CN116925233A - 抗tigit-抗pvrig双特异性抗体、其药物组合物及用途 - Google Patents
抗tigit-抗pvrig双特异性抗体、其药物组合物及用途 Download PDFInfo
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Abstract
本发明属于生物医药领域,涉及一种抗TIGIT‑抗PVRIG双特异性抗体、其药物组合物及用途。具体地,本发明涉及一种双特异性抗体,其包括:靶向PVRIG的第一蛋白功能区,和靶向不同于PVRIG的靶点(例如TIGIT)的第二蛋白功能区;其中:所述第一蛋白功能区为抗PVRIG免疫球蛋白或其抗原结合片段;所述抗PVRIG免疫球蛋白的重链可变区包含氨基酸序列如SEQ IDNO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ IDNO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。本发明的双特异性抗体具有良好的抗肿瘤效果。
Description
技术领域
本发明属于生物医药领域,涉及一种抗TIGIT-抗PVRIG双特异性抗体、其药物组合物及用途。
背景技术
T细胞免疫球蛋白和ITIM结构域(T cell immunoreceptor with Ig and ITIMdomains,TIGIT,又称WUCAM、Vstm3或VSIG9)是一种新型免疫抑制性受体,属于PVR受体家族,由活化的CD8+T和CD4+T细胞、自然杀伤(NK)细胞、调节性T细胞(Tregs)和滤泡辅助性T细胞表达。
脊髓灰质炎病毒受体相关免疫球蛋白结构域(poliovirus receptor relatedimmunoglobulin domain-containing protein,PVRIG,又称CD112R)同属于PVR受体家族成员,其胞外区具有一个IgV结构域,胞内区含有一个ITIM(Immunoreceptor tyrosine-basedinhibitory motif)结构域,主要表达在自然杀伤(NK)细胞和T细胞上。
在肺癌、肾癌、子宫内膜癌、乳腺癌、皮肤癌及其肿瘤微环境中,PVRIG或其配体PVRL2均高表达,且PVRIG在***癌患者的NK细胞上也高表达(Whelan S,et al.CancerImmunol Res.2019;7(2):257-268.)。此外,PVRIG与耗竭性CD8+T细胞标志TIGIT和PD-1分子呈共表达,提示了PVRIG的表达有着一定的肿瘤特异性,并且可能与肿瘤内的TIL的激活/耗竭状态有关(Whelan S,et al.Cancer Immunol Res.2019;7(2):257-268.)。WO2021180205A1报道了抗PVRIG抗体能够用于肺癌、乳腺癌、卵巢癌、肾癌、胃癌、子宫内膜癌、头颈癌等的防治。
TIGIT/PVRIG共同参与一个复杂的调控网络:CD226(DNAM-1)是T/NK细胞上的激活性受体,通过与CD155和CD112的结合来介导T/NK细胞的活化信号;而TIGIT和PVRIG是T/NK细胞上的抑制性受体,在细胞被活化后会上调表达,分别通过与CD155和CD112两个配体的结合来独立地介导抑制信号,同时它们也与CD226竞争配体而阻断其传递的刺激信号,从而实现对免疫细胞功能的负调控。
研究人员用抗体分别阻断TIGIT/CD155与PVRIG/CD112的相互作用可分别增强NK细胞对肿瘤细胞的细胞毒性,但PVRIG与TIGIT阻断单抗联用可进一步增强NK细胞对乳腺癌细胞的杀伤效果(Xu F等人,Blockade of CD112R and TIGIT signaling sensitizeshuman natural killer cell functions.Cancer Immunol Immunother.2017Oct;66(10):1367-1375.)。T细胞的体外功能性研究表明,TIGIT抗体和PVRIG抗体可以分别增加T细胞扩增或者IFN-γ分泌,而两者结合可以产生加和或协同作用,进一步提高T细胞功能(WhelanS等人,PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+T-cellFunction.Cancer Immunol Res.2019Feb;7(2):257-268.)。在基因敲除小鼠模型中,PVRIG抗体可减少TIGIT-/-小鼠肿瘤的生长,并且PVRIG与TIGIT的双敲除小鼠中的肿瘤生长控制,与单敲除小鼠相比也有进一步提高(Kathryn Logronio等人,COM902,a NovelTherapeutic Antibody Targeting TIGIT Augments T Cell Function and theActivity of PVRIG Pathway Blockade In Vitro and In Vivo.SITC 2019.)。这些实验数据都证明TIGIT/CD155与PVRIG/CD112是两条独立非冗余的T细胞负调通路,同时靶向干预TIGIT和PVRIG这两个靶点,有望在肿瘤治疗中更好地释放由CD226产生的T细胞激活信号。
恒瑞医药研发的SHR-2002是目前为止同类TIGIT/PVRIG双靶点抗体中首个也是唯一一个进入临床开发的药物,于2021年12月初获批临床,目前处于Ⅰ期临床阶段,用于癌症治疗。
同时靶向TIGIT和PVRIG两个靶点在体内外实验中都展现了良好的效果。双特异性抗体能同时特异性结合两个抗原或抗原表位,具有特异性和双功能性的特点,现已成为抗体工程领域的研究热点。但双特异性抗体研发中遇到的临床前评价模型复杂、表达量低、稳定性差、工艺复杂、质控差异性大等问题,一直以来影响双特异性抗体的研发进展。
因此,本领域仍迫切需要开发一种特异性佳、疗效好且易于制备的针对TIGIT和PVRIG两个靶点的双特异性抗体。
发明内容
本发明人经过深入的研究和创造性的劳动,得到了新的双特异性抗体。本发明人惊奇地发现,本发明的双特异性抗体具有良好的亲和力和生物活性,具有抗肿瘤的潜力。由此提供了下述发明:
本发明的一个方面涉及一种双特异性抗体,其包括:
靶向PVRIG的第一蛋白功能区,和
靶向不同于PVRIG的靶点(例如TIGIT)的第二蛋白功能区;
其中:
所述第一蛋白功能区为抗PVRIG免疫球蛋白或其抗原结合片段;
所述抗PVRIG免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且
所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
在本发明的一些实施方式中,所述的双特异性抗体为抗TIGIT-抗PVRIG双特异性抗体,也表示为抗PVRIG-抗TIGIT双特异性抗体,简称为本发明的双特异性抗体。
在本发明的一些实施方式中,所述的双特异性抗体,其中,所述第二蛋白功能区为抗TIGIT免疫球蛋白或其抗原结合片段,其中:
所述抗TIGIT免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:13所示的HCDR1、氨基酸序列如SEQ ID NO:14所示的HCDR2以及氨基酸序列如SEQ ID NO:15所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:16所示的LCDR1、氨基酸序列如SEQ ID NO:17所示的LCDR2以及氨基酸序列如SEQ ID NO:18所示的LCDR3;
或者,
所述抗TIGIT免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:19所示的HCDR1、氨基酸序列如SEQ ID NO:20所示的HCDR2以及氨基酸序列如SEQ ID NO:21所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
轻链和重链的可变区决定抗原的结合;每条链的可变区均含有三个高变区,称互补决定区(CDR)(重链(H)的CDR包含HCDR1、HCDR2、HCDR3,轻链(L)的CDR包含LCDR1、LCDR2、LCDR3。在本发明的一些实施方式中,所述的双特异性抗体,其HCDR1-HCDR3以及LCDR1-LCDR3参照美国专利公开US20210380669A1或者文献Lu.et al(Deamidation andisomerization liability analysis of 131clinical-stage antibodies,MABS,2019,VOL.11,NO.1,45–57,DOI:10.1080/19420862.2018.1548233)进行定义或者编号。
在本发明的一些实施方式中,所述的双特异性抗体,其中,所述抗原结合片段独立地为单链抗体或半分子型单价抗体(IgG half molecule,IgG-HM)。
在本发明的一些实施方式中,所述的双特异性抗体,其中,
所述第一蛋白功能区为抗PVRIG免疫球蛋白,所述第二蛋白功能区为抗TIGIT单链抗体;其中:
所述抗PVRIG免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3;和
所述的抗TIGIT单链抗体,其重链可变区包含氨基酸序列如SEQ ID NO:13所示的HCDR1、氨基酸序列如SEQ ID NO:14所示的HCDR2以及氨基酸序列如SEQ ID NO:15所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:16所示的LCDR1、氨基酸序列如SEQ ID NO:17所示的LCDR2以及氨基酸序列如SEQ ID NO:18所示的LCDR3;或者
所述的抗TIGIT单链抗体,其重链可变区包含氨基酸序列如SEQ ID NO:19所示的HCDR1、氨基酸序列如SEQ ID NO:20所示的HCDR2以及氨基酸序列如SEQ ID NO:21所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
在本发明的一些实施方式中,所述的双特异性抗体,其中,
所述第一蛋白功能区为抗PVRIG单链抗体,所述第二蛋白功能区为抗TIGIT免疫球蛋白;其中:
所述抗PVRIG单链抗体的重链可变区包含氨基酸序列如SEQ ID NO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3;和
所述的抗TIGIT免疫球蛋白,其重链可变区包含氨基酸序列如SEQ ID NO:13所示的HCDR1、氨基酸序列如SEQ ID NO:14所示的HCDR2以及氨基酸序列如SEQ ID NO:15所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:16所示的LCDR1、氨基酸序列如SEQ ID NO:17所示的LCDR2以及氨基酸序列如SEQ ID NO:18所示的LCDR3;或者
所述的抗TIGIT免疫球蛋白,其重链可变区包含氨基酸序列如SEQ ID NO:19所示的HCDR1、氨基酸序列如SEQ ID NO:20所示的HCDR2以及氨基酸序列如SEQ ID NO:21所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
在本发明的一些实施方式中,所述的双特异性抗体,其中,
所述抗PVRIG免疫球蛋白或抗PVRIG单链抗体的重链可变区的氨基酸序列如SEQID NO:5所示;并且
所述抗PVRIG免疫球蛋白或抗PVRIG单链抗体的轻链可变区的氨基酸序列如SEQID NO:4所示。
在本发明的一些实施方式中,所述的双特异性抗体,其中,
所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的重链可变区的氨基酸序列如SEQID NO:1所示;并且所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的轻链可变区的氨基酸序列如SEQ ID NO:2所示;
或者,
所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的重链可变区的氨基酸序列如SEQID NO:3所示;并且所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的轻链可变区的氨基酸序列如SEQ ID NO:4所示。
在本发明的一些实施方式中,所述的双特异性抗体,其中,所述第一蛋白功能区和第二蛋白功能区直接连接或者通过连接片段连接;
优选地,所述连接片段为(GGGGS)m,m为正整数,例如1、2、3、4、5或6;
优选地,所述连接片段的氨基酸序列如SEQ ID NO:6所示。
在本发明的一些实施方式中,所述的双特异性抗体,其中,所述第一蛋白功能区和第二蛋白功能区独立地为1个、2个或者2个以上。
在本发明的一些实施方式中,所述的双特异性抗体,其中:
所述抗TIGIT单链抗体(两条分子)分别连接在抗PVRIG免疫球蛋白的两条重链的C末端;或者
所述抗PVRIG单链抗体(两条分子)分别连接在抗TIGIT免疫球蛋白的两条重链的C末端。
在本发明的一些实施方式中,所述的双特异性抗体,其中,
所述抗PVRIG免疫球蛋白或抗TIGIT免疫球蛋白的恒定区来自人抗体;
优选地,所述恒定区独立地选自人IgG1、IgG2、IgG3或IgG4的恒定区。
在本发明的一些实施方式中,所述的双特异性抗体,其中,
所述抗PVRIG免疫球蛋白或抗TIGIT免疫球蛋白的重链恒定区为人Ig gamma-1chain C region(例如NCBI ACCESSION:P01857)或人Ig gamma-4chain C region(例如NCBI ACCESSION:P01861.1),并且其轻链恒定区为人Ig kappa chain C region(例如NCBIACCESSION:P01834);
优选地,所述抗PVRIG免疫球蛋白和抗TIGIT免疫球蛋白的重链恒定区还包含按照EU编号***的L234A突变和L235A突变(简称为LALA)。
本发明中,如果没有特别说明,位点之前的字母表示突变前的氨基酸,位点之后的字母表示突变后的氨基酸。
在本发明的一些实施方式中,所述的双特异性抗体,其为氨基酸序列如SEQ IDNO:7和SEQ ID NO:8所示的两条肽链的二聚体,或者为氨基酸序列如SEQ ID NO:9和SEQ IDNO:10所示的两条肽链的二聚体。
本发明的另一方面涉及一种分离的核酸分子,其编码本发明中任一项所述的双特异性抗体。
本发明的再一方面涉及一种载体,其包含本发明的分离的核酸分子。
本发明的再一方面涉及一种宿主细胞,其包含本发明的分离的核酸分子,或者本发明的载体。
本发明的再一方面涉及一种偶联物,其包括双特异性抗体以及偶联部分,其中,所述双特异性抗体为本发明中任一项所述的双特异性抗体,所述偶联部分为可检测的标记;优选地,所述偶联部分为放射性同位素、荧光物质、有色物质或酶。
本发明的再一方面涉及一种试剂盒,其包含本发明中任一项所述的双特异性抗体,或者包含本发明的偶联物;
优选地,所述试剂盒还包含第二抗体,其能够特异性结合所述双特异性抗体;任选地,所述第二抗体还包括可检测的标记,例如放射性同位素、荧光物质、有色物质或酶。
本发明的再一方面涉及一种一种药物组合物,其包含本发明中任一项所述的双特异性抗体,以及一种或多种药学上可接受的辅料;
优选地,所述药物组合物还包含至少一种抗PD-1抗体;
优选地,所述双特异性抗体与抗PD-1抗体的摩尔比是(1:5)至(5:1),例如1:5、1:4、1:3、1:2、1:1、2:1、3:1、4:1或5:1;更优选为1:1。
在本发明的一些实施方式中,所述的药物组合物,其中,所述的抗PD-1抗体,其包含重链可变区和轻链可变区,所述重链可变区包含HCDR1至HCDR3,所述轻链可变区包含LCDR1至LCDR3,其中:
HCDR1的氨基酸序列如SEQ ID NO:36所示,HCDR2的氨基酸序列如SEQ ID NO:37所示,HCDR3的氨基酸序列如SEQ ID NO:38所示,LCDR1的氨基酸序列如SEQ ID NO:39所示,LCDR2的氨基酸序列如SEQ ID NO:40所示和LCDR3的氨基酸序列如SEQ ID NO:41所示;
优选地,所述的抗PD-1抗体,其重链可变区的氨基酸序列如SEQ ID NO:34所示,并且轻链可变区的氨基酸序列如SEQ ID NO:35所示。
