治疗癌症或肿瘤的药物的用途。
术语“癌症”或“肿瘤”是指或意指哺乳动物的通常以不受控制的细胞生长/增殖为特征的生理病症。
可以通过本发明的组合物治疗的癌症或癌瘤不受特别限制,并且包括实体癌和血液癌二者。这样的癌症的例子包括皮肤癌(例如黑色素瘤)、肝癌、肝细胞癌、胃癌、乳腺癌、肺癌、卵巢癌、支气管癌、鼻咽癌、喉癌、胰腺癌、膀胱癌、结直肠癌、结肠癌、***、脑癌、***癌、骨癌、甲状腺癌、甲状旁腺癌、肾癌、食道癌、胆管癌、睾丸癌、直肠癌、头颈癌、***、输尿管癌、骨肉瘤、神经母细胞瘤、纤维肉瘤、横纹肌肉瘤、星形细胞瘤、神经母细胞瘤、和神经胶质瘤,但不限于此。优选地,可以通过本发明的组合物治疗的癌症选自结肠癌、乳腺癌、肺癌和肾癌。
本发明提供了药物组合物,其含有治疗有效量的抗TIGIT抗体或其抗原结合片段、和药学上可接受的载体。术语“药学上可接受的载体”是指可以添加至活性成分中以帮助配制或稳定配制品,并且不会对患者产生显著有害毒性作用的物质。
载体是指不刺激患者并且不干扰所给予化合物的生物活性和特性的载体或稀释剂。可接受用于将组合物配制为液体溶液的药物载体包括无菌的生物相容性成分,并且其例子包括盐水、无菌水、林格溶液(Ringer's solution)、缓冲盐水、白蛋白注射溶液、右旋糖溶液、麦芽糊精溶液、甘油、乙醇及其混合物。如果需要,可添加其他常规添加剂,如抗氧化剂、缓冲剂和抑菌剂。另外,可另外添加稀释剂、分散剂、表面活性剂、粘合剂和润滑剂,以配制可注射溶液(如水性溶液、悬浮液和乳液)、丸剂、胶囊、颗粒剂或片剂。其他载体例如描述于[Remington's Pharmaceutical Sciences(E.W.Martin)]中。这样的组合物可以含有治疗有效量的至少一种抗TIGIT抗体或其抗原结合片段。
药学上可接受的载体包括无菌水性溶液或分散液、以及用于制备临时应用的无菌可注射溶液或分散液的无菌粉末。此类介质和试剂用于医药活性成分的使用在本领域中是熟知的。优选地将组合物配制用于肠胃外注射。组合物可被配制成溶液、微乳液、脂质体或适合高药物浓度的其他有序结构。载体可以是例如含有水、乙醇、多元醇(如甘油、丙二醇和液体聚乙二醇)及其合适混合物的溶剂或分散介质。在一些情况下,组合物可包含等渗剂,例如糖、多元醇(如甘露醇、山梨醇)或氯化钠。无菌可注射溶液可通过以下方式来制备:将所需量的活性成分任选地连同上述成分中的一种或组合掺入适当的溶剂中,然后进行无菌微滤。一般而言,分散体是通过将活性化合物掺入含有基本分散介质和选自上述那些的其他所需成分的无菌媒介物中来制备的。在用于制备无菌可注射溶液的无菌粉末的情况下,一些制备方法涉及真空干燥和冷冻干燥(冻干),以由其预先灭菌和过滤的溶液产生活性成分和任何另外的所需成分的粉末。
根据本发明的药物组合物的剂量不受特别限制,但是根据各种因素而改变,所述因素包括患者的健康状况和体重、疾病严重程度、药物类型、给予途径和给予时间。根据本发明的药物组合物可以通过通常可接受的途径以一天单次或多次剂量给予至哺乳动物(如大鼠、小鼠、家畜和人),所述可接受的途径包括但不限于腹膜内给予、静脉内给予、肌内给予、皮下给予、皮内给予、口服给予、局部给予、鼻内给予、肺内给予或直肠内给予。
如果需要,根据本发明的药物组合物可以以推注的形式或通过连续注射给予至患者。例如,呈现为Fab片段的根据本发明的抗TIGIT抗体或其抗原结合片段的推注给予可以以0.01μg/kg体重至100mg/kg体重、优选1μg/kg体重至10mg/kg体重的剂量给予。
如本文所用,术语“治疗有效量”意指抗TIGIT抗体或其抗原结合片段的组合在需要治疗的患者体内引起可测量的益处所需的量。确切的量将取决于许多因素(包括但不限于治疗性组合物的成分和物理特性、预期患者的群体和相应患者的考虑因素),并且可以由本领域技术人员容易地确定。当充分考虑这些因素时,重要的是给予足以实现最大效果而不会引起不良影响的最小剂量,并且该剂量可以由本领域的专家容易地确定。
另一方面,本发明涉及用于通过以下方式来治疗癌症并抑制癌症生长的方法:向需要治疗的受试者给予抗TIGIT抗体或其抗原结合片段或含有所述抗TIGIT抗体或其抗原结合片段的药物组合物。
根据本发明的抗TIGIT抗体或其抗原结合片段或含有所述抗TIGIT抗体或其抗原结合片段的药物组合物可以以治疗癌细胞或其转移、或抑制癌症的生长的药学有效量给予。
药学有效量可以取决于癌症的类型、患者的年龄和体重、症状的性质和严重程度、当前治疗的类型、治疗次数、给予形式和给予途径,并且可以由本领域技术人员容易地确定。本发明的组合物可以与前述药理学或生理学成分同时或依序给予,并且可以与常规治疗剂组合给予,并且可以与常规治疗剂依序或同时给予。这样的给予可以是单次或多次给予。重要的是,考虑到以上所有因素,以能够实现最大效果而不会引起副作用的最小量给予,并且这可以由本领域技术人员容易地确定。
如本文所用,术语“受试者”旨在意指哺乳动物,优选人,其罹患或易患可通过给予抗TIGIT抗体或其抗原结合片段或含有所述抗TIGIT抗体或其抗原结合片段的药物组合物来减轻、抑制或治疗的病症或疾病。
根据本发明的抗TIGIT抗体或其抗原结合片段以及含有所述抗TIGIT抗体或其抗原结合片段的药物组合物可以与常规治疗剂组合使用。
因此,另一方面,本发明涉及用于治疗癌症或肿瘤的用于共给予的组合物和用于使用所述组合物治疗癌症或肿瘤的方法,所述组合物含有抗TIGIT抗体或其抗原结合片段、和其他癌症治疗剂。
其他癌症治疗剂意指除了根据本发明的抗TIGIT抗体或其抗原结合片段之外,可用于治疗癌症的任何治疗剂。
在本发明中,癌症治疗剂可以是免疫检查点抑制剂,但本发明不限于此。
在本发明中,免疫检查点抑制剂也称为“检查点抑制剂”,并且可以是抗CTLA-4抗体、抗PD-1抗体或抗PD-L1抗体,但本发明并不限于此。具体地,免疫检查点抑制剂可以是伊匹单抗、纳武单抗、派姆单抗、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗等,但本发明不限于此。
术语“组合使用(共给予)”意指抗TIGIT抗体或其抗原结合片段和每种其他癌症治疗剂可以同时、依序或以相反顺序给予,并且可以以在本领域技术人员可以设想的范围内的适当有效量的组合给予。
在本发明的一个实施方案中,确认了抗PD-L1抗体和根据本发明的抗TIGIT抗体的组合给予(共给予)进一步抑制了肿瘤的生长。
用于共给予的组合物包含抗TIGIT抗体,并且与之相关的配置与如上所述的用于预防或治疗癌症的组合物中所包含的那些配置相同,使得每种配置的描述同样适用于用于共给予的组合物。
一方面,本发明提供了包括与根据本发明的抗TIGIT抗体或其抗原结合片段缀合的药物的抗体-药物缀合物和含有所述抗体-药物缀合物的药物组合物。本发明还提供了用于使用包括与根据本发明的抗TIGIT抗体或其抗原结合片段缀合的药物的抗体-药物缀合物和含有所述抗体-药物缀合物的药物组合物***的方法。
