CN113754772A - 一种抗pdl1×kdr的双特异性抗体 - Google Patents
一种抗pdl1×kdr的双特异性抗体 Download PDFInfo
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Abstract
本发明提供了一种抗PDL1×KDR的双特异性抗体,实验结果显示该双抗能够较好的保持各自单抗的活性,并且能够同时特异性结合PD‑L1和KDR两个靶点,具有良好的理化性质。
Description
技术领域
本发明涉及抗体领域,更具体地,本发明公开了一种抗PDL1×KDR的双特异性抗体。
背景技术
人程序性细胞死亡受体-1(PD-1)是一种有288个氨基酸的I型膜蛋白,是已知的主要免疫检查点(Immune Checkpoint)之一(Blank et al,2005,Cancer Immunotherapy,54:307-314)。PD-1表达在已经激活的T淋巴细胞,它与配体PD-L1(程序性细胞死亡受体-配体1,programmed cell death-Ligand 1)和PD-L2(程序性细胞死亡受体-配体2,programmedcell death-Ligand 2)结合可以抑制T淋巴细胞的活性及相关的体内细胞免疫反应。PD-L2主要表达在巨噬细胞和树突状细胞,而PD-L1则广泛表达于B、T淋巴细胞及外周细胞如微血管上皮细胞,肺、肝、心等组织细胞中。大量研究表明,PD-1和PD-L1的相互作用不但是维持体内免疫系统平衡所必须,也是导致PD-L1表达阳性肿瘤细胞规避免疫监视的主要机制和原因。通过阻断癌细胞对PD-1/PD-L1信号通路的负调控,激活免疫系统,能够促进T细胞相关的肿瘤特异性细胞免疫反应,从而打开了一扇新的肿瘤治疗方法的大门--肿瘤免疫疗法。
PD-1(由基因Pdcd1编码)为与CD28和CTLA-4有关的免疫球蛋白超家族成员。研究成果显示,当PD-1与其配体(PD-L1和/或PD-L2)结合时会负调节抗原受体信号转导。目前已弄清鼠PD-1结构以及小鼠PD-1与人PD-L1的共结晶结构(Zhang,X.等,Immunity 20:337-347(2004);Lin等,Proc.Natl.Acad.Sci.USA 105:3011-6(2008))。PD-1及类似的家族成员为I型跨膜糖蛋白,其含有负责配体结合的Ig可变型(V-型)结构域和负责结合信号转导分子的胞质尾区。PD-1胞质尾区含有两个基于酪氨酸的信号转导模体ITIM(免疫受体酪氨酸抑制作用模体)和ITSM(免疫受体酪氨酸转换作用模体)。
PD-1在肿瘤的免疫逃避机制中起到了重要的作用。肿瘤免疫疗法,即利用人体自身的免疫系统抵御癌症,是一种突破性的肿瘤治疗方法,但是肿瘤微环境可保护肿瘤细胞免受有效的免疫破坏,因此如何打破肿瘤微环境成为抗肿瘤研究的重点。现有研究成果已确定了PD-1在肿瘤微环境中的作用:PD-L1在许多小鼠和人肿瘤中表达(并在大多数PD-L1阴性肿瘤细胞系中可由IFN-γ诱导),并被推定为介导肿瘤免疫逃避的重要靶点(Iwai Y.等,Proc.Natl.Acad.Sci.U.S.A.99:12293-12297(2002);Strome S.E.等,Cancer Res.,63:6501-6505(2003))。通过免疫组织化学评估活组织检查,已经在人的很多原发性肿瘤中发现PD-1(在肿瘤浸润淋巴细胞上)和/或PD-L1在肿瘤细胞上的表达。这样的组织包括肺癌、肝癌、卵巢癌、宫颈癌、皮肤癌、结肠癌、神经胶质瘤、膀胱癌、乳腺癌、肾癌、食道癌、胃癌、口腔鳞状细胞癌、尿道上皮细胞癌和胰腺癌以及头颈肿瘤等。由此可见,阻断PD-1/PD-L1的相互作用可以提高肿瘤特异性T细胞的免疫活性,有助于免疫系统清除肿瘤细胞,因此PD-L1成为开发肿瘤免疫治疗药物的热门靶点。
KDR所编码的蛋白也命名为血管内皮生长因子受体-2(Vascular endothelialgrowth factor receptor-2,VEGFR-2),是血管生长因子重要信号转导的重要受体。VEGFR2主要表达在血管内皮细胞,尤其是肿瘤的血管内皮细胞,主要与VEGF-C、D、A结合,促进血管生存。VEGF与VEGFR2的胞外区特异性结合,可以激活MAPK、PI3K、PKC、FAK等多条下游信号通路,参与了内皮细胞芽生、迁移、血管通透性、肿瘤细胞存活。VEGFR-2与多种疾病如肿瘤,牛皮癣,类风湿性关节炎,糖尿病性视网膜病变等密切相关。尤其是在肿瘤的生长,转移及肿瘤的多重耐药方面作用显著。因此VEGFR-2已成为治疗这些疾病特别是肿瘤的理想靶点。目前已知肿瘤血管丰富,临床试验数据表明靶向VEGFR-2对抑制肿瘤血管生成至关重要。但单独使用抗VEGFR-2药物往往药效十分短暂,这可能与血管过度修剪、极度缺氧密切相关。2018年已揭示了血管正常化和免疫反应之间相互调节的关系。肿瘤微环境中存在大量的免疫抑制细胞和功能失常的效应T细胞,联合使用免疫检查点抑制剂和抗血管生成药物,可显著延长肿瘤血管正常化的治疗窗,而血管的正常化减弱了肿瘤微环境中的免疫抑制过程,增加T细胞的浸润,最终促进肿瘤消退。