在本发明的一个或多个实施方式中,所述的药物组合物,其中,所述药物组合物的单位剂量,按照其中的双特异性抗体的质量计算,为100mg-1000mg、200mg-800mg、200mg-500mg、300mg-600mg、400mg-500mg或者450mg。
本发明的再一方面涉及一种组合产品,其包含独立包装的第一产品和第二产品,其中,
所述第一产品包含其包含本发明中任一项所述的双特异性抗体;
所述第二产品包含至少一种抗PD-1抗体;
优选地,所述第一产品和所述第二产品还独立地包含一种或多种药学上可接受的辅料;
优选地,所述组合产品还包含产品说明书。
在本发明的一些实施方式中,所述的组合产品,其中,所述双特异性抗体与抗PD-1抗体的摩尔比是(1:5)至(5:1),例如1:5、1:4、1:3、1:2、1:1、2:1、3:1、4:1或5:1;更优选为1:1。
在本发明的一些实施方式中,所述的组合产品,其中,所述的抗PD-1抗体,其包含重链可变区和轻链可变区,所述重链可变区包含HCDR1至HCDR3,所述轻链可变区包含LCDR1至LCDR3,其中:
HCDR1的氨基酸序列如SEQ ID NO:36所示,HCDR2的氨基酸序列如SEQ ID NO:37所示,HCDR3的氨基酸序列如SEQ ID NO:38所示,LCDR1的氨基酸序列如SEQ ID NO:39所示,LCDR2的氨基酸序列如SEQ ID NO:40所示和LCDR3的氨基酸序列如SEQ ID NO:41所示;
优选地,所述的抗PD-1抗体,其重链可变区的氨基酸序列如SEQ ID NO:34所示,并且轻链可变区的氨基酸序列如SEQ ID NO:35所示。
本发明的再一方面涉及本发明中任一项所述的双特异性抗体或者本发明的偶联物在制备治疗或预防肿瘤的药物中的用途;
优选地,所述肿瘤选自结肠癌、黑色素瘤、肺癌、肾癌、子宫内膜癌、乳腺癌、皮肤癌、卵巢癌、胃癌、头颈癌、肝癌、脑瘤、尿路上皮癌、骨肿瘤、胆管癌、卵巢癌、直肠癌、胰腺癌、宫颈瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、B淋巴细胞瘤、浆细胞癌、***癌和睾丸癌中的一种或多种;
优选地,所述肺癌为非小细胞肺癌或小细胞肺癌。
根据本发明中任一项所述的双特异性抗体、本发明的偶联物或者本发明中任一项所述的药物组合物,其用于治疗或预防肿瘤;
优选地,所述肿瘤选自结肠癌、黑色素瘤、肺癌、肾癌、子宫内膜癌、乳腺癌、皮肤癌、卵巢癌、胃癌、头颈癌、肝癌、脑瘤、尿路上皮癌、骨肿瘤、胆管癌、卵巢癌、直肠癌、胰腺癌、宫颈瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、B淋巴细胞瘤、浆细胞癌、***癌和睾丸癌中的一种或多种;
优选地,所述肺癌为非小细胞肺癌或小细胞肺癌。
本发明的再一方面涉及一种治疗或预防肿瘤的方法,包括给予有需求的受试者以有效量的本发明中任一项所述的双特异性抗体、本发明的偶联物或者本发明中任一项所述的药物组合物的步骤;
优选地,所述肿瘤选自结肠癌、黑色素瘤、肺癌、肾癌、子宫内膜癌、乳腺癌、皮肤癌、卵巢癌、胃癌、头颈癌、肝癌、脑瘤、尿路上皮癌、骨肿瘤、胆管癌、卵巢癌、直肠癌、胰腺癌、宫颈瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、B淋巴细胞瘤、浆细胞癌、***癌和睾丸癌中的一种或多种;
优选地,所述肺癌为非小细胞肺癌或小细胞肺癌。
在本发明的一个或多个实施方式中,所述的方法,其中,
双特异性抗体的单次给药剂量为每千克体重0.1-100mg,优选1-10mg(例如1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg或10mg);或者,双特异性抗体的单次给药剂量为每位受试者10-1000mg(例如大约100mg、大约150mg、大约200mg、大约250mg、大约300mg、大约350mg、大约400mg、大约450mg、大约500mg、大约600mg、大约700mg、大约800mg、大约900mg或大约1000mg),优选50-500mg、100-400mg、150-300mg、150-250mg或200mg;
优选地,每3天、4天、5天、6天、10天、1周、2周或3周给药一次;
优选地,给药方式为静脉滴注或静脉注射。
在一些方案中,双特异性抗体的施用治疗以2周(14天)或3周(21天)为一个周期,优选在每个周期第一天(D1)静脉给予抗PVRIG抗体。例如,所述双特异性抗体以每两周一次(q2w)或者每三周一次(q3w)的频率施用。
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、分子遗传学、核酸化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文中所使用的,当提及PVRIG(NCBI GenBank ID:NP_076975.2)的氨基酸序列时,其包括PVRIG蛋白的全长或者细胞外片段;还包括PVRIG的融合蛋白,例如与小鼠或人IgG的Fc蛋白片段(mFc或hFc)进行融合的片段。然而,本领域技术人员理解,在PVRIG蛋白的氨基酸序列中,可天然产生或人工引入突变或变异(包括但不限于置换,缺失和/或添加),而不影响其生物学功能。因此,在本发明中,术语“PVRIG蛋白”或“PVRIG”应包括所有此类序列,包括所示的序列以及其天然或人工的变体。并且,当描述PVRIG蛋白的序列片段时,其不仅包括的序列片段,还包括其天然或人工变体中的相应序列片段。
如本文中所使用的,当提及TIGIT(NCBI GenBank ID:NP_776160.2)的氨基酸序列时,其包括TIGIT蛋白的全长或功能片段;还包括TIGIT的融合蛋白,例如与小鼠或人IgG的Fc蛋白片段(mFc或hFc)进行融合的片段。然而,本领域技术人员理解,在TIGIT蛋白的氨基酸序列中,可天然产生或人工引入突变或变异(包括但不限于置换,缺失和/或添加),而不影响其生物学功能。因此,在本发明中,术语“TIGIT蛋白”或“TIGIT”应包括所有此类序列,包括所示的序列以及其天然或人工的变体。并且,当描述TIGIT蛋白的序列片段时,其不仅包括的序列片段,还包括其天然或人工变体中的相应序列片段。
如本文中所使用的,术语EC50是指半最大效应浓度(concentration for 50%ofmaximal effect),是指能引起50%最大效应的浓度。
如本文中所使用的,术语“抗体”是指通常由两对多肽链(每对具有一条“轻”(L)链和一条“重”(H)链)组成的免疫球蛋白分子。抗体轻链可分类为κ和λ轻链。重链可分类为μ、δ、γ、α或ε,并且分别将抗体的同种型定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链内,可变区和恒定区通过大约12或更多个氨基酸的“J”区连接,重链还包含大约3个或更多个氨基酸的“D”区。各重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1、CH2和CH3)组成。各轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由一个结构域CL组成。抗体的恒定区可介导免疫球蛋白与宿主组织或因子,包括免疫***的各种细胞(例如,效应细胞)和经典补体***的第一组分(C1q)的结合。VH和VL区还可被细分为具有高变性的区域(称为互补决定区(CDR)),其间散布有较保守的称为构架区(FR)的区域。各VH和VL由按下列顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4从氨基末端至羧基末端排列的3个CDR和4个FR组成。各重链/轻链对的可变区(VH和VL)分别形成抗原结合部位。氨基酸至各区域或结构域的分配遵循Kabat Sequences of Proteins of Immunological Interest(National Institutes of Health,Bethesda M.d.(1987and 1991)),或Chothia&LeskJ.Mol.Biol.1987;196:901-917;Chothia等人Nature 1989;342:878-883或者IMGT编号***定义,见Ehrenmann,Francois,Quentin Kaas,and Marie-Paule Lefranc."IMGT/3Dstructure-DB and IMGT/DomainGapAlign:a database and a tool forimmunoglobulins or antibodies,T cell receptors,MHC,IgSF and MhcSF."Nucleicacids research 2009;38(suppl_1):D301-D307.的定义。术语“抗体”不受任何特定的产生抗体的方法限制。例如,其包括,特别地,重组抗体、单克隆抗体和多克隆抗体。抗体可以是不同同种型的抗体,例如,IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或IgM抗体。
如本文中所使用的,术语抗体的“抗原结合片段”是指包含全长抗体的片段的多肽,其保持特异性结合全长抗体所结合的相同抗原的能力,和/或与全长抗体竞争对抗原的特异性结合,其也被称为“抗原结合部分”。通常参见,Fundamental Immunology,Ch.7(Paul,W.,ed.,第2版,Raven Press,N.Y.(1989),其以其全文通过引用合并入本文,用于所有目的。可通过重组DNA技术或通过完整抗体的酶促或化学断裂产生抗体的抗原结合片段。在一些情况下,抗原结合片段包括Fab、Fab'、F(ab')2、Fd、Fv、dAb和互补决定区(CDR)片段、单链抗体(例如,scFv)、嵌合抗体、双抗体(diabody)和这样的多肽,其包含足以赋予多肽特异性抗原结合能力的抗体的至少一部分。
如本文中所使用的,术语“Fd片段”意指由VH和CH1结构域组成的抗体片段;术语“Fv片段”意指由抗体的单臂的VL和VH结构域组成的抗体片段;术语“dAb片段”意指由VH结构域组成的抗体片段(Ward等人,Nature 341:544-546(1989));术语“Fab片段”意指由VL、VH、CL和CH1结构域组成的抗体片段;术语“F(ab')2片段”意指包含通过铰链区上的二硫桥连接的两个Fab片段的抗体片段。
在一些情况下,抗体的抗原结合片段是单链抗体(例如,scFv),其中VL和VH结构域通过使其能够产生为单个多肽链的连接体配对形成单价分子(参见,例如,Bird等人,Science 242:423-426(1988)和Huston等人,Proc.Natl.Acad.Sci.USA 85:5879-5883(1988))。此类scFv分子可具有一般结构:NH2-VL-接头-VH-COOH或NH2-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,可使用具有氨基酸序列(GGGGS)4的接头,但也可使用其变体(Holliger等人(1993),Proc.Natl.Acad.Sci.USA 90:6444-6448)。可用于本发明的其他接头由Alfthan等人(1995),Protein Eng.8:725-731,Choi等人(2001),Eur.J.Immunol.31:94-106,Hu等人(1996),Cancer Res.56:3055-3061,Kipriyanov等人(1999),J.Mol.Biol.293:41-56和Roovers等人(2001),Cancer Immunol.描述。
在一些情况下,抗体的抗原结合片段是双抗体,即,双价抗体,其中VH和VL结构域在单个多肽链上表达,但使用太短的连接体以致不允许在相同链的两个结构域之间配对,从而迫使结构域与另一条链的互补结构域配对并且产生两个抗原结合部位(参见,例如,Holliger P.等人,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993),和Poljak R.J.等人,Structure 2:1121-1123(1994))。
在另一些情况下,抗体的抗原结合片段是“双特异性抗体”,指由第一抗体(片段)和第二抗体(片段)或抗体类似物通过偶联臂所形成的偶联物,偶联的方式包括但不限于化学反应、基因融合和酶促。抗体的抗原结合片段可以是“多特异性抗体”包括例如:三特异性抗体和四特异性抗体,前者是具有三种不同抗原结合特异性的抗体,而后者是具有四种不同抗原结合特异性的抗体。例如,经设计的锚蛋白重复蛋白(DARPin),与IgG抗体,scFv-Fc抗体片段相连或其组合,如CN104341529A。抗IL-17a的fynomer与抗IL-6R抗体结合,如WO2015141862A1。
可使用本领域技术人员已知的常规技术(例如,重组DNA技术或酶促或化学断裂法)从给定的抗体(例如本发明提供的单克隆抗体ADI-56127、ADI-55796和ADI-55812)获得抗体的抗原结合片段(例如,上述抗体片段),并且以与用于完整抗体的方式相同的方式就特异性筛选抗体的抗原结合片段。
如本文中所使用的,术语“单抗”和“单克隆抗体”是指,来自一群高度同源的抗体分子中的一个抗体或抗体的一个片段,也即除可能自发出现的自然突变外,一群完全相同的抗体分子。单抗对抗原上的单一表位具有高特异性。多克隆抗体是相对于单克隆抗体而言的,其通常包含至少2种或更多种的不同抗体,这些不同的抗体通常识别抗原上的不同表位。单克隆抗体通常可采用Kohler等首次报道的杂交瘤技术获得(G,MilsteinC.Continuous cultures of fused cells secreting antibody of predefinedspecificity[J].nature,1975;256(5517):495),但也可采用重组DNA技术获得(如参见U.S.Patent 4,816,567)。
如本文中所使用的,术语“人源化抗体”是指,人源免疫球蛋白(受体抗体)的全部或部分CDR区被一非人源抗体(供体抗体)的CDR区替换后得到的抗体或抗体片段,其中的供体抗体可以是具有预期特异性、亲和性或反应性的非人源(例如,小鼠、大鼠或兔)抗体。此外,受体抗体的构架区(FR)的一些氨基酸残基也可被相应的非人源抗体的氨基酸残基替换,或被其他抗体的氨基酸残基替换,以进一步完善或优化抗体的性能。关于人源化抗体的更多详细内容,可参见例如,Jones et al.,Nature 1986;321:522-525;Reichmann etal.,Nature 1988;332:323-329;Presta,Curr.Op.Struct.Biol.,1992;2:593-596;和Clark M.Antibody humanization:a case of the‘Emperor’s new clothes’?[J].Immunol.Today,2000;21(8):397-402。
如本文中所使用的,术语“分离的”或“被分离的”指的是,从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”或“被分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
如本文中所使用的,术语“载体(vector)”是指,可将多聚核苷酸***其中的一种核酸运载工具。当载体能使***的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、***瘤病毒、***多瘤空泡病毒(如SV40)。一种载体可以含有多种控制表达的元件,包括但不限于,启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。
如本文中所使用的,术语“宿主细胞”是指,可用于导入载体的细胞,其包括但不限于,如大肠杆菌或枯草杆菌等的原核细胞,如酵母细胞或曲霉菌等的真菌细胞,如S2果蝇细胞或Sf9等的昆虫细胞,或者如纤维原细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,GS细胞,BHK细胞,HEK 293细胞或人细胞等的动物细胞。
如本文中使用的,术语“特异性结合”是指,两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。在某些实施方式中,特异性结合某抗原的抗体(或对某抗原具有特异性的抗体)是指,抗体以小于大约10-5M,例如小于大约10-6M、10-7M、10-8M、10-9M或10-10M或更小的亲和力(KD)结合该抗原。