抗TIGIT抗体或其抗原结合片段可以经由接头与药物结合。接头是将抗TIGIT抗体或其抗原结合片段与药物连接的位点。例如,接头使得能够通过在可以在细胞内条件下,即在细胞内环境中裂解的试剂的存在下裂解接头而从抗体中释放药物。
接头可以被存在于细胞内环境中的裂解剂(如溶酶体或胞内体)裂解,并且可以是例如可以被细胞内肽酶或蛋白酶(如溶酶体或胞内体蛋白酶)裂解的肽接头。通常,肽接头具有至少两个氨基酸的长度。裂解剂可以包括组织蛋白酶B和组织蛋白酶D或纤溶酶,并且可以水解肽以将药物释放到靶细胞中。
肽接头可以被在癌症组织中过表达的硫醇依赖性蛋白酶即组织蛋白酶-B裂解,并且可以是例如Phe-Leu或Gly-Phe-Leu-Gly接头。此外,肽接头可以例如被细胞内蛋白酶裂解,所述肽接头是Val-Cit接头或Phe-Lys接头。
在一个实施方案中,可裂解接头可以对pH敏感并且可能易于在一定的pH值下水解。通常,pH敏感性接头可以在酸性条件下水解。可以在溶酶体中水解的酸不稳定性接头的例子包括腙、半卡巴腙、硫代半卡巴腙、顺式乌头酰胺、原酸酯、乙缩醛、缩酮等。
在另一个实施方案中,接头可以在还原条件下裂解,并且其例子是二硫化物接头。可以使用N-琥珀酰亚胺基-S-乙酰硫代乙酸酯(SATA)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丁酸酯(SPDB)和N-琥珀酰亚胺基-氧羰基-α-甲基-α-(2-吡啶基-二硫代)甲苯(SMPT)形成各种二硫键。
药物和/或药物接头可以通过抗体的赖氨酸随机缀合,或者可以通过在二硫键链还原时暴露的半胱氨酸来缀合。在一些情况下,接头-药物可以通过存在于基因工程化标签(例如肽或蛋白质)中的半胱氨酸来缀合。基因工程化标签(例如肽或蛋白质)可以含有可以被例如类异戊二烯转移酶识别的氨基酸基序。肽或蛋白质具有在肽或蛋白质的羧基端的缺失,或在肽或蛋白质的羧基(C)端的通过间隔子单元的共价键进行的添加。
此外,接头可以是例如不可裂解的接头,并且药物可以仅通过抗体水解以产生例如氨基酸-接头-药物复合物的一个步骤来释放。这种类型的接头可以是硫醚或马来酰亚胺基己酰基,并且在血液中保持稳定。
抗体-药物缀合物中的药物可以作为具有药理作用的药剂与抗体结合,并且可以具体地是化学治疗剂、毒素、微小RNA(miRNA)、siRNA、shRNA或放射性同位素。化学治疗剂可以例如是细胞毒性剂或免疫抑制剂。具体地,药物可以含有微管蛋白抑制剂、有丝***抑制剂、拓扑异构酶抑制剂、或能够用作DNA嵌入剂的化学治疗剂。药物也可以含有免疫调节化合物、抗癌剂和抗病毒剂或其组合。
这样的药物可以包括选自以下的一种或多种:美登木素生物碱(maytansinoid)、澳瑞司他汀(auristatin)、氨基蝶呤、放线菌素、博来霉素、沙利度胺、喜树碱、N8-乙酰基亚精胺、1-(2-氯乙基)-1,2-二甲基磺酰肼、埃斯培拉霉素(esperamycin)、依托泊苷、6-巯基嘌呤、尾海兔素、单端孢霉烯、卡奇霉素、紫杉醇(taxol)、紫杉烷、紫杉醇(paclitaxel)、多西他赛、甲氨蝶呤、长春新碱、长春碱、多柔比星、美法仑、苯丁酸氮芥、倍癌霉素、L-天冬酰胺酶、巯基嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺(cyclophosphamide)、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素(丝裂霉素A、丝裂霉素C)、达卡巴嗪、丙卡巴肼、拓扑替康、氮芥、环磷酰胺(cytoxan)、依托泊苷、5-氟尿嘧啶、CNU(二氯乙基亚硝基脲)、伊立替康、喜树碱、博来霉素、伊达比星、柔红霉素、更生霉素、普卡霉素、米托蒽醌、天冬酰胺酶、长春瑞滨、苯丁酸氮芥、美法仑、卡莫司汀、洛莫司汀、白消安、曲奥舒凡、达卡巴嗪、依托泊苷、替尼泊苷、拓扑替康、9-氨基喜树碱、克立那托(crisnatol)、三甲曲沙、霉酚酸、噻唑呋林(tiazofurin)、利巴韦林(ribavirin)、EICAR(5-乙炔基-1-β-D核糖呋喃糖基咪唑-4-甲酰胺)、羟基脲、去铁胺、氟尿苷、多西氟尿啶、雷替曲塞、阿糖胞苷(ara C)、胞嘧啶***糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、乙酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、Pe4(光敏剂)、脱甲氧基-竹红菌素A、干扰素-α、干扰素-γ、肿瘤坏死因子、吉西他滨、万珂(Velcade)、雷利米得(Revamid)、撒利多迈(thalomid)、洛伐他汀、1-甲基-4-苯基吡啶鎓离子、星形孢菌素、放线菌素D、更生霉素、博来霉素A2、博来霉素B2、培洛霉素、表柔比星、吡柔比星、佐柔比星、维拉帕米(verapamil)、毒胡萝卜素、源自细菌或植物和动物的核酸酶和毒素,但不限于此。
在下文中,将参考以下实施例更加详细地描述本发明。然而,对本领域技术人员而言将明显的是,提供这些实施例仅仅是为了说明本发明,而不应解释为限制本发明的范围。
实施例1:抗TIGIT抗体的筛选
1.1抗TIGIT人抗体scFv和Fab克隆的筛选
通过噬菌体展示筛选方法使用scFv和Fab人抗体文库选择与TIGIT特异性地结合的抗体。参考“Construction of a Large Synthetic Human scFv Library with SixDiversified CDRs and High Functional Diversity(Yang HY等人Molecules and Cells27,225-235)”中的描述产生scFv文库,并参考韩国专利号1694832中的描述产生Fab文库。进行噬菌体展示筛选直至总共第四轮,并且随着轮数的增加,抗原的数量减少并且洗涤次数增加。第一和第三噬菌体展示筛选使用人TIGIT-ECD-Fc抗原并且第二和第四噬菌体展示筛选使用小鼠TIGIT-ECD-Fc抗原进行抗原交叉方法。将在PBS缓冲液中稀释的20μg TIGIT抗原添加至免疫管中,并且在4℃下孵育过夜以用TIGIT抗原涂布免疫管的表面。在室温下将涂布有TIGIT抗原的免疫管在PBS-T/BSA(5%)溶液中封闭1小时,分别以4.7×1012或1.2×1013的量向其中添加scFv或Fab人抗体文库噬菌体,并且将混合物在室温下孵育2小时,以使人抗体文库噬菌体与TIGIT抗原结合。通过用PBST(pH 7.4)溶液洗涤来除去未结合TIGIT抗原的噬菌体。将残余物用0.1M甘氨酸(pH 3.0)溶液洗脱,并且用1M Tris-HCl(pH 8.0)溶液中和。将所洗脱的噬菌体在37℃下用ER2537大肠杆菌(OD600为0.5)感染,用VCSM13辅助噬菌体扩增并用于下一轮筛选中。在每个淘选筛选轮次期间噬菌体数量以及噬菌体总数量与所洗脱的噬菌体数量之比的确定的结果显示,与TIGIT抗原结合的噬菌体数量随着淘选次数的增加而增加。