双特异性抗体是指能同时特异性结合两种抗原或两种表位的抗体分子。根据对称性,双特异性抗体可以分为结构对称的和不对称的分子。根据结合位点的多少,双特异性抗体可以分为二价、三价、四价和多价分子。双特异性抗体正在逐步成为一类新的治疗性抗体,可以用于治疗各种炎性疾病、癌症和其它疾病。
发明内容
本发明提供了一种抗PDL1×KDR的双特异性抗体。
因此,本发明的第一个目的在于提供一种抗PDL1×KDR的双特异性抗体。
本发明的第二个目的在于提供一种编码所述的双特异性抗体的分离的核苷酸。
本发明的第三个目的在于提供一种包含所述的核苷酸的表达载体。
本发明的第四个目的在于提供一种包含所述的表达载体的宿主细胞。
本发明的第五个目的在于提供所述的双特异性抗体的制备方法。
本发明的第六个目的在于提供包含所述的双特异性抗体的药物组合物。
本发明的第七个目的在于提供所述的双特异性抗体或所述的药物组合物在制备治疗癌症的药物中的用途。
本发明的第八个目的在于提供所述的双特异性抗体或所述的药物组合物用于治疗癌症的方法。
为了达到上述目的,本发明提供了以下技术方案:
本发明的第一个方面提供了一种抗PDL1×KDR的双特异性抗体,包含两条多肽链和两条轻链,其中:
(a)所述的多肽链从N末端至C末端包含VH-PDL1-CH1-CH2-CH3-linker2-VL-KDR-linker1-VH-KDR或VH-PDL1-CH1-CH2-CH3-linker2-VH-KDR-linker1-VL-KDR,所述的轻链从N末端至C末端包含VL-PDL1-CL;或
(b)所述的多肽链从N末端至C末端包含VL-PDL1-linker1-VH-PDL1-linker2-VH-KDR-CH1-CH2-CH3,所述的轻链从N末端至C末端包含VL-KDR-CL;
其中,所述的VH-PDL1为结合PD-L1的重链可变区,所述的VL-PDL1为结合PD-L1的轻链可变区,所述的VH-KDR为结合KDR的重链可变区,所述的VL-KDR为结合KDR的轻链可变区,所述的linker1为4个G4S,所述的linker2为3个G4S,所述的CH1-CH2-CH3为重链恒定区,所述的CL为轻链恒定区,所述的VH-PDL1与所述的VL-PDL1形成特异性结合PD-L1的抗原结合位点,所述的VH-KDR与所述的VL-KDR形成特异性结合KDR的抗原结合位点。
根据本发明的优选实施例,所述的VH-PDL1包含氨基酸序列如SEQ ID NO:1-3所示的重链CDR,所述的VL-PDL1包含氨基酸序列如SEQ ID NO:4-6所示的轻链CDR,所述的VH-KDR包含氨基酸序列如SEQ ID NO:7-9所示的重链CDR,所述的VL-KDR包含氨基酸序列如SEQID NO:10-12所示的轻链CDR。
根据本发明的优选实施例,所述的VH-PDL1具有如SEQ ID NO:13所示的氨基酸序列,所述的VL-PDL1具有如SEQ ID NO:14所示的氨基酸序列,所述的VH-KDR具有如SEQ IDNO:15所示的氨基酸序列,所述的VL-KDR具有如SEQ ID NO:16所示的氨基酸序列。
根据本发明的优选实施例,所述的多肽链具有如SEQ ID NO:17或SEQ ID NO:18所示的氨基酸序列,所述的轻链具有如SEQ ID NO:19所示的氨基酸序列;或所述的多肽链具有如SEQ ID NO:20所示的氨基酸序列,所述的轻链具有如SEQ ID NO:21所示的氨基酸序列。
根据本发明,所述的重链恒定区包括IgG1、IgG2、IgG3或IgG4重链恒定区,所述的轻链恒定区包括κ或λ轻链恒定区。
本发明的第二个方面提供了一种分离的核苷酸,所述的核苷酸编码所述的双特异性抗体。
本发明的第三个方面提供了一种表达载体,所述的表达载体含有如上所述的核苷酸。
本发明的第四个方面提供了一种宿主细胞,所述的宿主细胞含有如上所述的表达载体。
本发明的第五个方面提供了所述的双特异性抗体的制备方法,所述方法包含以下步骤:
(a)在表达条件下,培养如上所述的宿主细胞,从而表达所述的双特异性抗体;
(b)分离并纯化(a)所述的双特异性抗体。
本发明的第六个方面提供了一种药物组合物,所述药物组合物含有如上所述的双特异性抗体和药学上可接受的载体。
本发明的第七个方面提供了如上所述的双特异性抗体或如上所述的药物组合物在制备治疗癌症的药物中的用途。
根据本发明,所述癌症选自由以下组成的组:结直肠癌、非小细胞肺癌、胃癌、胃食管连接部腺癌、黑色素瘤、肺癌、肝癌、淋巴癌、白血病、前列腺癌、骨髓癌及其它赘生性恶性疾病等。
本发明的第八个方面提供了一种治疗癌症的方法,包括向有需要的受试者施用如上所述的双特异性抗体或如上所述的药物组合物。
根据本发明,所述癌症选自由以下组成的组:结直肠癌、非小细胞肺癌、胃癌、胃食管连接部腺癌、黑色素瘤、肺癌、肝癌、淋巴癌、白血病、前列腺癌、骨髓癌及其它赘生性恶性疾病等。
有益效果:本发明提供了一种抗PDL1×KDR的双特异性抗体,实验结果显示该双抗能够较好的保持各自单抗的活性,并且能够同时特异性结合PD-L1和KDR两个靶点,具有良好的理化性质。
附图说明
图1为本发明的抗PDL1×KDR双抗分子的结构示意图,其中,图1A为anti-KDR scFv串联在anti-PDL1 mAb的C末端,图1B为anti-PDL1 scFv串联在anti-KDR mAb的N末端。
图2为抗PDL1×KDR双抗的HPLC检测图谱和SDS-PAGE检测结果,其中,图2A为HPLC检测图谱,图2B为SDS-PAGE检测结果。