如本文中所使用的,术语“KD”是指特定抗体-抗原相互作用的解离平衡常数,其用于描述抗体与抗原之间的结合亲和力。平衡解离常数越小,抗体-抗原结合越紧密,抗体与抗原之间的亲和力越高。通常,抗体以小于大约10-5M,例如小于大约10-6M、10-7M、10-8M、10- 9M或10-10M或更小的解离平衡常数(KD)结合抗原(例如,TIGIT蛋白)。可以使用本领域技术人员知悉的方法测定KD,例如使用Fortebio分子相互作用仪测定。
如本文中所使用的,术语“单克隆抗体”和“单抗”具有相同的含义且可互换使用;术语“多克隆抗体”和“多抗”具有相同的含义且可互换使用;术语“多肽”和“蛋白质”具有相同的含义且可互换使用。并且在本发明中,氨基酸通常用本领域公知的单字母和三字母缩写来表示。例如,丙氨酸可用A或Ala表示。
如本文中所使用的,术语“药学上可接受的辅料”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的(参见例如Remington'sPharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:MackPublishing Company,1995),并且包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如肿瘤)有效量是指,足以预防,阻止,或延迟疾病(例如肿瘤)的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。
如本文中所使用的,术语“杂交瘤”和“杂交瘤细胞株”可互换使用,并且当提及术语“杂交瘤”和“杂交瘤细胞株”时,其还包括杂交瘤的亚克隆和后代细胞。
在本发明中,如果没有特别说明,所述“第一”(例如第一产品)和“第二”(例如第二产品)是为了指代上的区分或表述上的清楚,并不具有典型的次序上的含义。
发明的有益效果
本发明实现了如下的(1)至(4)项中所述技术效果中的一项或多项:
(1)本发明的双特异性抗体能够与TIGIT和PVRIG结合,亲和力较高。
(2)本发明的双特异性抗体与抗PD-1抗体或者抗PD-L1抗体之间很可能具有协同作用。
(3)本发明的抗体能够有效地治疗和/或预防肿瘤,例如结肠癌、黑色素瘤、肺癌、肾癌、子宫内膜癌、乳腺癌、皮肤癌、卵巢癌、胃癌、头颈癌、肝癌、脑瘤、尿路上皮癌、骨肿瘤、胆管癌、卵巢癌、直肠癌、胰腺癌、宫颈瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、B淋巴细胞瘤、浆细胞癌、***癌和睾丸癌等。
(4)本发明的双特异性抗体具有较低的毒副作用。
附图说明
图1A至图1C:本发明的双特异性抗体的结构示意图。
图2:本发明的双特异性抗体对于CHO细胞上过表达的人TIGIT的结合曲线图。
图3:本发明的双特异性抗体对于CHO细胞上过表达的食蟹猴TIGIT的结合曲线图。
图4:本发明的双特异性抗体对于CHO细胞上过表达的小鼠TIGIT的结合曲线图。
图5:本发明的双特异性抗体阻断人CD155与CHO细胞上过表达的人TIGIT结合的曲线图。
图6:本发明的双特异性抗体阻断小鼠CD155与CHO细胞上过表达的小鼠TIGIT结合的曲线图。
图7:本发明的双特异性抗体对于CHO细胞上过表达的人PVRIG的结合曲线图。
图8:本发明的双特异性抗体对于CHO细胞上过表达的食蟹猴PVRIG的结合曲线图。
图9:本发明的双特异性抗体对于CHO细胞上过表达的小鼠PVRIG的结合曲线图。
图10:本发明的双特异性抗体阻断人PVRIG与CHO细胞上过表达的人CD112结合的曲线图。
图11:本发明的双特异性抗体阻断小鼠CD112与小鼠PVRIG蛋白结合的曲线图。
图12:本发明的双特异性抗体同时结合人PVRIG和人TIGIT蛋白的曲线图。
图13:本发明的双特异性抗体阻断TIGIT/CD155与PVRIG/CD112信号通路的曲线图。
图14A至图14B:本发明的双特异性抗体联合抗PD-1/L1单抗阻断TIGIT/CD155、PVRIG/CD112及PD-1/PD-L1信号通路的曲线图。
图15:本发明的双特异性抗体在混合接种A375和人PBMC的B-NDG小鼠模型的药效曲线图。
图16A至图16B:本发明的双特异性抗体联合抗PD-1单抗在混合接种A375和人PBMC的B-NDG小鼠模型的药效曲线图。
图17:本发明的双特异性抗体在小鼠体内半衰期曲线。
图18:本发明抗TIGIT抗体对于CHO细胞上过表达的人TIGIT的结合活性曲线。
图19:本发明抗TIGIT抗体对于CHO细胞上过表达的食蟹猴TIGIT的结合活性曲线。
图20:本发明抗TIGIT抗体对于CHO细胞上过表达的小鼠TIGIT的结合活性曲线。
图21:本发明抗TIGIT抗体阻断人CD155与CHO细胞上过表达的人TIGIT的结合的阻断活性曲线。
图22:本发明抗TIGIT抗体阻断小鼠CD155与CHO细胞上过表达的小鼠TIGIT的结合的阻断活性曲线。
图23:本发明抗TIGIT抗体与激活的人原代T细胞上TIGIT的结合活性曲线。
图24:本发明抗PVRIG抗体对于CHO细胞上过表达的人PVRIG的结合活性曲线。
图25:本发明抗PVRIG抗体对于CHO细胞上过表达的食蟹猴PVRIG的结合活性曲线。
图26:本发明抗PVRIG抗体对于CHO细胞上过表达的小鼠PVRIG的结合活性曲线。
图27:本发明抗PVRIG抗体阻断人PVRIG与CHO细胞上过表达的人CD112的结合的阻断活性曲线。
图28:抗PVRIG抗体阻断小鼠CD112与小鼠PVRIG蛋白结合的曲线图。
图29:抗PVRIG抗体与激活的人原代T细胞上PVRIG的结合曲线图。
图30:抗PVRIG抗体在混合接种A375和人PBMC的NDG小鼠模型的药效图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
抗体Atezolizumab:抗PD-L1单抗,商品名Tecentriq,罗氏Roche。
抗体Pembrolizumab:抗PD-1单抗,商品名Keytruda,默沙东(Merck)。
由HEK293细胞表达并纯化下述对照抗体:
COM701是由HEK293细胞表达的来自Compugen公司的抗人PVRIG抗体,其轻链可变区序列和重链可变区序列与美国专利US10227408B2中的SEQ ID NO:1372、SEQ ID NO:1380一致;
Mab46是由HEK293细胞表达的来自Surface Oncology公司的抗人PVRIG抗体,其轻链可变区和重链可变区序列与美国专利公开US20200040081A1中的SEQ ID NO:912、SEQ IDNO:918一致。
Tiragolumab是由HEK293细胞表达的来自Genentech公司的抗人TIGIT抗体,其轻链和重链序列来源于WHO Drug Information,Vol.31,No.2,2017,Proposed INN:List117,CAS号:1918185-84-8。
实施例1:抗TIGIT-抗PVRIG双特异性抗体的设计与制备
在本实施例中,采用全基因合成方式分别将抗PVRIG单抗ADI-56127的scFv通过GGGGSGGGGS连接子串联至抗TIGIT单抗ADI-55796的重链C端(图1A),将抗TIGIT单抗ADI-55796的scFv通过GGGGSGGGGS连接子串联至抗PVRIG单抗ADI-56127的重链C端(图1B)以及将抗TIGIT单抗ADI-55812的重链(CH3区突变形成“Knob”结构)与抗PVRIG单抗ADI-56127的重链(CH3区突变形成“Hole”结构)并通过“Knob into hole”的方式组合成“1+1”的分子结构(图1C),分别形成三个不同结构的抗TIGIT/PVRIG双特异性抗体,分别命名为TP-007-008、TP-003-009、TP-001-002-003,其示意结构如图1A至图1C所示。抗TIGIT抗体的scFv以及抗PVRIG抗体的scFv均分别采用“VH-linker-VL”的连接方式,VH与VL之间柔性肽linker为“GGGGSGGGGSGGGGSGGGGS”,同时将抗TIGIT单抗ADI-55796的VH46、VL100和抗PVRIG单抗ADI-56127的VH44和VL101的甘氨酸突变为半胱氨酸以增强scFv的稳定性。三种双特异性抗体均采用人IgG1亚型。抗TIGIT单抗ADI-55796、ADI-55812和抗PVRIG单抗ADI-56127以及形成的双特异性抗体的序列如下面的表1所示。
表1:抗TIGIT-抗PVRIG双抗及对应单端抗体的抗体序列
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利用分子克隆技术将抗体肽段序列分别构建到pcDNA3.1表达框内。使用化学转染的方法将带有抗TIGIT-抗PVRIG双特异性抗体TP-007-008的肽链#1和肽链#2的pcDNA3.1载体转入HEK293细胞中制备TP-007-008双抗,将带有抗TIGIT-抗PVRIG双特异性抗体TP-003-009的肽链#1和肽链#2的pcDNA3.1载体转入HEK293细胞中制备TP-003-009双抗,将带有抗TIGIT-抗PVRIG双特异性抗体TP-001-002-003的肽链#1、肽链#2和肽链#3的pcDNA3.1载体转入HEK293细胞中制备TP-001-002-003双抗。细胞培养5天后收集上清,采用蛋白A磁珠(购自金斯瑞)分选法纯化目的蛋白。将磁珠用适当体积的结合缓冲液(PBS+0.1%吐温20,pH7.4)重悬(1-4倍磁珠体积)后加入至待纯化样品中,室温孵育1小时,期间温柔振荡。样品置于磁力架上(购自海狸),弃去上清,磁珠用结合缓冲液清洗3遍。按照磁珠体积的3-5倍体积加入洗脱缓冲液(0.1M sodium citrate,pH 3.2)室温振荡5-10分钟,置回磁力架上,收集洗脱缓冲液,转移至已加入中和缓冲液(1MTris,pH 8.54)的收集管中混匀。获得纯化的TP-007-008,TP-003-009,TP-001-002-003三株双抗,超滤置换成PBS,经LC-MS确认分子量,用于后续体内外活性检测。
实施例2:抗体亲和力检测
采用生物膜层光学干涉技术(ForteBio)测定实施例1获得的3个双特异性抗体及其对应的3个单端抗体分子Anti-TIGIT单抗ADI-55796、Anti-TIGIT单抗ADI-55812和Anti-PVRIG单抗ADI-56127结合人、食蟹猴TIGIT和PVRIG蛋白的结合解离常数(KD)。Fortebio亲和力测定按照现有方法(Este,P等人High throughput solution-based measurement ofantibody-antigen affinity and epitope binning.Mabs,2013.5(2):p.270-8)进行,其中人TIGIT和食蟹猴TIGIT的胞外段氨基酸序列,人PVRIG和食蟹猴PVRIG的胞外段氨基酸序列参见上面的表1。
具体操作如下:
测量抗体与人、食蟹猴TIGIT-his蛋白及人PVRIG-his蛋白的单价亲和力:传感器在分析缓冲液中线下平衡20分钟,然后线上检测120s建立基线,加载完整的抗体至AHQ传感器至厚度1nm进行亲和力检测。将已加载抗体的传感器于100nM靶抗原中作用至平台期,然后将传感器转移到分析缓冲液中至少2分钟用于解离速率测量。使用1:1结合模型进行动力学分析。
测量抗体与食蟹猴PVRIG-Fc蛋白的双价亲和力:传感器在分析缓冲液中线下平衡20分钟,然后线上检测120s建立基线,加载完整的抗体至AHQ传感器至厚度1nm进行亲和力检测。将已加载抗体的传感器于高浓度无关完整抗体液中继续加载10分钟,饱和封闭AHQ传感器上Fc结合位点,将封闭完成的传感器于100nM靶抗原中作用至平台期,然后将传感器转移到分析缓冲液中至少2分钟用于解离速率测量。使用1:1结合模型进行动力学分析。
双特异性抗体及其对应单端抗体分子结合人、食蟹猴TIGIT及PVRIG的KD值如下面的表2所示。
表2:抗TIGIT-抗PVRIG双抗及对应单端抗体的KD值
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注:"N.D":未检测。“W.B”:结合弱。
结果显示,抗TIGIT/PVRIG双抗TP-007-008、TP-003-009与人TIGIT、食蟹猴TIGIT抗原结合的单价亲和力与其单端抗体分子ADI-55796的单价亲和力相似;抗TIGIT/PVRIG双抗TP-001-002-003与人TIGIT抗原结合的单价亲和力与其单端抗体分子ADI-55812的单价亲和力相似;抗TIGIT/PVRIG双抗TP-007-008、TP-003-009、TP-001-002-003与人PVRIG抗原结合的单价亲和力与其单端抗体分子ADI-56127的单价亲和力相似;抗TIGIT/PVRIG双抗TP-007-008、TP-003-009、TP-001-002-003与食蟹猴PVRIG抗原结合的双价亲和力与其单端抗体分子ADI-56127的双抗亲和力相似。
实施例3:抗TIGIT-抗PVRIG双特异性抗体与过表达人/食蟹猴/小鼠TIGIT CHO细
胞的结合活性及阻断活性
3.1基于流式细胞术检测法检测抗TIGIT-抗PVRIG双特异性抗体与过表达在CHO细胞上人/食蟹猴/小鼠TIGIT的结合活性。
具体地,通过转染克隆到MCS的人TIGIT、食蟹猴TIGIT、小鼠TIGIT cDNA的pCHO1.0载体(购自Invitrogen)加压筛选产生过表达人TIGIT的CHO-S细胞(CHO-huTIGIT细胞),过表达食蟹猴TIGIT的CHO-S细胞(CHO-cynoTIGIT细胞)以及过表达小鼠TIGIT的CHO-S细胞(CHO-muTIGIT细胞)。将扩大培养的过表达细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟。PBS清洗两次,加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得EC50数值。
结果如表3、图2至图4所示。
表3:抗TIGIT-抗PVRIG双抗对TIGIT/CD155结合或阻断活性
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注:”N.B”不结合。
结果显示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008与过表达在CHO细胞上人/食蟹猴/小鼠TIGIT的结合活性与其TIGIT端单抗分子ADI-55796相似。
3.2基于流式细胞术检测法检测抗TIGIT-抗PVRIG双特异性抗体对于人CD155与过表达在CHO细胞上人TIGIT的结合阻断以及小鼠CD155与过表达在CHO细胞上小鼠TIGIT的结合阻断活性。
具体地,将扩大培养的CHO-huTIGIT细胞调整细胞密度至2×106细胞/mL,100μL/孔加入96孔流式板,离心备用。将待测抗体用PBS稀释,400nM开始3倍稀释共12个点。将稀释好的样品60μL/孔加入上述带有细胞的96孔流式板中,4℃共孵育30分钟。然后60μL/孔加入带有Mouse IgG2a Fc Tag的人CD155蛋白,终浓度为2μg/mL,4℃共孵育30分钟。PBS清洗两次,100μL/孔加入用PBS稀释100倍的APC羊抗鼠IgG抗体,4℃孵育30分钟。PBS清洗两次,100μL/孔加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。
将扩大培养的CHO-muTIGIT细胞调整细胞密度至2×106细胞/mL,100μL/孔加入96孔流式板,离心备用。将待测抗体用PBS稀释,400nM开始3倍稀释共12个点。将稀释好的样品60μL/孔加入上述带有细胞的96孔流式板中,4℃共孵育30分钟。然后60μL/孔加入带有Mouse IgG2a Fc Tag的小鼠CD155蛋白,终浓度为2μg/mL,4℃共孵育30分钟。PBS清洗两次,100μL/孔加入用PBS稀释100倍的APC羊抗鼠IgG抗体,4℃孵育30分钟。PBS清洗两次,100μL/孔加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得IC50数值。
结果如表3、图5至图6所示。结果显示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008对于人CD155与过表达在CHO细胞上人TIGIT的结合阻断以及小鼠CD155与过表达在CHO细胞上小鼠TIGIT的结合阻断活性与其TIGIT端单抗分子ADI-55796相似。