将从每个淘选轮次的所得产物获得的噬菌体克隆用ER2537大肠杆菌菌株感染,并且接种在氨苄青霉素板上以获得菌落。使用周质提取物通过以下ELISA方法确定菌落对TIGIT抗原的结合特异性。在分配有120μL SB/羧苄青霉素(50μg/mL)培养基的96孔板中通过挑取接种菌落,并且在37℃板振荡器(2速)中进行培养,直到OD600达到0.6。添加30μL SB/羧苄青霉素(50μg/mL)/IPTG 5mM培养基,并且在37℃板振荡器(2速)中孵育过夜。将样品以3,000rpm离心10分钟以除去上清液。将所得的沉淀物完全重悬(解离)在100μL BBS溶液(200mM硼酸,150mM NaCl,1mM EDTA)中,并且在4℃下孵育1小时。在3,000rpm下离心20分钟后,仅分离所得的上清液,从而获得周质提取物。将80μL周质提取物与80μL TBST(5%BSA)混合,然后在室温下封闭1小时。将封闭的周质提取物以80μL/孔的剂量添加至涂布有人IgG、人TIGIT-Fc和小鼠TIGIT-Fc抗原的96孔板中,并且在室温下孵育1小时以使抗体与抗原结合。用TBST洗涤3次后,将以1:3000稀释有抗HA-HRP(Roche)的TBST(5%BSA)溶液以30μL/孔的剂量添加至孔中,并且在室温下孵育1小时。用TBST洗涤3次后,以30μL/孔的剂量添加TMB溶液以诱导显色。用1N H2SO4停止反应后,在450nm处测量吸光度。使用抗体周质提取物通过ELISA筛选具有与TIGIT抗原的结合亲和力的抗体克隆,并且对于scFv文库,筛选14种类型的抗体克隆(S02、S03、S04、S05、S06、S11、S12、S14、S19、S32、S39、S43、S62、S64),并且对于Fab文库,筛选四种类型的抗体克隆(F01、F02、F03、F04)。
1.2筛选的scFv和Fab克隆的IgG克隆以及抗体的产生和纯化
为了从筛选的scFv和Fab克隆产生IgG型抗体,使用含有IgG1抗体的恒定区基因的表达载体对每个可变区基因进行基因克隆。使用ClaI(NEB)、NheI(NEB)或ClaI与BsiWI的组合(NEB)的限制性酶对从scFv和Fab克隆PCR扩增的重链和轻链的可变区基因进行克隆,以产生可以以IgG的形式表达的载体。PcDNA3.3(Invitrogen)载体用于重链,并且pOptiVEC(Invitrogen)载体用于轻链。通过使用293F细胞系(Invitrogen)的瞬时转染进行IgG型抗体的产生。用以IgG形式克隆的pcDNA3.3和pOptiVEC载体DNA转染293F细胞,并且在第6天收获细胞培养物并将其用于纯化。使用蛋白A树脂进行Fc纯化以从抗体培养物中纯化抗体。使抗体培养物以1mL/min的流速流入用1XPBS(pH 7.4)平衡的MabSelect SuRe蛋白A树脂(GEHealthcare)中以诱导结合。抗体结合完成后,首先用1XPBS(pH 7.4)洗涤树脂,然后其次用0.1M甘氨酸(pH 5.5)溶液洗涤。为了获得最终抗体,使用0.1M甘氨酸(pH3.5)溶液进行洗脱并用1M Tris-HCl(pH 8.0)进行中和。
为了确定通过噬菌体展示筛选所筛选的抗TIGIT抗体的物种交叉反应性,通过ELISA鉴定抗TIGIT抗体是否与人TIGIT(R&D Systems)、小鼠TIGIT(R&D Systems)和恒河猴TIGIT抗原结合。参考恒河猴TIGIT基因序列(NCBI登录号XP_014985303.1),通过基因合成以Fc融合物的形式表达并纯化本文使用的恒河猴TIGIT抗原。将在PBS中以1mg/mL的浓度稀释的三种类型的TIGIT抗原中的每一种以30μl/孔添加至96孔板中,并且在4℃下孵育过夜以诱导涂布。然后,使30ng筛选的抗体与TIGIT抗原结合,并且将30μL的以1:3,000稀释的TBST(5%BSA)溶液添加至每个孔中,并且在室温下孵育1小时。用TBST洗涤3次后,将30μLTMB溶液添加至每个孔中,以诱导显色。用1N H2SO4停止反应后,在450nm的吸光度下确定显色。鉴定了与六种抗原结合的所筛选抗体的物种交叉反应性(图1)。结果显示,用于测试的大多数抗体与人TIGIT和小鼠TIGIT二者结合。
通过ELISA鉴定了抗TIGIT抗体与TIGIT超家族如CD96(Sinobiologic)、CD155(Sinobiologic)、CD112(R&D Systems)、CD113(R&D Systems)和CD226(R&D Systems)抗原的结合,以便确定通过噬菌体展示筛选而筛选的抗TIGIT抗体的TIGIT特异性。将包括TIGIT在内的六种类型的抗原以100ng/孔涂布在96孔板上,用30ng每种筛选的抗体处理,并且在室温下孵育1小时。用TBST洗涤3次后,将30μL的以1:3,000稀释有抗人Fab-HRP二抗(Jackson)的TBST(5%BSA)添加至每个孔中,并在室温下孵育1小时。用TBST洗涤3次后,将30μL所得的TMB溶液添加至每个孔中。用1N H2SO4停止反应后,在450nm的吸光度下确定显色。鉴定了所选择的抗体与六种抗原的结合。结果,可见所有抗体都仅特异性地结合TIGIT抗原(图2)。
最后,使用过表达人TIGIT蛋白的CHO-S细胞系(CHO-hTIGIT)进行FACS分析,以便鉴定所筛选的抗体与细胞表面上表达的TIGIT抗原的结合。通过以下方式来产生CHO-S细胞系(CHO-hTIGIT):使用慢病毒载体转导全长人TIGIT基因CHO-S细胞,然后用抗生素杀稻瘟菌素仅筛选过表达人TIGIT的CHO细胞。用冰冷的PBS洗涤所产生的CHO-hTIGIT细胞系,并且将5x104个细胞转移至管中,用1μg每种IgG产生的抗体处理,并且在冰上孵育1小时。随后,将细胞系用1μg抗人IgG FITC二抗(Invitrogen)处理,并且在冰上孵育1小时。用冰冷的PBS洗涤细胞,然后进行FACS分析以鉴定抗体与细胞表面上表达的人TIGIT抗原的结合(图3)。用作阳性对照的10A7抗体是仓鼠来源的抗人抗体,从而允许小鼠交联,并且本发明人基于美国专利号2015/0216970中描述的序列通过产生呈具有小鼠IgG2a恒定区的抗体形式的基因来产生可变区。10A7抗体与人TIGIT抗原结合,但不与用作阴性对照的纳武单抗(抗PD1抗体)结合。这意味着CHO-hTIGIT细胞正常产生。鉴定出所筛选抗体特异性地结合CHO-hTIGIT细胞。