图3为ELISA检测抗PDL1×KDR双抗分别与PD-L1和KDR的结合结果,其中,图3A为与PD-L1的结合结果,图3B为与KDR的结合结果。
图4为双特异ELISA检测抗PDL1×KDR双抗同时与PD-L1和KDR的结合结果。
图5为FACS检测抗PDL1×KDR双抗与N87-PDL1细胞的结合结果。
图6为抗PDL1×KDR双抗阻断细胞上PD1/PD-L1的活性结果。
图7为抗PDL1×KDR双抗阻断细胞上KDR与VEGF结合的活性结果。
具体实施方式
本发明中,术语“抗体(Antibody,缩写Ab)”和“免疫球蛋白G(Immunoglobulin G,缩写IgG)”是有相同结构特征的约150000道尔顿的异四聚糖蛋白,其由两条相同的轻链(L)和两条相同的重链(H)组成。每条轻链通过一个共价二硫键与重链相连,而不同免疫球蛋白同种型(isotype)的重链间的二硫键数目不同。每条重链和轻链也有规则间隔的链内二硫键。每条重链的一端有可变区(VH),其后是恒定区,重链恒定区由三个结构域CH1、CH2、以及CH3构成。每条轻链的一端有可变区(VL),另一端有恒定区,轻链恒定区包括一个结构域CL;轻链的恒定区与重链恒定区的CH1结构域配对,轻链的可变区与重链的可变区配对。恒定区不直接参与抗体与抗原的结合,但是它们表现出不同的效应功能,例如参与抗体依赖的细胞介导的细胞毒性作用(ADCC,antibody-dependent cell-mediated cytotoxicity)等。重链恒定区包括IgG1、IgG2、IgG3、IgG4亚型;轻链恒定区包括κ(Kappa)或λ(Lambda)。抗体的重链和轻链通过重链的CH1结构域和轻链的CL结构域之间的二硫键共价连接在一起,抗体的两条重链通过铰链区之间形成的多肽间二硫键共价连接在一起。
本发明中,术语“双特异性抗体(双抗)”是指能同时特异性结合两种抗原(靶点)或两种表位的抗体分子。
本发明中,术语“单克隆抗体(单抗)”指从一类基本均一的群体获得的抗体,即该群体中包含的单个抗体是相同的,除少数可能存在的天然发生的突变外。单克隆抗体高特异性地针对单个抗原位点。而且,与常规多克隆抗体制剂(通常是具有针对不同抗原决定簇的不同抗体的混合物)不同,各单克隆抗体是针对抗原上的单个决定簇。除了它们的特异性外,单克隆抗体的好处还在于它们可以通过杂交瘤培养来合成,不会被其它免疫球蛋白污染。修饰语“单克隆”表示了抗体的特性,是从基本均一的抗体群中获得的,这不应被解释成需要用任何特殊方法来生产抗体。
本发明中,术语“Fab”和“Fc”是指木瓜蛋白酶可将抗体裂解为两个完全相同的Fab段和一个Fc段。Fab段由抗体的重链的VH和CH1以及轻链的VL和CL结构域组成。Fc段即可结晶片段(fragment crystallizable,Fc),由抗体的CH2和CH3结构域组成。Fc段无抗原结合活性,是抗体与效应分子或细胞相互作用的部位。
本发明中,术语“scFv”为单链抗体(single chain antibody fragment,scFv),由抗体重链可变区和轻链可变区通过15~25个氨基酸的短肽(linker)连接而成。
本发明中,术语“可变”表示抗体中可变区的某些部分在序列上有所不同,它形成各种特定抗体对其特定抗原的结合和特异性。然而,可变性并不均匀地分布在整个抗体可变区中。它集中于重链可变区和轻链可变区中称为互补决定区(complementarity-determining region,CDR)或超变区中的三个片段中。可变区中较保守的部分称为框架区(frame region,FR)。天然重链和轻链的可变区中各自包含四个FR区,它们大致上呈β-折叠构型,由形成连接环的三个CDR相连,在某些情况下可形成部分β折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位(参见Kabat等,NIH Publ.No.91-3242,卷I,647-669页(1991))。
本发明中,术语“抗”、“结合”、“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。通常,抗体以小于大约10-7M,例如小于大约10-8M、10-9M、10-10M、10-11M或更小的平衡解离常数(KD)结合该抗原。本发明中,术语“KD”是指特定抗体-抗原相互作用的平衡解离常数,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。例如,使用表面等离子体共振术(Surface Plasmon Resonance,缩写SPR)在BIACORE仪中测定抗体与抗原的结合亲和力或使用ELISA测定抗体与抗原结合的相对亲和力。
本发明中,术语“表位”是指与抗体特异性结合的多肽决定簇。本发明的表位是抗原中被抗体结合的区域。
本发明中,术语“表达载体”可以为pTT5,pSECtag系列,pCGS3系列,pcDNA系列载体等,以及其它用于哺乳动物表达系统的载体等,表达载体中包括连接有合适的转录和翻译调节序列的融合DNA序列。
本发明中,术语“宿主细胞”是指适用于表达上述表达载体的细胞,可以是真核细胞,如哺乳动物或昆虫宿主细胞培养系统均可用于本发明的融合蛋白的表达,CHO(中国仓鼠卵巢,Chinese Hamster Ovary),HEK293,COS,BHK以及上述细胞的衍生细胞均可适用于本发明。