实施例4:抗TIGIT-抗PVRIG双特异性抗体与过表达人/食蟹猴/小鼠PVRIG CHO细
胞的结合活性及阻断活性
4.1基于流式细胞术检测法检测抗TIGIT-抗PVRIG双特异性抗体与过表达在CHO细胞上人/食蟹猴/小鼠PVRIG的结合活性。
具体地,通过转染克隆到MCS的人PVRIG、食蟹猴PVRIG和小鼠PVRIG的pCHO1.0载体(购自Invitrogen)加压筛选产生过表达人PVRIG的CHO-S细胞(CHO-huPVRIG细胞)、过表达食蟹猴PVRIG的CHO-S细胞(CHO-cynoPVRIG细胞)和过表达小鼠PVRIG的CHO-S细胞(CHO-muPVRIG细胞)。将扩大培养的过表达细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟。PBS清洗两次,加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得EC50数值。
结果如表4、图7至图9所示。
表4:抗TIGIT-抗PVRIG双抗对PVRIG/CD112结合或阻断活性
结果显示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-003-009与过表达在CHO细胞上人/食蟹猴/小鼠PVRIG的结合活性与其PVRIG端单抗分子ADI-56127相似;本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008与过表达在CHO细胞上人PVRIG的结合活性与其PVRIG端单抗分子ADI-56127相似。
4.2基于流式细胞术检测法检测抗TIGIT-抗PVRIG双特异性抗体对于人PVRIG与过表达在CHO细胞上人CD112结合的阻断活性。
具体地,通过转染克隆到MCS的人CD112的pCHO1.0载体(购自Invitrogen)加压筛选产生过表达人CD112的CHO-S细胞(CHO-huCD112细胞)。将纯化的待测抗体用PBS稀释,将稀释好的样品60μL/孔加入96孔流式板中。然后60μL/孔加入1μg/mL的带有Mouse IgG2a FcTag的人PVRIG蛋白,混匀后4℃孵育30分钟。将扩大培养的CHO-huCD112细胞调整细胞密度至2×106细胞/mL,100μL/孔加入96孔流式板,离心后弃上清。100μL/孔加入上述共孵育完成的抗体抗原混合液,4℃孵育30分钟。PBS清洗两次,100μL/孔加入用PBS稀释100倍的APCgoat anti-Mouse IgG,4℃孵育30分钟。PBS清洗两次,100μL/孔加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得IC50数值。
结果如表4和图10所示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008、TP-003-009对于人PVRIG与过表达在CHO细胞上人CD112的结合的阻断活性与其PVRIG端单抗分子ADI-56127相似。
4.3基于酶联免疫吸附测定法检测抗TIGIT-抗PVRIG双特异性抗体对于小鼠PVRIG与小鼠CD112蛋白结合的阻断活性。
具体地,小鼠CD112-his蛋白按照说明书溶解,用1×ELISA包被液稀释至1μg/mL,100μL/孔包被96孔ELISA板中,4℃覆膜过夜。弃去包被液,1×PBST清洗3次,200μL/孔加入5%BSA/PBS室温封闭2小时。封闭期间,将纯化的待测抗体用1%BSA/PBS进行梯度稀释,终体积为60μL/孔。然后60μL/孔加入生物素化标记的带有Mouse IgG2a Fc Tag的小鼠PVRIG蛋白,混匀后室温孵育1小时。封闭结束弃去ELISA板中封闭液,100μL/孔加入上述抗体抗原混合液,室温孵育2小时。弃去抗体抗原混合液,1×PBST清洗3次,100μL/孔加入1%BSA/PBS稀释的SA-HRP,室温孵育1小时。弃去SA-HRP稀释液,1×PBST清洗3次,100μL/孔加入ELISA显色液室温反应1-3分钟,50μL/孔加入ELISA终止液,读取450nm处吸光度数值。采用Graphpad软件作图获得浓度-吸光度值的结合曲线图,并获得IC50数值。
结果如表4和图11所示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-003-009对于小鼠PVRIG与小鼠CD112蛋白结合的阻断活性与其PVRIG端单抗分子ADI-56127相似。
实施例5:抗TIGIT-抗PVRIG双特异性抗体与人TIGIT和人PVRIG共结合活性
基于酶联免疫吸附剂检测法(ELISA)检测本发明抗TIGIT-抗PVRIG双特异性抗体与人TIGIT和人PVRIG蛋白共结合活性。
具体地,人PVRIG蛋白按照说明书溶解,用1×ELISA包被液稀释至1μg/mL,100μL/孔包被96孔ELISA板中,4℃覆膜过夜。弃去包被液,1×PBST清洗3次,200μL/孔加入5%BSA/PBS室温封闭2小时。弃去封闭液,100μL/孔加入1%BSA/PBS梯度稀释的待测抗体,室温孵育2小时。弃去抗体稀释液,1×PBST清洗3次,100μL/孔加入1%BSA/PBS稀释的生物素标记的TIGIT蛋白,终浓度为1μg/mL,室温孵育1小时。弃去抗原稀释液,1×PBST清洗3次,100μL/孔加入1%BSA/PBS稀释的SA-HRP,室温孵育1小时。弃去SA-HRP稀释液,1×PBST清洗3次,100μL/孔加入ELISA显色液室温反应1-3分钟,50μL/孔加入ELISA终止液,读取450nm处吸光度数值。采用Graphpad软件作图获得浓度-吸光度值的结合曲线图。
结果如图12所示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008、TP-003-009、TP-001-002-003均可同时结合人TIGIT和人PVRIG蛋白。
实施例6:抗TIGIT-抗PVRIG双特异性抗体在荧光素酶报告基因***对TIGIT/
CD155与PVRIG/CD112信号通路的阻断活性
为进一步在细胞水平检测抗TIGIT-抗PVRIG双特异性抗体同时阻断TIGIT/CD155与PVRIG/CD112信号通路的活性,本实施例构建了如下荧光素酶报告基因***。简言之,利用慢病毒转染细胞,构建了过表达人CD155、人CD112和anti-CD3 scFv的CHO-K1细胞株(CHO-K1-CD155-CD112-aAPC),构建了过表达人TIGIT、人PVRIG和NF-AT luciferase报告基因(购自promega)的Jurkat细胞株(Jurkat-TIGIT-PVRIG-NF-AT-luc),后续利用这一报告基因***开展相关试验。
具体地,消化获取CHO-K1-CD155-CD112-aAPC功能细胞,调整细胞密度,100μL/孔加入96孔白底板中,贴壁培养过夜。第二天,制备Jurkat-TIGIT-PVRIG-NF-AT-luc效应细胞悬液,将待测样品用反应培养基梯度稀释。取出白底板,吸去培养上清,将上述稀释好的样品40μL/孔加入白底板,同时40μL/孔加入Jurkat-TIGIT-PVRIG-NF-AT-luc效应细胞悬液,置于37℃,5%CO2培养箱培养6小时,期间将Bio-Glo TM reagent恢复至室温。培养完成,取出细胞,室温平衡5分钟,80μL/孔加入Bio-Glo TM reagent,使用多功能酶标仪读取荧光信号值。
结果如图13所示。结果显示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008、TP-003-009、TP-001-002-003均可以分别解除CD155介导的TIGIT下游抑制信号通路,以及CD112介导的PVRIG下游抑制信号通路,上调报告基因荧光素酶表达,且TP-007-008阻断活性与两单端抗体分子的联合应用相似。
实施例7:荧光素酶报告基因***检测抗TIGIT-抗PVRIG双特异性抗体与抗PD-1/
L1抗体联合阻断效应
为检测抗TIGIT-抗PVRIG双特异性抗体与抗PD-1/抗PD-L1抗体在细胞水平的协同联合阻断活性,本实施例构建了如下荧光素酶报告基因***,简略描述为:在实施例6的基础上,慢病毒感染CHO-K1-CD155-CD112-aAPC以过表达PD-L1获得CHO-K1-CD155-CD112-PD-L1-aAPC功能细胞,慢病毒感染Jurkat-TIGIT-PVRIG-NF-AT-luc以过表达PD-1,获得Jurkat-TIGIT-PVRIG-PD-1-NF-AT-luc效应细胞,后续利用这一报告基因***开展相关试验。
具体地,消化获取CHO-K1-CD155-CD112-PD-L1-aAPC功能细胞,调整细胞密度,100μL/孔加入96孔白底板中,贴壁培养过夜。第二天,制备Jurkat-TIGIT-PVRIG-PD-1-NF-AT-luc效应细胞悬液,将待测样品用反应培养基梯度稀释。取出白底板,吸去培养上清,将上述稀释好的样品40μL/孔加入白底板,同时40μL/孔加入Jurkat-TIGIT-PVRIG-PD-1-NF-AT-luc效应细胞悬液,置于37℃,5%CO2培养箱培养6小时。培养完成后80μL/孔加入Bio-GloTMreagent,使用多功能酶标仪读取荧光信号值。
结果如图14A至图14B所示。结果显示,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008、TP-003-009、TP-001-002-003按照1:1的摩尔比与抗PD-1抗体Pembrolizumab(Pembro)或与抗PD-L1抗体Atezolizumab(ATE)联合可以协同阻断PVRIG/CD112、TIGIT/CD155和PD-1/PD-L1分别介导的下游抑制信号,进一步增强报告基因荧光素酶表达。
实施例8:抗TIGIT-抗PVRIG双特异性抗体在B-NDG小鼠混合接种A375和人PBMC体
内药效学研究
本实验在B-NDG小鼠混合接种A375(购自Addexbio,C0020004,一种人恶性黑色素瘤细胞),人PBMC细胞(上海妙顺,A10S033014/PB100C)的模型(A375 huPBMC模型)中测定本发明的抗TIGIT-抗PVRIG双特异性抗体的抗肿瘤作用。其中,通过将人的免疫细胞(PBMC)接种至免疫缺陷小鼠中,产生局部重组人类免疫***的人源化肿瘤小鼠模型。
具体地,首先A375细胞与人PBMC 1:1等体积混合成0.1mL细胞悬液,在小鼠右腹沟以皮下注射的方式建立A375 huPBMC模型,待平均肿瘤体积长至75mm3左右时进行分组,腹腔注射给予不同剂量、相同给药体积的PBS或抗体治疗,每组6只小鼠。监测各组小鼠瘤体积和体重变化,监测频率均为2-3天/次,连续监测2到3周,给药剂量和方式如表5。
表5:抗TIGIT-抗PVRIG双特异性抗体A375 huPBMC模型给药方案
组别 | 给药剂量 | 给药频率/次数 |
PBS | N/A | Q2-3d×8 |
TP-001-002-003 | 20mg/kg | Q2-3d×8 |
TP-003-009 | 13.33mg/kg | Q2-3d×8 |
TP-007-008 | 13.33mg/kg | Q2-3d×8 |
ADI-55796+ADI-56127 | 10mg/kg+10mg/kg | Q2-3d×8 |
备注:TP-001-002-003、TP-003-009、TP-007-008、ADI-55796、ADI-56127分子量分别约为150KD、200KD、200KD、150KD、150KD,给药剂量按各组分等摩尔浓度剂量给药。
结果如图15所示。结果表明,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008与TP-003-009具有显著的抗肿瘤作用,且抑瘤效果与两单端抗体分子联用相当。
实施例9:抗TIGIT-抗PVRIG双特异性抗体联合抗PD-1单抗在B-NDG小鼠混合接种
A375和人PBMC体内药效学研究
本实验采用皮下混合接种的方式建立A375 huPBMC模型(建模步骤与实施例8相同),待平均肿瘤体积长至200mm3左右时进行分组,腹腔注射给予不同剂量、相同给药体积的PBS或抗体治疗,每组6只小鼠。监测各组小鼠瘤体积和体重变化,监测频率均为2-3天/次,连续监测2到3周,给药剂量和方式如表6。
表6:抗TIGIT-抗PVRIG双抗肿瘤抑制活性试验方案
为了进一步研究抗TIGIT-抗PVRIG双特异性抗体TP-007-008与抗PD-1单抗联合疗法的剂量依赖性药效,设计了下述试验方案:采用皮下混合接种的方式建立A375 huPBMC模型(建模步骤与实施例8相同),待平均肿瘤体积长至300mm3左右时进行分组,腹腔注射给予不同剂量TP-007-008与固定剂量抗PD-1抗体联合治疗,每组6只小鼠。监测各组小鼠瘤体积和体重变化,监测频率均为2-3天/次,连续监测2到3周,给药剂量和方式如表7。
表7:抗TIGIT-抗PVRIG双抗肿瘤抑制活性试验方案
组别 | 给药剂量 | 给药频率/次数 |
PBS | N/A | Q2-3d×4 |
Anti-PD-1+TP-007-008 | 3mg/kg+3mg/kg | Q2-3d×4 |
Anti-PD-1+TP-007-008 | 3mg/kg+12mg/kg | Q2-3d×4 |
Anti-PD-1+TP-007-008 | 3mg/kg+48mg/kg | Q2-3d×4 |
结果如图16A所示,当初始给药肿瘤体积达到200mm3以上,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008、抗PD-1单抗以及抗TIGIT与抗PVRIG单抗联合用药组均未观察到明显的抑瘤药效,而TP-007-008与抗PD-1单抗联用时则能显著抑制肿瘤生长,并且与抗PD-1、抗TIGIT、抗PVRIG三单抗联合用药具有相似的药效。如图16B所示,抗TIGIT-抗PVRIG双特异性抗体TP-007-008与固定剂量PD-1单抗(3mg/kg)联合具有剂量依赖性的显著肿瘤抑制活性。
本实施例中用到的抗PD-1单抗的序列如下:
抗PD-1抗体VH氨基酸序列
QVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYIYWVRQAPGQGLEWIGGINPSNGGTNFNEKFKPRVTMTVDTSTSTAYMELSSLRSEDTAVYYCTVRDFRFDKGFKYWGQGTLVTVSS(SEQ ID NO:34)
抗PD-1抗体VL氨基酸序列
EIVLTQSPATLSLSPGERATLSCRASKSVSTSGLNYVHWYQRKPGQAPRLLIYLGSYLDSGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWELPLTFGGGTKVEIK(SEQ ID NO:35)
上述抗PD-1抗体的CDR,如下:
HCDR1:YTFTEYYIY(SEQ ID NO:36)
HCDR2:GINPSNGGTNFNEKFKP(SEQ ID NO:37)
HCDR3:TVRDFRFDKGFKY(SEQ ID NO:38)
LCDR1:RASKSVSTSGLNYVH(SEQ ID NO:39)
LCDR2:LGSYLDS(SEQ ID NO:40)
LCDR3:QQSWELPLT(SEQ ID NO:41)
本实施例中用到的抗PD-1单抗重链恒定区采用经L234A、L235A改造的IgG1重链恒定区:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:42)
本实施例中用到的抗PD-1单抗重链恒定区采用人kappa轻链恒定区:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:43)
实施例10:抗TIGIT-抗PVRIG双特异性抗体小鼠体内半衰期研究
采用尾静脉单次注射法,检测本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008在小鼠体内半衰期。
具体地,实验用Balb/c小鼠,雌雄各3只,12/12小时光/暗调节,温度24℃±2℃,湿度40%-70%,自由进水饮食。实验当天对Balb/c小鼠单次尾静脉注射单克隆抗体分子,注射剂量为10mg/kg。取血时间点:给药后5分钟、0.5小时、2小时、6小时、24小时、48小时、96小时、168小时、336小时、504小时于小鼠眼眶采血。全血样品2℃-8℃放置30分钟,12000rpm离心5分钟收集血清,所得血清再于2℃-8℃,12000rpm离心5分钟,-80℃保存,ELISA检测血清中双特异性抗体分子含量(ELISA检测方法与实例5相同)。