实施例2.抗TIGIT抗体的优化
2.1 F04和S64抗体的优化
通过上述抗体筛选过程,最终将两种类型的克隆F04和S64筛选为抗TIGIT人抗体。为了改善这些抗体的稳定性,基于F04和S64抗体的氨基酸序列构建子文库,并且在高温下使用延长的洗涤方法进行筛选以改善稳定性。F04抗体的子文库是通过同时对CDRH1和CDRH2进行改组而获得的文库,所述文库是通过重叠一种物种制备的。通过重叠PCR方法产生了三种类型的子文库,所述子文库包括通过同时对CDRH1和CDRH2进行改组而获得的文库,通过同时对CDRL1、CDRL2和CDRL3进行改组而获得的文库,以及通过对除了CDRH3以外的其他CDR进行改组而获得的文库。用于F04和S64克隆优化的具有氨基酸序列多样性的CDR区示出在下表5中(CDR区带下划线)。
[表5]
F04和S64的可变区序列
从已构建的子文库中拯救噬菌体,以便筛选比亲本克隆更稳定的克隆,并且然后在与抗原结合之前进行加热,以去除不稳定的克隆。在第一次和第二次噬菌体展示筛选中,将噬菌体在60℃下处理10分钟,并且在第三至第六次噬菌体展示筛选中,将噬菌体在80℃下处理10分钟。此外,在ELISA期间,以诱导的残余比率进行筛选,以区分对于2小时的增加的洗涤时间和在37℃的升高的温度下具有改善的稳定性的克隆与亲本克隆。基于此,筛选出具有改善的稳定性的克隆并分析其序列(表6和7)。
[表6]
基于F04克隆筛选的抗体的CDR序列
[表7]
基于scFv克隆筛选的抗体的CDR序列
最后,通过使用F04子文库进行筛选来筛选F04-10克隆,并且通过使用S64子文库进行筛选来筛选S64-39克隆。
基于F04-10克隆的抗体包括作为重链可变区的SEQ ID NO:13中所示的氨基酸序列和作为轻链可变区的SEQ ID NO:15中所示的氨基酸序列,并且基于S64-39克隆的抗体包括作为重链可变区的SEQ ID NO:14中所示的氨基酸和作为轻链可变区的SEQ ID NO:16中所示的氨基酸序列。
此外,基于F04-10克隆的抗体包括:重链可变区,所述重链可变区包括包含SEQ IDNO:1中所示的氨基酸序列的重链CDR1、包含SEQ ID NO:3中所示的氨基酸序列的重链CDR2、和包含SEQ ID NO:5中所示的氨基酸序列的重链CDR3;和轻链可变区,所述轻链可变区包括包含SEQ ID NO:7中所示的氨基酸序列的轻链CDR1、包含SEQ ID NO:9中所示的氨基酸序列的轻链CDR2、和包含SEQ ID NO:11中所示的氨基酸序列的轻链CDR3。
此外,基于S64-39克隆的抗体包括:重链可变区,所述重链可变区包括包含SEQ IDNO:2中所示的氨基酸序列的重链CDR1、包含SEQ ID NO:4中所示的氨基酸序列的重链CDR2、和包含SEQ ID NO:6中所示的氨基酸序列的重链CDR3;和轻链可变区,所述轻链可变区包括包含SEQ ID NO:8中所示的氨基酸序列的轻链CDR1、包含SEQ ID NO:10中所示的氨基酸序列的轻链CDR2、和包含SEQ ID NO:12中所示的氨基酸序列的轻链CDR3。
2.2抗TIGIT抗体的基因克隆和抗体的纯化
以与实施例1.2中相同的方式产生F04-10-IgG1和S64-39-IgG1抗体的表达载体。S64-39-IgG4抗体的重链表达载体如下产生。使用NheI和XhoI(NEB)限制性酶从S64-39-IgG1表达载体中去除对应于IgG1恒定区的基因,并且将其中用NheI和XhoI处理抗PD-1抗体纳武单抗的重链恒定区的基因亚克隆,然后添加至其中以产生重链表达载体,使得最终以IgG4的形式表达S64-39重链。分别使用ClaI和XhoI限制性酶将F04-10和S64-39抗体的轻链可变区亚克隆到pOptiVEC载体中。
以与以上实施例1.2中相同的方式,使用293F细胞系和MabSelect SuRe蛋白A树脂,使用瞬时表达来进行以IgG形式产生的三种类型的抗体的产生和纯化。
实施例3.鉴定抗TIGIT抗体与细胞表面上的TIGIT的结合的测试
为了鉴定实施例2中产生的三种类型的抗TIGIT抗体与细胞表面上表达的TIGIT的结合能力,将过表达TIGIT的CHO细胞系(在下文中称为CHO-TIGIT细胞系)用抗TIGIT抗体处理,然后使用荧光流式细胞仪检测与细胞表面上TIGIT结合的抗TIGIT抗体。
具体地,使用化学成分培养基(CD FortiCHO化学成分确定的培养基+8mM L-谷氨酰胺+20μg/mL杀稻瘟菌素+1%抗凝集剂)将CHO-TIGIT细胞系在5%CO2孵育器中在37℃下培养48至72小时。通过离心收获培养的CHO-TIGIT细胞系,将其在FACS溶液(PBS+5%FBS)中稀释,并且以1×105个细胞/孔的密度分配在96孔圆底板(Corning)中。然后,为了完全去除残留在细胞表面上的化学成分培养基,添加FACS溶液,以2,000rpm离心3分钟并洗涤3次以去除上清液。将经洗涤的CHO-TIGIT细胞系通过添加100μL FACS溶液而重悬。将使用FACS溶液稀释至2倍最终浓度的每种浓度的抗TIGIT抗体以100μL添加至其中分配了CHO-TIGIT细胞系的96孔圆底板中,并且在4℃下孵育1小时。然后,为了去除上清液中残留的未与细胞表面上的TIGIT结合的抗TIGIT抗体,将FACS溶液添加至每个孔中,以2,000rpm离心3分钟,并洗涤3次以去除上清液。然后,为了检测与细胞表面上的TIGIT结合的抗TIGIT抗体,使用FACS溶液将山羊抗人IgG(H+L)交叉吸附的二抗(Invitrogen)稀释至10μg/mL,并且将100μL的所稀释的抗体在4℃下孵育1小时。洗涤3次后,将每个样品转移至12x75 mm管(BDBiosciences)中,并且使用荧光流式细胞仪进行分析。结果,鉴定出抗TIGIT抗体与细胞表面上TIGIT的结合能力(EC50)对于F04-10-IgG1为16.41ng/mL,对于S64-39-IgG1为69.01ng/mL,对于S64-39-IgG4为80.78ng/mL,并且对于10A7为16.54ng/mL(图4)。
实施例4.对抗TIGIT抗体对TIGIT/CD155结合的抑制的测试
为了鉴定以上实施例2中产生的三种类型的抗TIGIT抗体的活性,测试对TIGIT与CD155之间的结合的抑制。
具体地,在该测试中,在表达CD155的aAPC/CHO-K1细胞系和表达TIGIT的效应细胞系的共培养***中,使用TIGIT/CD155阻断测定试剂盒(Promega)进行抗TIGIT抗体对TIGIT与CD155之间的结合的抑制活性。