本发明中,术语“药物组合物”是指本发明的双特异性抗体可以和药学上可以接受的载体一起组成药物制剂组合物从而更稳定地发挥疗效,这些制剂可以保证本发明公开的双特异性抗体的氨基酸核心序列的构象完整性,同时还保护蛋白质的多官能团防止其降解(包括但不限于凝聚、脱氨或氧化)。
以下实施例中使用的实验材料说明如下:
CHO细胞:购自Thermo fisher公司,货号A29133;
293E细胞:来自NRC biotechnology Research Institute;
人胃癌细胞株NCI-N87:购自美国典型培养物保藏中心(ATCC);
PD-1/PD-L1 Blockade Bioassay,Propagation model:购自Promega公司,货号J1252;
VEGF Bioassay,Propagation Model:购自Promega公司,货号GA1082。
以下实施例中使用的实验试剂说明如下:
抗PD-L1单抗:根据PCT/CN2020/090442中的序列制备;
抗KDR单抗:CDR区序列来自Dan Lu等(Dan Lu et al.Tailoring in VitroSelection for a Picomolar Affinity Human Antibody Directed against VascularEndothelial Growth Factor Receptor 2for Enhanced Neutralizing Activity.TheJournal of Biological Chemistry,2003,278:43496-43507.)中的克隆号3A10的序列,其他框架区为本公司突变后获得;
HRP标记的羊抗人Fc抗体:购自sigma,货号A0170;
FITC标记的羊抗人Fc抗体:购自sigma,货号F9512;
HRP标记的鼠抗人Fab抗体:购自sigma,货号A0293;
HRP标记的anti-6×His抗体:购自abcam,货号ab178563;
羊抗人IgG-FITC:购自sigma,货号F4143;
PBS:购自生工生物工程(上海)股份有限公司,货号B548117;
PBST:PBS+0.05%Tween 20;
BSA:购自生工生物工程(上海)股份有限公司,货号A60332;
FBS:购自Gibco,货号10099;
TMB:购自BD公司,货号555214;
Bio-Glo Luciferase Assay System:购自Promega,货号G7940;
以下实施例中使用的实验仪器说明如下:
PCR仪:购自BioRad,货号C1000 Touch Thermal Cycler;
HiTrap MabSelectSuRe柱:购自GE公司,货号11-0034-95;
Beckman Coulter CytoFLEX流式细胞仪:购自Beckman公司;
SpectraMax i3x酶标仪:购自Molecular Devices公司。
以下实施例、实验例是对本发明进行进一步的说明,不应理解为对本发明的限制。实施例不包括对传统方法的详细描述,如那些用于构建载体和质粒的方法,将编码蛋白的基因插入到这样的载体和质粒的方法或将质粒引入宿主细胞的方法。这样的方法对于本领域中具有普通技术的人员是众所周知的,并且在许多出版物中都有所描述,包括Sambrook,J.,Fritsch,E.F.and Maniais,T.(1989)Molecular Cloning:A Laboratory Manual,2ndedition,Cold spring Harbor Laboratory Press。
实施例1抗PDL1×KDR双抗分子的构建
本发明采用将抗人KDR单抗的scFv1(VL-linker1-VH),通过linker2串联在抗人PD-L1单抗的重链C末端的方式,构建了抗PDL1×KDR双特异性抗体,命名为anti-PDL1×KDRBsAb1。结构如图1A所示。
本发明采用将抗人KDR单抗的scFv2(VH-linker1-VL),通过linker2串联在抗人PD-L1单抗的重链C末端,构建了抗PDL1×KDR双特异性抗体,命名为anti-PDL1×KDRBsAb2。结构如图1A所示。
本发明采用将抗人PD-L1单抗的scFv3(VL-linker1-VH),通过linker2串联在抗人KDR单抗的重链N末端,构建了抗PDL1×KDR双特异性抗体,命名为anti-PDL1×KDR BsAb3。结构如图1B所示。
其中,linker1为4个GGGGS,linker2为3个GGGGS,抗人KDR单抗的CDR区序列来自Dan Lu等(Dan Lu et al.Tailoring in Vitro Selection for a Picomolar AffinityHuman Antibody Directed against Vascular Endothelial Growth Factor Receptor2for Enhanced Neutralizing Activity.The Journal of Biological Chemistry,2003,278:43496-43507.)中的克隆号3A10的序列,其他框架区为本公司突变后获得,抗人PD-L1单抗M8的序列来源于PCT/CN2020/090442。