结果如图17所示。结果表明,本发明的抗TIGIT-抗PVRIG双特异性抗体TP-007-008单次注射在小鼠体内半衰期为103小时。
制备例1:抗TIGIT单抗的制备
将抗TIGIT单抗的各重链可变区(氨基酸序列分别如SEQ ID NO:1-2所示)分别重组到人IgG1重链恒定区,以及人IgG1重链L234A、L235A改造的恒定区中。此外,将各轻链可变区(氨基酸序列分别如SEQ ID NO:3-4所示)重组到人kappa轻链恒定区,将抗TIGIT单抗分别命名为55796-G1、55796-G1LALA、55812-G1、55812-G1LALA。经由HEK293表达***瞬时表达纯化。具体操作如下:使用化学转染的方法将带有抗体重链和轻链的pcDNA3.1载体转入HEK293细胞中,在37℃,8%CO2条件下,培养7天。收集细胞液,13000rpm离心20分钟。取上清液,Protein A纯化上清液,SEC检测抗体纯度,同时控制内毒素含量。
由此制得抗TIGIT单抗55796-G1、55796-G1LALA、55812-G1、55812-G1LALA。
试验例1:抗TIGIT单抗的亲和力检测
采用生物膜层光学干涉技术(ForteBio)测定制备例1制得的抗TIGIT单抗结合人、食蟹猴、小鼠TIGIT的结合解离常数(KD)。Fortebio亲和力测定按照现有方法(Este,P等人High throughput solution-based measurement of antibody-antigen affinity andepitope binning.Mabs,2013.5(2):p.270-8)进行。其中人TIGIT的胞外段氨基酸序列、食蟹猴TIGIT的胞外段氨基酸序列、小鼠TIGIT的胞外段氨基酸序列参见上面的表1。
测量完整抗体(即,通过Adimab原始获得的全长IgG)与人、食蟹猴、小鼠TIGIT-his蛋白的单价亲和力:传感器在分析缓冲液中线下平衡20分钟,然后线上检测120s建立基线,加载完整的TIGIT抗体至AHQ传感器至厚度1nm进行亲和力检测。将已加载抗体的传感器于100nM TIGIT-his抗原中作用至平台期,然后将传感器转移到分析缓冲液中至少2分钟用于解离速率测量。使用1:1结合模型进行动力学分析。
在如上测定方法中,测得的KD值如下表8所示:
表8:抗TIGIT单抗的KD值
注:"NA":not available。"N.B.":no binding。
由表8结果可见:(1)抗TIGIT单抗与人TIGIT-his蛋白的单价亲和力高于对照分子Tiragolumab;(2)抗TIGIT单抗与食蟹猴TIGIT-his蛋白的单价亲和力与对照分子Tiragolumab相当;(3)抗TIGIT单抗55796-G1和55796-G1LALA与小鼠TIGIT有交叉结合活性。
试验例2:抗TIGIT单抗与过表达人/食蟹猴/小鼠TIGIT CHO细胞的结合活性及阻
断活性
2.1基于流式细胞术检测法检测抗TIGIT单抗与过表达在CHO细胞上人/食蟹猴/小鼠TIGIT的结合活性。
具体地,通过转染克隆到MCS的人TIGIT、食蟹猴TIGIT、小鼠TIGIT cDNA的pCHO1.0载体(购自Invitrogen)加压筛选产生过表达人TIGIT的CHO-S细胞(CHO-huTIGIT细胞),过表达食蟹猴TIGIT的CHO-S细胞(CHO-cynoTIGIT细胞)以及过表达小鼠TIGIT的CHO-S细胞(CHO-muTIGIT细胞)。将扩大培养的过表达细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟,PBS清洗两次。加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得EC50数值。结果如表9和图18至图20所示。
2.2基于流式细胞术检测法检测抗TIGIT单抗,阻断人CD155与过表达在CHO细胞上人TIGIT的结合,阻断小鼠CD155与过表达在CHO细胞上小鼠TIGIT的结合的阻断活性。
具体地,将扩大培养的CHO-huTIGIT细胞调整细胞密度至2×106细胞/mL,100μL/孔加入96孔流式板,离心备用。将纯化的单克隆抗体用PBS稀释,400nM开始3倍稀释共12个点。将稀释好的样品60μL/孔加入上述带有细胞的96孔流式板中,4℃共孵育30分钟。然后60μL/孔加入带有Mouse IgG2a Fc Tag的人CD155蛋白,终浓度为2μg/mL,4℃共孵育30分钟,PBS清洗两次。100μL/孔加入用PBS稀释100倍的APC羊抗鼠IgG抗体,4℃孵育30分钟,PBS清洗两次。100μL/孔加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。
将扩大培养的CHO-muTIGIT细胞调整细胞密度至2×106细胞/mL,100μL/孔加入96孔流式板,离心备用。将纯化的单克隆抗体用PBS稀释,400nM开始3倍稀释共12个点。将稀释好的样品60μL/孔加入上述带有细胞的96孔流式板中,4℃共孵育30分钟。然后60μL/孔加入带有Mouse IgG2a Fc Tag的小鼠CD155蛋白,终浓度为2μg/mL,4℃共孵育30分钟,PBS清洗两次。100μL/孔加入用PBS稀释100倍的APC羊抗鼠IgG抗体,4℃孵育30分钟,PBS清洗两次。100μL/孔加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得IC50数值。结果如表9和图21至图22所示。
表9:抗TIGIT单抗过表达细胞结合阻断活性汇总表
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注:"N.B.":no binding;and"NA":not available.
由表9和图18至图20可见:本发明的抗TIGIT单抗,(1)与CHO细胞表面过表达的人TIGIT蛋白结合活性优于对照分子Tiragolumab;(2)与CHO细胞表面过表达的食蟹猴TIGIT蛋白结合活性优于对照分子Tiragolumab;(3)55796-G1和55796-G1LALA与CHO细胞表面过表达的小鼠TIGIT蛋白有明显结合。
由表9和图21至图22可见:本发明的抗TIGIT单抗,(1)阻断人CD155与CHO细胞表面过表达的人TIGIT蛋白结合的能力优于对照分子Tiragolumab;(2)与CHO细胞表面过表达的小鼠TIGIT蛋白有结合的抗TIGIT抗体分子55796-G1和55796-G1LALA可以明显阻断小鼠CD155与CHO细胞表面过表达的小鼠TIGIT蛋白的结合。
试验例3:抗TIGIT单抗与原代T细胞表面TIGIT结合
基于流式细胞术检测法检测发明抗TIGIT抗体与激活T细胞表面的TIGIT结合活性。
具体地,将人PBMC按照STEMCELL公司提供的试验方案(stemcell,货号:#17951C)进行分选获得human total T细胞。用X-VIVO15培养基(购自lonza,货号:04-418Q)调整T细胞浓度至1.0×106细胞/mL,加入1μL IL-2储备液(100万IU),同时1:1(bead-to-cell)加入CD3/CD28 Dynabeads(购自gibco,货号:11132D),于37℃,5%CO2培养箱内培养48小时。将活化后的T细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟,PBS清洗两次。加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。
结果如图23所示。结果表明,本发明抗TIGIT抗体55796-G1、55796-G1LALA、55812-G1、55812-G1LALA能够结合T细胞表面的TIGIT分子,且结合活性优于对照分子Tiragolumab。
制备例2:抗PVRIG单抗的制备
将抗PVRIG单抗的重链可变区(氨基酸序列如SEQ ID NO:5所示)分别重组到人IgG1重链恒定区,以及人IgG1重链L234A、L235A改造的恒定区中。此外,将轻链可变区(氨基酸序列分别如SEQ ID NO:4所示)重组到人kappa轻链恒定区,将抗PVRIG单抗分别命名为ADI-56127-G1、ADI-56127-G1LALA。经由HEK293表达***瞬时表达纯化。具体操作如下:使用化学转染的方法将带有抗体重链和轻链的pcDNA3.1载体转入HEK293细胞中,在37℃,8%CO2条件下,培养7天。收集细胞液,13000rpm离心20分钟。取上清液,Protein A纯化上清液,SEC检测抗体纯度,同时控制内毒素含量。
由此制得抗PVRIG单抗ADI-56127-G1、ADI-56127-G1LALA。
试验例4:抗PVRIG抗体与过表达人/食蟹猴/小鼠PVRIG CHO细胞的结合活性及阻
断活性
4.1基于流式细胞术检测法检测抗PVRIG抗体与过表达在CHO细胞上人/食蟹猴/小鼠PVRIG的结合活性。
具体地,通过转染克隆到MCS的人PVRIG、食蟹猴PVRIG、小鼠PVRIG cDNA的pCHO1.0载体(购自Invitrogen)加压筛选产生过表达人PVRIG的CHO细胞(CHO-huPVRIG细胞),过表达食蟹猴PVRIG的CHO细胞(CHO-cynoPVRIG细胞)以及过表达小鼠PVRIG的CHO细胞(CHO-muPVRIG细胞)。将扩大培养的过表达细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟,PBS清洗两次。加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。采用Graphpad软件作图分析获得EC50数值。结果如表10、图24至图26所示。
4.2基于流式细胞术检测法检测抗PVRIG抗体阻断人PVRIG与过表达在CHO细胞上人CD112结合的活性。
具体地,通过转染克隆到MCS的人CD112 cDNA的pCHO1.0载体(购自Invitrogen)加压筛选产生过表达人CD112的CHO细胞(CHO-huCD112细胞)。将扩大培养的CHO-huCD112细胞调整细胞密度至2×106细胞/mL,100μL/孔加入96孔流式板,离心备用。用PBS梯度稀释纯化的单克隆抗体,将稀释好的样品60μL/孔加入空白96孔流式板中,然后60μL/孔加入1ug/mL的带有Mouse IgG2a Fc Tag的人PVRIG蛋白,混匀后4℃孵育30分钟。将上述孵育完毕的样品100μL/孔加入含有CHO-huCD112细胞的96孔流式板中,4℃共孵育30分钟,PBS清洗两次。100μL/孔加入用PBS稀释100倍的APC羊抗鼠IgG抗体,4℃孵育30分钟,PBS清洗两次。100μL/孔加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。结果如表10、图27所示。
4.3基于ELISA检测法检测抗PVRIG抗体阻断小鼠PVRIG蛋白与小鼠CD112蛋白结合的活性。
具体地,用1×包被缓冲液稀释mouse CD112-his蛋白至终浓度为1μg/mL,100μL/孔加入酶标板中,覆膜,4℃静置包被过夜。弃去酶标板中包被液,用1×PBST清洗3次,200μL/孔加入5%BSA/PBS室温封闭2小时。封闭期间,取待测样品用1%BSA/PBS梯度稀释,终体积为60μL/孔。取生物素标记的Mouse PVRIG huFc蛋白用1%BSA/PBS稀释至2μg/mL,60μL/孔加入上述样品孔中,混匀后室温孵育1小时。弃去酶标板中封闭液,100μL/孔加上上述样品混合液,室温孵育2小时。弃去上述共孵育样品,用1×PBST清洗3次,100μL/孔加入1%BSA/PBS稀释的SA-HRP,室温孵育1小时。弃去SA-HRP稀释液,1×PBST清洗3次,100μL/孔加入ELISA显色液室温反应1-3分钟,50μL/孔加入ELISA终止液,读取450nm处吸光度数值。采用Graphpad软件作图获得浓度-吸光度值的结合曲线图,结果如表10、图28所示。
表10:抗PVRIG抗体分子过表达细胞结合阻断活性汇总表
注:"N.B.":no binding(无结合);"NA":not available(未检测)。
由表10、图24至图26可以得出如下结论:
(1)ADI-56127-G1、ADI-56127-LALA与CHO细胞表面过表达的人PVRIG蛋白结合活性优于对照分子Mab46-G1、Mab46-G1LALA和COM701-G4;
(2)ADI-56127-G1、ADI-56127-LALA与CHO细胞表面过表达的食蟹猴PVRIG蛋白结合活性优于对照分子Mab46-G1、Mab46-G1LALA和COM701-G4;
(3)ADI-56127-G1、ADI-56127-LALA与CHO细胞表面过表达的小鼠PVRIG蛋白有明显结合,结合活性与对照分子Mab46-G1、Mab46-G1LALA相当。
由表10和图27至图28可以得出如下结论:
(1)ADI-56127-G1、ADI-56127-LALA阻断人PVRIG与CHO细胞表面过表达的人CD112蛋白结合的活性与对照分子Mab46-G1、Mab46-G1LALA和COM701-G4相当;
(2)ADI-56127-G1、ADI-56127-G1LALA可以明显阻断小鼠PVRIG与小鼠CD112蛋白的结合,且阻断活性优于对照分子Mab46-G1、Mab46-G1LALA。
试验例5:抗PVRIG抗体与原代T细胞表面PVRIG结合
基于流式细胞术检测法检测发明抗PVRIG抗体与激活T细胞表面的PVRIG结合活性。
具体地,将人PBMC按照STEMCELL公司提供的试验方案(stemcell,货号:#17951C)进行分选获得human total T细胞。用X-VIVO15培养基(购自Lonza,货号:04-418Q)调整T细胞浓度至1.0×106细胞/mL,加入1μL IL-2储备液(100万IU),同时1:1(bead-to-cell)加入CD3/CD28 Dynabeads(购自gibco,货号:11132D),于37℃,5%CO2培养箱内培养48小时。将活化后的T细胞调整至合适细胞密度加入96孔流式板,离心后加入梯度稀释的待测样品,4℃孵育30分钟。PBS清洗两次,加入对应稀释至合适浓度的荧光二抗,4℃孵育30分钟,PBS清洗两次。加入PBS重悬细胞,在CytoFlex流式细胞仪上进行检测并计算对应的MFI。
结果如图29所示。结果表明,本发明抗PVRIG抗体ADI-56127-G1、ADI-56127-G1LALA可以结合激活T细胞表面的PVRIG分子,且结合活性优于对照分子Mab46-G1、Mab46-G1LALA、COM701-G4。
试验例6:抗PVRIG抗体在NDG小鼠混合接种A375和人PBMC体内药效学研究
本实验在B-NDG小鼠混合接种A375(购自Addexbio,C0020004,一种人恶性黑色素瘤细胞),人PBMC细胞(上海妙顺,A10S033014/PB100C)的模型(A375 huPBMC模型)中测定本发明的抗PVRIG抗体的抗肿瘤作用。其中,通过将人的免疫细胞(PBMC)接种至免疫缺陷小鼠中,产生局部重组人类免疫***的人源化肿瘤小鼠模型。
具体地,首先A375细胞与人PBMC 1:1等体积混合成0.1mL细胞悬液,在小鼠右腹沟以皮下注射的方式建立A375 huPBMC模型。待平均肿瘤体积长至30-50mm3左右时进行分组,腹腔注射给予不同剂量、相同给药体积的PBS或抗体治疗,每组6只小鼠。监测各组小鼠瘤体积和体重变化,监测频率均为2-3天/次,连续监测2到3周,给药剂量和方式如表11。
表11:抗PVRIG抗体A375 PBMC模型给药方案
组别 | 给药剂量 | 给药频率/次数 |
PBS | N/A | Q2-3d×8 |
ADI-56127-G1 | 10mg/kg | Q2-3d×8 |
Mab46-G1 | 10mg/kg | Q2-3d×8 |
COM701-G4 | 10mg/kg | Q2-3d×8 |
结果如图30所示。结果表明,本发明的抗PVRIG抗体ADI-56127-G1能够显著抑制小鼠A375肿瘤的生长,且抗肿瘤活性优于对照分子Mab46-G1和COM701-G4。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
SEQUENCE LISTING
<110> 普米斯生物技术(珠海)有限公司