将表达CD155的aAPC/CHO-K1细胞系溶解并稀释于14.5mL的基本培养基(含有10%FBS的F-12培养基)中,并且将100μL所得的细胞系添加至96孔板(Costar)中,并且在CO2孵育器中储存16至24小时。对于F04-10-IgG1,使用分析培养基(含有10%FBS的RPMI 1640培养基)将含有TIGIT抗体的浓缩物以2mg/mL(其是处理浓度的两倍高)连续稀释4倍,并且通过以3mg/mL进行2倍连续稀释来制备S64-39-IgG1和S64-39-IgG4。通过以2.4mg/mL进行3倍系列稀释来制备用作对照的10A7抗体。完全去除96孔板中含有表达CD155的aAPC/CHO-K1细胞系的培养基,并且将制备的抗TIGIT抗体以40μL添加至每个孔中以如下调整实际浓度:对于F04-10-IgG1,使用以1mg/mL连续稀释4倍的样品进行处理;对于S64-39-IgG1和S64-39IgG4,使用以1mg/mL连续稀释2倍的样品进行处理。对于对照10A7,使用以1.2mg/mL连续稀释3倍的样品进行处理。然后,将表达TIGIT的效应细胞系溶解并稀释于6mL分析培养基中,并且向每个孔中添加40μL所稀释的细胞系,然后在5%CO2孵育器中在37℃下孵育6小时。将每个孔用80μL Bio-GloTM试剂(通过将Bio-GloTM缓冲液添加至Bio-GloTM底物来制备)处理,并且在室温下反应10分钟。用可发光测量的微板读取器(Molecular devices,SpectraMaxL)测量响应值(相对发光计单位,RLU),以计算响应值的比率(响应倍数=RLU抗体稀释液/RLU无抗体对照),所述比率意指用抗TIGIT抗体处理时的响应值相对于未用抗TIGIT抗体处理时的响应值的比率。结果如下:抗TIGIT抗体的结合抑制(EC50)为:对于F04-10-IgG1为23.89nM,对于S64-39-IgG1为0.581μM,对于S64-39-IgG4为1.08μM,并且对于10A7为0.752μM(图5)。
实施例5.对抗TIGIT抗体的NK细胞激活的测试
为了分析用实施例2中产生的三种类型的抗TIGIT抗体处理后的NK92细胞系的活性,测量NK92细胞系中IFN-g分泌的量,并且在过表达TIGIT的NK92细胞系和过表达PVR的人源性卵巢癌细胞系(HeLa细胞系)的共培养的条件下使用荧光流式细胞仪进行鉴定NKG2D表达的测试。
具体地,将过表达TIGIT的NK92细胞系在完全培养基(α-MEM+12.5%FBS+12.5%马血清+0.1mM 2-巯基乙醇+100U/mL IL-2)中稀释至2x105/mL的浓度,然后在5%CO2孵育器中在37℃下以5mL的体积在T25烧瓶(Corning)中培养16至24小时。将细胞用25μg/mL的抗TIGIT抗体处理以抑制培养的NK92细胞系中过表达的TIGIT,并且在5%CO2孵育器中在37℃下培养72小时。在NK92细胞系和抗TIGIT抗体的培养期间,将过表达PVL的HeLa细胞系以3x105/mL的浓度以15mL的体积在T75烧瓶(Corning)中在完全培养基(补充有10%FBS的RPMI1640培养基)中溶解并培养,并且在5%CO2孵育器中在37℃下培养24至48小时。然后,将NK92细胞系和HeLa细胞系在5%CO2孵育器中在37℃下以1:10(1×105NK92:1×106HeLa)的比率在12孔板(Corning)中以1mL的体积共培养4至6小时。共培养完成后,获得培养上清液并储存在-20℃下以用于IFN-g ELISA测试,并且将培养的细胞稀释于PBS(Gibco)中进行制备。
使用通过以上程序获得的培养上清液和细胞系,
首先,使用培养上清液进行ELISA测试以确定从NK92细胞系分泌的IFN-g的量。该测试使用人IFN-γQantikine ELISA测定试剂盒(R&D systems)进行。从用抗TIGIT抗体处理后的NK92细胞分泌的IFN-g的量的分析结果可以看出,与用对照抗体处理的组相比,用F04-10-IgG1和S64-39-IgG1抗体处理的组展现出IFN-g分泌的显著增加,并且用S64-39-IgG4抗体处理的组的IFN-g分泌水平与用对照抗体处理的组的IFN-g分泌水平相当(图6)。
其次,本发明人使用荧光流式细胞仪进行分析以鉴定通过上述共培养获得的细胞系的NKG2D的表达,NKG2D是NK细胞激活标记蛋白之一。对于细胞系的免疫染色,首先,将细胞系以1×106/mL的浓度稀释于细胞染色缓冲液(Biolegend)中,并且在无光下在4℃下进行eFluor-抗CD56抗体(eBioscience)染色和PE-抗NKG2D抗体(BD Biosciences)染色20分钟,以特异性地仅分离NK92细胞。然后,为了清除染色剂,添加1mL的细胞染色缓冲液并且以2,000rpm离心5分钟,并且将该操作重复3次。然后,将每个样品转移至12x75 mm管中以进行荧光流式细胞术(BD Biosciences),并且使用荧光流式细胞仪在表达CD56的细胞系中鉴定NKG2D的表达模式。结果,鉴定出,与对照抗体处理组相比,在F04-10-IgG1、S64-39-IgG1和S64-39-IgG4抗体处理组中,NKG2D表达显著增加(图7)。
实施例6.测量抗TIGIT抗体与TIGIT抗原的亲和力的测试
为了测量实施例2中产生的三种类型的抗TIGIT抗体与人TIGIT(rhTIGIT-Fc)和小鼠TIGIT(rmTIGIT-Fc)的结合能力,使用了使用BIAcore T200(GE Healthcare)进行的表面等离体共振(SPR)。SPR方法是基于这样的原理,即穿过传感器芯片的光的折射率根据涂布在传感器芯片上的物质的状态而变化。当使抗原或抗体流入涂布有抗原或抗体的芯片中时,折射率由于它们之间的结合而改变,并且从测量值计算亲和力(KD)值。
使用10mM乙酸盐溶液(pH 4.0)和胺偶联试剂盒(GE Healthcare),将抗TIGIT抗体固定在Series S CM5传感器芯片(GE Healthcare)上至500RU的水平。将人或小鼠TIGIT-Fc(R&D Systems)蛋白在HBS-EP缓冲液(0.01M HEPES,pH 7.4,0.15M NaCl,3mM EDTA,0.005%表面活性剂P20,GE Healthcare)中从40nM浓度连续稀释2倍,并且各自流动以在诱导与固定在传感器芯片上的抗体的缔合、解离和再生的同时测量抗原-抗体亲和力。在30μL/min的速率下测量TIGIT-Fc蛋白的缔合600秒,测量解离2,000秒,并且在10mM甘氨酸溶液(pH 1.5)中在100μL/min的速率下进行再生25秒。与rhTIGIT-Fc和rmTIGIT-Fc的结合能力的测量结果示出在下表8和9中。
[表8]
与rhTIGIT-Fc的结合能力的测量结果
抗体名称 | 缔合速率(1/Ms) | 解离速率(1/s) | 亲和力(K<sub>D</sub>,nM) |