通过基因合成及常规的分子克隆方法获得各双特异性抗体及其对应的单克隆抗体的重链和轻链表达载体,其对应的氨基酸序列如表1所示,其中CDR根据Kabat规则编码。
表1、本发明的抗体的序列信息
实施例2抗PDL1×KDR双抗的表达与纯化
将抗PDL1×KDR双抗的多肽链和轻链的DNA片段分别亚克隆到pcDN3.4载体中,抽提重组质粒共转染CHO细胞和/或293E细胞,细胞培养5-7天后,将培养液通过高速离心、微孔滤膜抽真空过滤后,上样至HiTrap MabSelectSuRe柱,用含有100mM柠檬酸,pH3.5的洗脱液洗脱蛋白,回收目标样品并透析至pH7.4的PBS。
将纯化后的蛋白用HPLC检测,抗PDL1×KDR双抗的HPLC检测图谱如图2A所示,anti-PDL1×KDR BsAb1双抗单体纯度达到96%以上。另两个双抗图谱类似,单体纯度均在96%以上。SDS-PAGE检测结果如图2B所示,泳道1与2为anti-PDL1×KDR BsAb1的还原与非还原SDS-PAGE,泳道3与4为抗PDL1单抗的还原与非还原SDS-PAGE,泳道5与6为anti-PDL1×KDR BsAb2的还原与非还原SDS-PAGE,泳道7与8为anti-PDL1×KDR BsAb3的还原与非还原SDS-PAGE。anti-PDL1×KDR BsAb1和anti-PDL1×KDR BsAb2理论分子量为197KD,anti-PDL1×KDR BsAb3的理论分子量为196KD。
实施例3酶联免疫吸附法(ELISA)测定抗PDL1×KDR双抗对抗原的亲和力
实施例3.1与PD-L1抗原的亲和力检测
为了检测抗PDL1×KDR双抗与PD-L1抗原的亲和力,用pH7.4的PBS缓冲液将PDL1-ECD-His蛋白(根据NCBI提供的序列(NCBI登记号为NP_054862.1)合成PD-L1胞外域基因并在其N端加上信号肽序列,C末端加上6×His标签,通过EcoRI和HindIII两个酶切位点分别构建到表达载体中,转染HEK-293E细胞表达并纯化获得)稀释至2000ng/ml,然后100μl/孔加入ELISA板中;4℃孵育过夜;次日用PBST洗板两次;每孔加入PBST+1%BSA进行封闭,37℃封闭1h;用PBST洗板两次;然后加入用PBS+1%BSA梯度稀释的待检测抗体,抗PD-L1单抗作为阳性对照,起始浓度为300nM,逐级3倍稀释12个梯度。37℃孵育1h;PBST洗板两次,加入HRP标记的羊抗人Fc抗体,37℃再孵育40min;PBST洗板三次并拍干,每孔加入100μl TMB,室温(20±5℃)避光放置5分钟;每孔加入50μl 2M H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,GraphPad Prism进行数据分析,作图并计算EC50。实验结果如图3A所示,抗PD-L1单抗、anti-PDL1×KDR BsAb1、anti-PDL1×KDR BsAb2、anti-PDL1×KDR BsAb3的EC50分别为0.13nM、0.13nM、0.14nM、0.15nM,三个双抗亲和力与单抗相当,抗PD-L1单抗平台稍高,可能是由于二抗为抗Fc的原因,已经过实验证明,本样品的ELISA因二抗不同,而结果稍有不同。可认为双抗的亲和力不弱于单抗。
实施例3.2与KDR抗原的亲和力检测
为了检测抗PDL1×KDR双抗与KDR抗原的亲和力,用pH7.4的PBS缓冲液将KDR-ECD-His蛋白(根据UniProt提供的序列(序列号P35968)合成胞外域基因并在其N端加上信号肽序列,C末端加上6×His标签,通过EcoRI和HindIII两个酶切位点分别构建到表达载体中,转染HEK-293E细胞表达并纯化获得)稀释至2000ng/ml,然后100μl/孔加入ELISA板中;4℃孵育过夜;次日用PBST洗板两次;每孔加入PBST+1%BSA进行封闭,37℃封闭1h;用PBST洗板两次;然后加入用PBS+1%BSA梯度稀释的待检测抗体,抗KDR单抗作为阳性对照,起始浓度为300nM,逐级3倍稀释12个梯度。37℃孵育1h;PBST洗板两次,加入HRP-anti-Fab抗体,37℃再孵育40min;PBST洗板三次并拍干,每孔加入100μl TMB,室温(20±5℃)避光放置5分钟;每孔加入50μl 2M H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,GraphPad Prism进行数据分析,作图并计算EC50。实验结果如图3B所示,抗KDR单抗、anti-PDL1×KDR BsAb1、anti-PDL1×KDR BsAb2、anti-PDL1×KDR BsAb3的EC50分别为0.26nM、0.23nM、0.23nM、0.41nM,anti-PDL1×KDR BsAb1和anti-PDL1×KDR BsAb2亲和力比单抗稍强,可能是由于二抗为抗Fab的原因,已经过实验证明,本样品的ELISA因二抗不同,而结果稍有不同。可认为双抗的亲和力不弱于单抗。
实施例4双特异ELISA检测抗PDL1×KDR双抗同时结合两个抗原的能力