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Gly Asp Ile Ile Pro Phe Phe Asp Thr Asp Tyr Ala Gln Lys Phe Gln
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Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
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Arg Glu Gly Gly Thr Ser Trp Thr His Phe Phe Asp Leu Trp Gly Arg
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Gly Thr Leu Val Thr Val Ser Ser
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Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
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Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
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Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
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Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
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His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
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Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
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His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
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Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
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Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
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Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
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Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
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Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
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Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
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Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
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Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gln Val
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Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
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Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Glu Ser Val Asp Ala Ile
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Ser Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Asp
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Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu
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Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
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Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
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Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
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Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
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Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
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Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
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Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
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Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
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Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
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Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met
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Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
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Arg Glu Gly Gly Thr Ser Trp Thr His Phe Phe Asp Leu Trp Gly Arg
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Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
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Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
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Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
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Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
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Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
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Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
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Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
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Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
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Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
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Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
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Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
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Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
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Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
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Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
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Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
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Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
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Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
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Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
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Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
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Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
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Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gln Leu Gln Leu
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Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ala Glu Thr Leu Ser Leu
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Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr Asp His Tyr Trp
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Thr Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile Gly Thr
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Val Tyr Tyr Ser Gly Ser Thr Phe His Asn Pro Ser Leu Lys Ser Arg
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Val Thr Ile Pro Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu
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Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val
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Gly Pro Asp Val Ser His Pro Pro Phe Asp Tyr Trp Gly Gln Gly Thr
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Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Asp Ile Gln Met Thr
595 600 605
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
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Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