F04-10-IgG1 | 7.052x 10<sup>4</sup> | 3.760x 10<sup>-5</sup> | 0.533 |
S64-39-IgG1 | 3.366x 10<sup>4</sup> | 4.414x 10<sup>-5</sup> | 1.311 |
S64-39-IgG4 | 2.821x 10<sup>4</sup> | 3.232x 10<sup>-5</sup> | 1.146 |
10A7 | 1.624x 10<sup>5</sup> | 1.927x 10<sup>-4</sup> | 1.187 |
[表9]
与rmTIGIT-Fc的结合能力的测量结果
抗体名称 | 缔合速率(1/Ms) | 解离速率(1/s) | 亲和力(K<sub>D</sub>,nM) |
F04-10-IgG1 | 1.196x 10<sup>5</sup> | 2.933x 10<sup>-5</sup> | 0.245 |
S64-39-IgG1 | 6.283x 10<sup>4</sup> | 2.008x 10<sup>-4</sup> | 3.196 |
S64-39-IgG4 | 6.218x 10<sup>4</sup> | 1.942x 10<sup>-4</sup> | 3.123 |
10A7 | 4.904x 10<sup>5</sup> | 8.913x 10<sup>-5</sup> | 0.182 |
实施例7.抗TIGIT抗体对肿瘤生长的抑制作用
为了评价抗TIGIT抗体的体内活性,制备了小鼠肿瘤模型(使用BALB/c小鼠的同系CT26结直肠癌模型)。在此,将阳性对照抗体(10A7)和实施例2中产生的三种类型的抗体(F04-10-IgG1、S64-39-IgG1、S64-39-IgG4)单独给予或与抗PD-L1抗体(10F.9G2-大鼠IgG2b)组合给予,并且在它们之间比较性地评价对肿瘤生长的抑制作用。
首先,为了建立小鼠肿瘤模型,将培养的CT26肿瘤细胞通过以100μL(1×106个细胞)/小鼠的剂量注射皮下植入(第0天),并且使肿瘤生长到超过一定尺寸。8天后,当肿瘤体积达到119mm3(第8天,给予开始日)时,与抗PD-L1抗体(剂量为10mg/kg)组合地腹膜内给予阴性对照(大鼠IgG2b,剂量为10mg/kg)和四种测试物质(剂量为25mg/kg),总共3次,以3天为间隔。然后以2周为间隔测量肿瘤体积和体重。对肿瘤生长的抑制作用表示为通过将在体内测试的最后一天(第28天)测量的肿瘤体积应用于以下公式计算的TGI:
TGI率(%)=100×(1-ΔT/ΔC)
ΔT=在最后一天测量的测试物质给予组的平均肿瘤体积-在给予开始日测量的测试物质给予组的平均肿瘤体积
ΔC=在最后一天测量的阴性对照给予组的平均肿瘤体积-在给予开始日测量的阴性对照给予组的平均肿瘤体积
在阴性对照给予组中,与给予开始日相比,肿瘤体积在最后一天增加了大约23倍。与阴性对照相比,在单独给予时,阳性对照抗体和抗PD-L1抗体显示出中等的抗肿瘤作用,并且两种抗体的组合给予显示出更强且显著的肿瘤抑制作用(图8)。在抗TIGIT抗体的情况下,当单独给予时,两种IgG1型抗体(S64-39-IgG1、F04-10-IgG1)显示出与阳性对照抗体的作用类似的作用,并且当组合给予时,S64-39-IgG1显示出等同的作用水平。当单独给予和组合给予时,S64-39-IgG4抗体的作用略低于S64-39-IgG1。
总之,当单独给予或与抗PD-L1抗体组合给予时,与阴性对照给予组相比,以上实施例2中产生的三种抗体(F04-10-IgG1、S64-39-IgG1、S64-39-IgG4)具有显著的抗肿瘤作用(F04-10-IgG1、S64-39-IgG1)。具体地,当单独给予时,两种抗体(F04-10-IgG1、S64-39-IgG1)与阴性对照给予组相比具有等同的抗肿瘤作用,并且当组合给予时,一种抗体(S64-39-IgG1)与阴性对照组相比具有等同的抗肿瘤作用。
图8中所示的统计分析是使用GraphPad Prism 5通过Dunnett氏多重比较进行的,并且相对于阴性对照给予组的差异的统计显著性表示如下。*:p<0.05,**:p<0.01并且***:p<0.001
实施例9.根据剂量和组合使用的抗TIGIT抗体的肿瘤生长抑制作用
为了评价抗TIGIT抗体根据剂量和组合使用的体内活性,制备了小鼠肿瘤模型(使用BALB/c小鼠的同系CT26结直肠癌模型)。将实施例2中产生的抗体F04-10单独或与抗PD-L1抗体(10F.9G2-大鼠IgG2b)组合给予至小鼠肿瘤模型以比较评价肿瘤生长抑制作用。
首先,为了建立小鼠肿瘤模型,将培养的CT26肿瘤细胞通过以100μL(1×106个细胞)/小鼠的剂量注射皮下植入(第0天),并且使肿瘤生长到超过一定尺寸。7天后,当肿瘤体积达到80mm3(第7天,在给予开始日)时,将测试组随机分为具有类似平均肿瘤体积的组,并且将阴性对照(大鼠IgG2b10mg/kg和人IgG1 25mg/kg的组合)或F04-10(5、10、25mg/kg)单独地或与抗PD-L1抗体组合地腹膜内给予,以3天为间隔,总共3次。然后以2周为间隔测量肿瘤体积和体重。对肿瘤生长的抑制作用表示为通过将在体内测试的最后一天(第24天)测量的肿瘤体积应用于以下公式计算出的TGI:
TGI率(%)=100×(1-ΔT/ΔC)
ΔT=在最后一天测量的测试物质给予组的平均肿瘤体积-在给予开始日测量的测试物质给予组的平均肿瘤体积
ΔC=在最后一天测量的阴性对照给予组的平均肿瘤体积-在给予开始日测量的阴性对照给予组的平均肿瘤体积
在阴性对照给予组中,与给予开始日相比,肿瘤体积在最后一天增加了大约16倍。另一方面,仅用F04-10治疗的组在3和10mg/kg的剂量下展现出轻微的抗肿瘤作用,并且在25mg/kg的剂量下展现出最大的作用,因此对肿瘤生长具有强抑制作用。单独给予10mg/kg抗PD-L1抗体展现出中等的肿瘤抑制作用。当与3和10mg/kg的剂量的F04-10组合给予抗PD-L1抗体时,与单独给予相同剂量的F04-10相比,对肿瘤生长的抑制作用更强。另一方面,展现出最高作用的25mg/kg F04-10在与抗PD-L1抗体组合时未显示出作用增加(图9)。
总之,实施例2中产生的抗体F04-10在单独给予时在25mg/kg下显示出显著的最大抑制作用,而以低于25mg/kg的3和10mg/kg的剂量给予的抗体F04-10在与抗PD-L1抗体组合给予时显示出与单独给予相比改善的作用。
图9中所示的统计分析是使用GraphPad Prism 5通过Dunnett氏多重比较进行的,并且相对于阴性对照给予组的差异的统计显著性表示如下。*:p<0.05
工业利用度