为了检测抗PDL1×KDR双抗同时结合KDR抗原和PD-L1抗原的能力,用pH7.4的PBS缓冲液将PDL1-ECD-hFc蛋白(将PDL1-ECD-His蛋白C末端更换为hFc标签)稀释至1μg/ml,然后100μl/孔加入ELISA板中;4℃孵育过夜;次日用PBST洗板两次;每孔加入PBST+1%BSA进行封闭,37℃封闭1h;用PBST洗板两次;然后加入用PBS+1%BSA梯度稀释的待检测抗体,起始浓度为12nM,逐级3倍稀释12个梯度。37℃孵育1h;PBST洗板两次,再加入pH7.4的PBS稀释的1μg/ml的KDR-ECD-His抗原,100μl/孔加入ELISA板中。37℃孵育1h;PBST洗板两次,加入二抗HRP-anti-His,37℃再孵育40min;PBST洗板三次并拍干,每孔加入100μl TMB,室温(20±5℃)避光放置5分钟;每孔加入50μl 2M H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,GraphPad Prism进行数据分析,作图并计算EC50。实验结果如图4所示,anti-PDL1×KDR BsAb1、anti-PDL1×KDR BsAb2、anti-PDL1×KDR BsAb3的EC50分别为0.13nM、0.14nM、0.20nM。其中anti-PDL1×KDR BsAb3稍弱于其他两个双抗,而单抗没有同时结合这两种抗原的能力。
实施例5FACS检测抗PDL1×KDR双抗对靶细胞的结合亲和力
N87-PDL1为本实验室采用慢病毒转染法,给NCI-N87转染了PD-L1构建的稳细胞株。取对数生长期的N87-PDL1用胰酶消化后,用含有0.5%BSA的PBS洗涤三次,每次300g离心5分钟,弃上清。0.5%BSA的PBS重悬细胞,细胞密度为1×106细胞/mL,100μL/孔加入96孔板。将抗PDL1×KDR双抗及阳性对照抗PD-L1单抗稀释为120nM,逐级稀释11个梯度,100μL/孔加入96孔板,与N87-PDL1细胞混合均匀。4℃孵育1h。PBS洗涤细胞两次以去除未结合的待检抗体。再加入100μL/孔的FITC标记的羊抗人Fc抗体,于4℃孵育30分钟。300g离心5分钟,PBS洗涤细胞两次以去除未结合的二抗。最后将细胞重悬在200μl PBS中,通过BeckmanCoulter CytoFLEX流式细胞仪测定双抗对该细胞的结合亲和力。所得数据通过GraphPadPrism软件拟合分析。
实验结果如图5所示,抗PD-L1单抗的EC50为0.13nM,anti-PDL1×KDR BsAb1的EC50为0.15nM,anti-PDL1×KDR BsAb2的EC50为0.15nM,anti-PDL1×KDR BsAb3的EC50为0.21nM,三个双抗与阳性对照抗PD-L1单抗的亲和力相当。
实施例6抗PDL1×KDR双抗阻断PD1/PD-L1的细胞水平的活性
本实验采用Promega的PD-1/PD-L1 Blockade Bioassay,Propagation model及方法。
取对数期生长的PD-L1 aAPC/CHO-K1,胰酶消化成单个细胞后转移到白色底透96孔板,100μL/孔,40000细胞/孔,置于37℃,5%CO2,孵育过夜。取抗PDL1×KDR双抗、抗PD-L1单抗,稀释成2×工作液浓度,起始浓度为24nM,逐级3倍梯度。取密度在1.4-2×106细胞/mL,细胞活率在95%以上的PD1效应细胞,胰酶消化成1.25×106细胞/ml的单细胞悬液。取前一天铺好的PD-L1 aAPC/CHO-K1细胞,弃掉上清,加入40μl梯度稀释的双抗/PD-L1单抗工作液;再加入等体积的PD1效应细胞。置于37℃,5%CO2,孵育6小时。每孔加入80μl检测试剂Bio-Glo。室温孵育10分钟后,用spectramax i3读取luminescence。读板前用不透光膜封住板底。用GraphPad Prism进行数据分析,作图并计算IC50。
实验结果如图6所示,抗KDR单抗的IC50为0.23nM。anti-PDL1×KDR BsAb1、anti-PDL1×KDR BsAb2、anti-PDL1×KDR BsAb3三组双抗的IC50分别为0.27nM、0.22nM、0.30nM,与单抗相当。
实施例7抗PDL1×KDR双抗阻断细胞上KDR与VEGF结合的活性
本实验采用Promega的VEGF Bioassay,Propagation Model及方法。
KDR/NFAT-RE HEK293细胞表面表达KDR,当VEGF与细胞表面的KDR结合时,信号传导到胞内,荧光报告基因表达,可检测到生物荧光信号。当加入抗KDR抗体阻断VEGF与细胞表面KDR结合时,荧光信号减弱,在一定范围内与KDR抗体的浓度呈量效关系。