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Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser
645 650 655
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
660 665 670
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
675 680 685
Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Ile Thr Phe Gly Cys Gly
690 695 700
Thr Lys Val Glu Ile Lys
705 710
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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 Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 11
<211> 455
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT-抗PVRIG双特异性抗体TP-001-002-003 的肽链#1
<400> 11
Gln 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 Ala Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ser Ile Ile Pro Phe Ser Gly Glu Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Pro Gly Ser Leu Asp Arg Leu Trp Tyr Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr
355 360 365
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly
450 455
<210> 12
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT-抗PVRIG双特异性抗体TP-001-002-003 的肽链#2
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Glu Ser Val Asp
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Ile Pro Phe Phe Asp Thr Asp Tyr Ala Gln Lys Phe Gln
50 55 60
Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met
65 70 75 80
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Gly Thr Ser Trp Thr His Phe Phe Asp Leu Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 13
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55796重链可变区的HCDR1
<400> 13
Gly Ser Ile Ser Ser Tyr Asp His Tyr Trp Thr
1 5 10
<210> 14
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55796重链可变区的HCDR2
<400> 14
Thr Val Tyr Tyr Ser Gly Ser Thr Phe His Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 15
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55796重链可变区的HCDR3
<400> 15
Ala Arg Val Gly Pro Asp Val Ser His Pro Pro Phe Asp Tyr
1 5 10
<210> 16
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55796轻链可变区的LCDR1
<400> 16
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
1 5 10
<210> 17
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55796轻链可变区的LCDR2
<400> 17
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55796轻链可变区的LCDR3
<400> 18
Gln Gln Ser Tyr Ser Thr Pro Ile Thr
1 5
<210> 19
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55812重链可变区的HCDR1
<400> 19
Tyr Ala Phe Thr Gly Tyr Tyr Met His
1 5
<210> 20
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55812重链可变区的HCDR2
<400> 20
Ser Ile Ile Pro Phe Ser Gly Glu Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 21
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55812重链可变区的HCDR3
<400> 21
Ala Arg Gly Pro Gly Ser Leu Asp Arg Leu Trp Tyr Tyr Tyr Tyr Gly
1 5 10 15
Met Asp Val
<210> 22
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55812轻链可变区的LCDR1
<400> 22
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55812轻链可变区的LCDR2
<400> 23
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 24
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗TIGIT单抗ADI-55812轻链可变区的LCDR3
<400> 24
Gln Gln Tyr Gly Ser Ser Pro Ile Thr
1 5
<210> 25
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗PVRIG单抗ADI-56127重链可变区的HCDR1
<400> 25
Gly Thr Glu Ser Val Asp Ala Ile Ser
1 5
<210> 26
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗PVRIG单抗ADI-56127重链可变区的HCDR2
<400> 26
Asp Ile Ile Pro Phe Phe Asp Thr Asp Tyr Ala Gln Lys Phe Gln Gly
1 5 10 15
<210> 27
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗PVRIG单抗ADI-56127重链可变区的HCDR3
<400> 27
Ala Arg Glu Gly Gly Thr Ser Trp Thr His Phe Phe Asp Leu
1 5 10
<210> 28
<211> 171
<212> PRT
<213> Artificial Sequence
<220>
<223> 人PVRIG的胞外段氨基酸序列
<400> 28
Met Arg Thr Glu Ala Gln Val Pro Ala Leu Gln Pro Pro Glu Pro Gly
1 5 10 15
Leu Glu Gly Ala Met Gly His Arg Thr Leu Val Leu Pro Trp Val Leu
20 25 30
Leu Thr Leu Cys Val Thr Ala Gly Thr Pro Glu Val Trp Val Gln Val
35 40 45
Arg Met Glu Ala Thr Glu Leu Ser Ser Phe Thr Ile Arg Cys Gly Phe
50 55 60
Leu Gly Ser Gly Ser Ile Ser Leu Val Thr Val Ser Trp Gly Gly Pro
65 70 75 80
Asn Gly Ala Gly Gly Thr Thr Leu Ala Val Leu His Pro Glu Arg Gly
85 90 95
Ile Arg Gln Trp Ala Pro Ala Arg Gln Ala Arg Trp Glu Thr Gln Ser
100 105 110
Ser Ile Ser Leu Ile Leu Glu Gly Ser Gly Ala Ser Ser Pro Cys Ala
115 120 125
Asn Thr Thr Phe Cys Cys Lys Phe Ala Ser Phe Pro Glu Gly Ser Trp
130 135 140
Glu Ala Cys Gly Ser Leu Pro Pro Ser Ser Asp Pro Gly Leu Ser Ala
145 150 155 160
Pro Pro Thr Pro Ala Pro Ile Leu Arg Ala Asp
165 170
<210> 29
<211> 171
<212> PRT
<213> Artificial Sequence
<220>
<223> 食蟹猴PVRIG的胞外段氨基酸序列
<400> 29
Met Arg Thr Glu Ala Gln Val Leu Ala Leu Gln Ser Pro Glu Pro Gly
1 5 10 15
Leu Glu Gly Ala Met Gly Arg Arg Thr Leu Ala Leu Pro Trp Val Leu
20 25 30
Leu Thr Leu Cys Val Thr Ala Gly Thr Pro Glu Val Trp Val Gln Val
35 40 45
Gln Met Glu Ala Thr Glu Leu Ser Ser Phe Thr Val His Cys Gly Phe
50 55 60
Leu Gly Pro Gly Ser Ile Ser Leu Val Thr Val Ser Trp Gly Gly Pro
65 70 75 80
Asp Gly Ala Gly Gly Thr Lys Leu Ala Val Leu His Pro Glu Leu Gly
85 90 95
Thr Arg Gln Trp Ala Pro Ala Arg Gln Ala Arg Trp Glu Thr Gln Ser
100 105 110
Ser Ile Ser Leu Ala Leu Glu Asp Ser Gly Ala Ser Ser Pro Phe Ala
115 120 125
Asn Thr Thr Phe Cys Cys Lys Phe Ala Ser Phe Pro Glu Gly Ser Trp
130 135 140
Glu Ser Cys Gly Ser Leu Pro Pro Ser Ser Asp Pro Gly Leu Ser Ala
145 150 155 160
Pro Pro Thr Pro Val Pro Ile Leu Arg Ala Asp
165 170
<210> 30
<211> 131
<212> PRT
<213> Artificial Sequence
<220>
<223> 小鼠PVRIG的胞外段氨基酸序列
<400> 30
Ser Pro Glu Val Trp Val Gln Val Gln Met Glu Ala Thr Asn Leu Ser
1 5 10 15
Ser Phe Ser Val His Cys Gly Val Leu Gly Tyr Ser Leu Ile Ser Leu
20 25 30
Val Thr Val Ser Cys Glu Gly Phe Val Asp Ala Gly Arg Thr Lys Leu
35 40 45
Ala Val Leu His Pro Glu Phe Gly Thr Gln Gln Trp Ala Pro Ala Arg
50 55 60
Gln Ala His Trp Glu Thr Pro Asn Ser Val Ser Val Thr Leu Thr Met
65 70 75 80
Gly Gln Ser Lys Ala Arg Ser Ser Leu Ala Asn Thr Thr Phe Cys Cys
85 90 95
Glu Phe Val Thr Phe Pro His Gly Ser Arg Val Ala Cys Arg Asp Leu
100 105 110
His Arg Ser Asp Pro Gly Leu Ser Ala Pro Thr Pro Ala Leu Asn Leu
115 120 125
Gln Ala Asp
130
<210> 31
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 人TIGIT的胞外段氨基酸序列
<400> 31
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro
115 120
<210> 32
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 食蟹猴TIGIT的胞外段氨基酸序列
<400> 32
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Lys Lys
1 5 10 15
Gly Gly Ser Val Ile Leu Gln Cys His Leu Ser Ser Thr Met Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln His Asp His Ser Leu Leu Ala Ile
35 40 45
Arg Asn Ala Glu Leu Gly Trp His Ile Tyr Pro Ala Phe Lys Asp Arg
50 55 60
Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Met
65 70 75 80
Asn Asp Thr Gly Glu Tyr Phe Cys Thr Tyr His Thr Tyr Pro Asp Gly
85 90 95
Thr Tyr Arg Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala
100 105 110
Glu His Ser Ala Arg Phe Gln Ile Pro
115 120
<210> 33
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 小鼠TIGIT的胞外段氨基酸序列
<400> 33
Thr Ile Asp Thr Lys Arg Asn Ile Ser Ala Glu Glu Gly Gly Ser Val
1 5 10 15
Ile Leu Gln Cys His Phe Ser Ser Asp Thr Ala Glu Val Thr Gln Val