已经发现,与常规的抗TIGIT抗体相比,根据本发明的抗TIGIT抗体或其抗原结合片段以极高特异性且极强地与TIGIT结合,并且展现出优异的治疗功效。因此,含有根据本发明的抗TIGIT抗体或其抗原结合片段作为活性成分的药物组合物可以用作基于免疫细胞激活的抗癌免疫治疗剂。
此外,含有根据本发明的抗TIGIT抗体及其抗原结合片段作为活性成分的药物组合物可以与使用化学药物和其他化学治疗剂的疗法组合使用。
尽管已经详细描述了本发明的具体配置,但是本领域技术人员应理解,该描述是出于说明性目的作为优选实施方案提供的,并且不应解释为限制本发明的范围。因此,本发明的实质范围由所附权利要求及其等同物限定。
序列表文本
附在电子文件中。
<110> 株式会社柳韩洋行
<120> 抗TIGIT抗体及其用途
<130> PP-2160
<150> KR 10-2018-0024822
<151> 2018-02-28
<160> 21
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<213> 人工序列
<220>
<223> 细胞系S64-39_可变区重链CDR 3
<400> 6
Ala Ile Arg Thr Cys Ser Leu Ser His Cys Tyr Tyr Tyr Tyr Gly Met
1 5 10 15
Asp Val
<210> 7
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04-10_可变区轻链CDR 1
<400> 7
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 8
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64-39_可变区轻链CDR 1
<400> 8
Ser Ser Ser Ser Ser Asn Ile Gly Ser Asn Ala Val Asn
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04-10_可变区轻链CDR 2
<400> 9
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 10
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64-39_可变区轻链CDR 2
<400> 10
Tyr Asp Asn Gln Arg Pro Ser
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04-10_可变区轻链CDR 3
<400> 11
Gln Gln Gly Tyr His Arg Tyr Ala Thr
1 5
<210> 12
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64-39_可变区轻链CDR 3
<400> 12
Ala Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 13
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04-10_可变区重链
<400> 13
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Gly Ser Gly Ser Pro Ser Ser Thr Tyr Tyr Ala Asp Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Ser Tyr Ser Gly Gly Asn Gly Tyr Tyr Tyr Tyr Ala
100 105 110
Tyr Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 14
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64-39_可变区重链
<400> 14
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Pro Ser Gly Ser Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 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 Lys Ala Ile Arg Thr Cys Ser Leu Ser His Cys Tyr Tyr Tyr Tyr
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 15
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04-10_可变区轻链
<400> 15
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 Ser 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 Gly Tyr His Arg Tyr
85 90 95
Ala Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 16
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64-39_可变区轻链
<400> 16
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Ser Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 17
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04_可变区重链
<400> 17
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Gly Ser Tyr Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Ser Ser Tyr Ser Gly Gly Asn Gly Tyr Tyr Tyr Tyr Ala Tyr Ala Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 18
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 细胞系F04_可变区轻链