取一瓶T75培养的对数生长期的KDR/NFAT-RE HEK293细胞,先用D-PBS洗一遍,再加入3mLsolution在37℃消化2min左右,然后加入等体积的assay buffer(DMED+10%FBS)中和,并用移液器吹打细胞使其分散。200g离心5min。台盼蓝计数,然后调整细胞密度至1.6×106个/mL,25μL/孔铺96孔白色透底板。VEGF用assay buffer(DMED+10%FBS)稀释为3×稀释液,为60ng/mL,工作浓度为20ng/mL,25μL/孔加入96孔白色透底板。将待检抗体及阳性对照用assay buffer(DMED+10%FBS)分别稀释为1000ng/mL的3×稀释液,逐级四倍稀释,25μL/孔加入96孔白色透底板。37℃,5%的CO2培养箱继续培养6小时,取出96孔板,加入75μL/孔的Bio-Glo检测试剂,室温孵育10min后,用spectramax i3读取luminescence。读板前用不透光膜封住板底。用GraphPad Prism进行数据分析,作图并计算IC50。
实验结果如图7所示,抗KDR单抗的IC50为3.10nM。anti-PDL1×KDR BsAb1、anti-PDL1×KDR BsAb2、anti-PDL1×KDR BsAb3三组双抗的IC50分别为13.47nM、6.09nM、4.35nM,其中anti-PDL1×KDR BsAb1稍弱于anti-PDL1×KDR BsAb2和anti-PDL1×KDR BsAb3三组双抗与单抗的活性差别不大。
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290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Val Leu
450 455 460
Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile
465 470 475 480
Ser Cys Thr Gly Ser His Ser Asn Phe Gly Ala Gly Thr Asp Val His
485 490 495
Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile His Gly
500 505 510
Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys
515 520 525
Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp
530 535 540
Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Tyr Gly Leu Arg Gly Trp
545 550 555 560
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
580 585 590
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser
595 600 605
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ser
610 615 620
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
625 630 635 640
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
645 650 655
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
660 665 670
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
675 680 685
Arg Val Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
690 695 700
Val Ser Ser
705
<210> 18
<211> 707
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Trp Ser Gly Gly Gly Thr Asp Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Ile Ser Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gln Leu Gly Leu Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
450 455 460
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu
465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ser Met
485 490 495
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
500 505 510
Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys Gly
515 520 525
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
530 535 540
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