20 25 30
Asp Trp Lys Gln Gln Asp Gln Leu Leu Ala Ile Tyr Ser Val Asp Leu
35 40 45
Gly Trp His Val Ala Ser Val Phe Ser Asp Arg Val Val Pro Gly Pro
50 55 60
Ser Leu Gly Leu Thr Phe Gln Ser Leu Thr Met Asn Asp Thr Gly Glu
65 70 75 80
Tyr Phe Cys Thr Tyr His Thr Tyr Pro Gly Gly Ile Tyr Lys Gly Arg
85 90 95
Ile Phe Leu Lys Val Gln Glu Ser Ser Asp Asp Arg Asn Gly Leu Ala
100 105 110
Gln Phe Gln Thr Ala Pro Leu Gly
115 120
<210> 34
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗PD-1抗体VH氨基酸序列
<400> 34
Gln 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 Glu Tyr
20 25 30
Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Pro Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Arg Asp Phe Arg Phe Asp Lys Gly Phe Lys Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 35
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗PD-1抗体VL氨基酸序列
<400> 35
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser
20 25 30
Gly Leu Asn Tyr Val His Trp Tyr Gln Arg Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Gly Ser Tyr Leu Asp Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Trp
85 90 95
Glu Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 36
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR1
<400> 36
Tyr Thr Phe Thr Glu Tyr Tyr Ile Tyr
1 5
<210> 37
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR2
<400> 37
Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe Lys
1 5 10 15
Pro
<210> 38
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR3
<400> 38
Thr Val Arg Asp Phe Arg Phe Asp Lys Gly Phe Lys Tyr
1 5 10
<210> 39
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR1
<400> 39
Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Leu Asn Tyr Val His
1 5 10 15
<210> 40
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR2
<400> 40
Leu Gly Ser Tyr Leu Asp Ser
1 5
<210> 41
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR3
<400> 41
Gln Gln Ser Trp Glu Leu Pro Leu Thr
1 5
<210> 42
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> 经L234A、L235A改造的IgG1重链恒定区
<400> 42
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 43
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 人kappa轻链恒定区
<400> 43
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
Claims (23)
1.一种双特异性抗体,其包括:
靶向PVRIG的第一蛋白功能区,和
靶向不同于PVRIG的靶点(例如TIGIT)的第二蛋白功能区;
其中:
所述第一蛋白功能区为抗PVRIG免疫球蛋白或其抗原结合片段;
所述抗PVRIG免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且
所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
2.根据权利要求1所述的双特异性抗体,其中,所述第二蛋白功能区为抗TIGIT免疫球蛋白或其抗原结合片段,其中:
所述抗TIGIT免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:13所示的HCDR1、氨基酸序列如SEQ ID NO:14所示的HCDR2以及氨基酸序列如SEQ ID NO:15所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:16所示的LCDR1、氨基酸序列如SEQ ID NO:17所示的LCDR2以及氨基酸序列如SEQ ID NO:18所示的LCDR3;
或者,
所述抗TIGIT免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:19所示的HCDR1、氨基酸序列如SEQ ID NO:20所示的HCDR2以及氨基酸序列如SEQ ID NO:21所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
3.根据权利要求1至2中任一权利要求所述的双特异性抗体,其中,所述抗原结合片段独立地为单链抗体或半分子型单价抗体(IgG half molecule,IgG-HM)。
4.根据权利要求1至3中任一权利要求所述的双特异性抗体,其中,
所述第一蛋白功能区为抗PVRIG免疫球蛋白,所述第二蛋白功能区为抗TIGIT单链抗体;其中:
所述抗PVRIG免疫球蛋白的重链可变区包含氨基酸序列如SEQ ID NO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3;和
所述的抗TIGIT单链抗体,其重链可变区包含氨基酸序列如SEQ ID NO:13所示的HCDR1、氨基酸序列如SEQ ID NO:14所示的HCDR2以及氨基酸序列如SEQ ID NO:15所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:16所示的LCDR1、氨基酸序列如SEQ ID NO:17所示的LCDR2以及氨基酸序列如SEQ ID NO:18所示的LCDR3;或者
所述的抗TIGIT单链抗体,其重链可变区包含氨基酸序列如SEQ ID NO:19所示的HCDR1、氨基酸序列如SEQ ID NO:20所示的HCDR2以及氨基酸序列如SEQ ID NO:21所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
5.根据权利要求1至3中任一权利要求所述的双特异性抗体,其中,
所述第一蛋白功能区为抗PVRIG单链抗体,所述第二蛋白功能区为抗TIGIT免疫球蛋白;其中:
所述抗PVRIG单链抗体的重链可变区包含氨基酸序列如SEQ ID NO:25所示的HCDR1、氨基酸序列如SEQ ID NO:26所示的HCDR2以及氨基酸序列如SEQ ID NO:27所示的HCDR3;并且所述抗PVRIG免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3;和
所述的抗TIGIT免疫球蛋白,其重链可变区包含氨基酸序列如SEQ ID NO:13所示的HCDR1、氨基酸序列如SEQ ID NO:14所示的HCDR2以及氨基酸序列如SEQ ID NO:15所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:16所示的LCDR1、氨基酸序列如SEQ ID NO:17所示的LCDR2以及氨基酸序列如SEQ ID NO:18所示的LCDR3;或者
所述的抗TIGIT免疫球蛋白,其重链可变区包含氨基酸序列如SEQ ID NO:19所示的HCDR1、氨基酸序列如SEQ ID NO:20所示的HCDR2以及氨基酸序列如SEQ ID NO:21所示的HCDR3;并且所述抗TIGIT免疫球蛋白的轻链可变区包含氨基酸序列如SEQ ID NO:22所示的LCDR1、氨基酸序列如SEQ ID NO:23所示的LCDR2以及氨基酸序列如SEQ ID NO:24所示的LCDR3。
6.根据权利要求1至5中任一权利要求所述的双特异性抗体,其中,
所述抗PVRIG免疫球蛋白或抗PVRIG单链抗体的重链可变区的氨基酸序列如SEQ IDNO:5所示;并且
所述抗PVRIG免疫球蛋白或抗PVRIG单链抗体的轻链可变区的氨基酸序列如SEQ IDNO:4所示。
7.根据权利要求1至6中任一权利要求所述的双特异性抗体,其中,
所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的重链可变区的氨基酸序列如SEQ IDNO:1所示;并且所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的轻链可变区的氨基酸序列如SEQ ID NO:2所示;
或者,
所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的重链可变区的氨基酸序列如SEQ IDNO:3所示;并且所述抗TIGIT免疫球蛋白或抗TIGIT单链抗体的轻链可变区的氨基酸序列如SEQ ID NO:4所示。
8.根据权利要求1至7中任一权利要求所述的双特异性抗体,其中,所述第一蛋白功能区和第二蛋白功能区直接连接或者通过连接片段连接;
优选地,所述连接片段为(GGGGS)m,m为正整数,例如1、2、3、4、5或6;
优选地,所述连接片段的氨基酸序列如SEQ ID NO:6所示。
9.根据权利要求1至8中任一权利要求所述的双特异性抗体,其中,所述第一蛋白功能区和第二蛋白功能区独立地为1个、2个或者2个以上。
10.根据权利要求1至9中任一权利要求所述的双特异性抗体,其中:
所述抗TIGIT单链抗体分别连接在抗PVRIG免疫球蛋白的两条重链的C末端;或者
所述抗PVRIG单链抗体分别连接在抗TIGIT免疫球蛋白的两条重链的C末端。
11.根据权利要求1至10中任一权利要求所述的双特异性抗体,其中,
所述抗PVRIG免疫球蛋白或抗TIGIT免疫球蛋白的恒定区来自人抗体;
优选地,所述恒定区独立地选自人IgG1、IgG2、IgG3或IgG4的恒定区。
12.根据权利要求1至11中任一权利要求所述的双特异性抗体,其中,
所述抗PVRIG免疫球蛋白或抗TIGIT免疫球蛋白的重链恒定区为人Ig gamma-1chain Cregion(例如NCBI ACCESSION:P01857)或人Ig gamma-4chain C region(例如NCBIACCESSION:P01861.1),并且其轻链恒定区为人Ig kappa chain C region(例如NCBIACCESSION:P01834);
优选地,所述抗PVRIG免疫球蛋白和抗TIGIT免疫球蛋白的重链恒定区还包含按照EU编号***的L234A突变和L235A突变。
13.根据权利要求1至12中任一权利要求所述的双特异性抗体,其为氨基酸序列如SEQID NO:7和SEQ ID NO:8所示的两条肽链的二聚体,或者为氨基酸序列如SEQ ID NO:9和SEQID NO:10所示的两条肽链的二聚体。
14.分离的核酸分子,其编码权利要求1至13中任一权利要求所述的双特异性抗体。
15.一种载体,其包含权利要求14所述的分离的核酸分子。
16.一种宿主细胞,其包含权利要求14所述的分离的核酸分子,或者权利要求15所述的载体。
17.偶联物,其包括双特异性抗体以及偶联部分,其中,所述双特异性抗体为权利要求1至13中任一权利要求所述的双特异性抗体,所述偶联部分为可检测的标记;优选地,所述偶联部分为放射性同位素、荧光物质、有色物质或酶。
18.试剂盒,其包含权利要求1至13中任一权利要求所述的双特异性抗体,或者包含权利要求17所述的偶联物;
优选地,所述试剂盒还包含第二抗体,其能够特异性结合所述双特异性抗体;任选地,所述第二抗体还包括可检测的标记,例如放射性同位素、荧光物质、有色物质或酶。
19.一种药物组合物,其包含权利要求1至13中任一权利要求所述的双特异性抗体,以及一种或多种药学上可接受的辅料;
优选地,所述药物组合物还包含至少一种抗PD-1抗体;
优选地,所述双特异性抗体与抗PD-1抗体的摩尔比是(1:5)至(5:1),更优选为1:1。
20.根据权利要求19所述的药物组合物,其中,所述的抗PD-1抗体,其包含重链可变区和轻链可变区,所述重链可变区包含HCDR1至HCDR3,所述轻链可变区包含LCDR1至LCDR3,其中:
HCDR1的氨基酸序列如SEQ ID NO:36所示,HCDR2的氨基酸序列如SEQ ID NO:37所示,HCDR3的氨基酸序列如SEQ ID NO:38所示,LCDR1的氨基酸序列如SEQ ID NO:39所示,LCDR2的氨基酸序列如SEQ ID NO:40所示和LCDR3的氨基酸序列如SEQ ID NO:41所示;
优选地,所述的抗PD-1抗体,其重链可变区的氨基酸序列如SEQ ID NO:34所示,并且轻链可变区的氨基酸序列如SEQ ID NO:35所示。
21.一种组合产品,其包含独立包装的第一产品和第二产品,其中,
所述第一产品包含其包含权利要求1至13中任一权利要求所述的双特异性抗体;
所述第二产品包含至少一种抗PD-1抗体;
优选地,所述第一产品和所述第二产品还独立地包含一种或多种药学上可接受的辅料;
优选地,所述组合产品还包含产品说明书;
优选地,所述双特异性抗体与抗PD-1抗体的摩尔比是(1:5)至(5:1),更优选为1:1。
22.根据权利要求21所述的组合产品,其中,所述的抗PD-1抗体,其包含重链可变区和轻链可变区,所述重链可变区包含HCDR1至HCDR3,所述轻链可变区包含LCDR1至LCDR3,其中:
HCDR1的氨基酸序列如SEQ ID NO:36所示,HCDR2的氨基酸序列如SEQ ID NO:37所示,HCDR3的氨基酸序列如SEQ ID NO:38所示,LCDR1的氨基酸序列如SEQ ID NO:39所示,LCDR2的氨基酸序列如SEQ ID NO:40所示和LCDR3的氨基酸序列如SEQ ID NO:41所示;
优选地,所述的抗PD-1抗体,其重链可变区的氨基酸序列如SEQ ID NO:34所示,并且轻链可变区的氨基酸序列如SEQ ID NO:35所示。
23.权利要求1至13中任一权利要求所述的双特异性抗体或者权利要求17所述的偶联物在制备治疗或预防肿瘤的药物中的用途;
优选地,所述肿瘤选自结肠癌、黑色素瘤、肺癌、肾癌、子宫内膜癌、乳腺癌、皮肤癌、卵巢癌、胃癌、头颈癌、肝癌、脑瘤、尿路上皮癌、骨肿瘤、胆管癌、卵巢癌、直肠癌、胰腺癌、宫颈瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、B淋巴细胞瘤、浆细胞癌、***癌和睾丸癌中的一种或多种;
优选地,所述肺癌为非小细胞肺癌或小细胞肺癌。
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