<400> 18
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 Ser 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 Gly Tyr His Arg Tyr
85 90 95
Ala Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64_可变区重链
<400> 19
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Pro Gly Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 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 Lys Ala Ile Arg Thr Cys Ser Leu Ser His Cys Tyr Tyr Tyr Tyr
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 20
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 细胞系S64_可变区轻链
<400> 20
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Cys Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Ala Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 21
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 具有Ig和ITIM结构域前体的T-细胞免疫受体[智人]
<400> 21
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
Claims (17)
1.一种抗TIGIT抗体或其抗原结合片段,所述抗TIGIT抗体或其抗原结合片段包含:
重链可变区,所述重链可变区包含:
重链CDR1,其包含SEQ ID NO:1或2中所示的氨基酸序列;
重链CDR2,其包含SEQ ID NO:3或4中所示的氨基酸序列;以及
重链CDR3,其包含SEQ ID NO:5或6中所示的氨基酸序列;以及
轻链可变区,所述轻链可变区包含:
轻链CDR1,其包含SEQ ID NO:7或8中所示的氨基酸序列;
轻链CDR2,其包含SEQ ID NO:9或10中所示的氨基酸序列;以及
轻链CDR3,其包含SEQ ID NO:11或12中所示的氨基酸序列。
2.根据权利要求1所述的抗TIGIT抗体或其抗原结合片段,其包含:
重链可变区,其包含SEQ ID NO:13或14中所示的氨基酸序列;以及
轻链可变区,其包含SEQ ID NO:15或16中所示的氨基酸序列。
3.根据权利要求1或2所述的抗TIGIT抗体或其抗原结合片段,其中所述抗TIGIT抗体是单克隆抗体。
4.根据权利要求1或2所述的抗TIGIT抗体或其抗原结合片段,其中所述抗原结合片段选自所述抗TIGIT抗体的scFv、(scFv)2、scFv-Fc、Fab、Fab'和F(ab')2。
5.一种用于治疗癌症或肿瘤的药物组合物,所述药物组合物包含根据权利要求1或2所述的抗TIGIT抗体或其抗原结合片段作为活性成分。
6.根据权利要求5所述的药物组合物,其中所述癌症或肿瘤选自皮肤癌、肝癌、肝细胞癌、胃癌、乳腺癌、肺癌、卵巢癌、支气管癌、鼻咽癌、喉癌、胰腺癌、膀胱癌、结直肠癌、结肠癌、***、脑癌、***癌、骨癌、甲状腺癌、甲状旁腺癌、肾癌、食道癌、胆管癌、睾丸癌、直肠癌、头颈癌、***、输尿管癌、骨肉瘤、神经母细胞瘤、纤维肉瘤、横纹肌肉瘤、星形细胞瘤、神经母细胞瘤、和神经胶质瘤。
7.一种用于治疗癌症或肿瘤的用于共给予的药物组合物,所述药物组合物包含根据权利要求1或2所述的抗TIGIT抗体或其抗原结合片段、和其他癌症治疗剂。
8.根据权利要求7所述的组合物,其中所述其他癌症治疗剂是免疫检查点抑制剂。
9.根据权利要求8所述的组合物,其中所述免疫检查点抑制剂是抗CTLA-4抗体、抗PD-1抗体或抗PD-L1抗体。
10.一种抗体-药物缀合物,所述抗体-药物缀合物包含根据权利要求1或2所述的抗TIGIT抗体或其抗原结合片段。
11.一种用于治疗癌症或肿瘤的组合物,所述组合物包含根据权利要求10所述的抗体-药物缀合物。
12.一种核酸,所述核酸编码根据权利要求1或2所述的抗TIGIT抗体或其抗原结合片段。
13.一种重组表达载体,所述重组表达载体包含根据权利要求12所述的核酸。
14.一种宿主细胞,所述宿主细胞用根据权利要求13所述的重组表达载体转化。
15.根据权利要求14所述的宿主细胞,其中所述宿主细胞选自动物细胞、植物细胞、酵母、大肠杆菌和昆虫细胞。
16.根据权利要求15所述的宿主细胞,其中所述宿主细胞选自猴肾细胞(COS7)、NSO细胞、SP2/0细胞、中国仓鼠卵巢(CHO)细胞、W138、幼仓鼠肾(BHK)细胞、MDCK、骨髓瘤细胞系,HuT 78细胞、HEK293细胞、大肠杆菌、枯草芽孢杆菌、链霉菌属物种、假单胞菌属物种、奇异变形杆菌、葡萄球菌属物种、曲霉属物种、巴斯德毕赤酵母、酿酒酵母、裂殖酵母属物种和粗糙脉孢菌。
17.一种用于产生抗TIGIT抗体或其抗原结合片段的方法,所述方法包括培养根据权利要求14至16中任一项所述的宿主细胞。
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2018
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- 2019-02-28 JP JP2020545179A patent/JP7011078B2/ja active Active
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RU2750705C1 (ru) | 2021-07-01 |
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US11505603B2 (en) | 2022-11-22 |
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CA3091639A1 (en) | 2019-09-06 |
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