545 550 555 560
Val Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val
565 570 575
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
580 585 590
Ser Gly Gly Gly Gly Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly
595 600 605
Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser His Ser Asn
610 615 620
Phe Gly Ala Gly Thr Asp Val His Trp Tyr Gln His Leu Pro Gly Thr
625 630 635 640
Ala Pro Lys Leu Leu Ile His Gly Asp Ser Asn Arg Pro Ser Gly Val
645 650 655
Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala
660 665 670
Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
675 680 685
Tyr Asp Tyr Gly Leu Arg Gly Trp Val Phe Gly Gly Gly Thr Lys Leu
690 695 700
Thr Val Leu
705
<210> 19
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Leu Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Thr Thr
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Ser Trp Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 20
<211> 705
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Leu Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Thr Thr
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Ser Trp Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Ser Gln Ser
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr Gly
145 150 155 160
Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
165 170 175
Leu Ile Trp Ser Gly Gly Gly Thr Asp Tyr Asn Pro Ser Leu Lys Ser
180 185 190
Arg Leu Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Val Ser Phe Lys
195 200 205
Ile Ser Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Gln Leu Gly Leu Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
225 230 235 240
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
260 265 270
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
275 280 285
Ser Ser Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
290 295 300
Glu Trp Val Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
325 330 335
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Ala Arg Val Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly
355 360 365
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
370 375 380
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
385 390 395 400
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
405 410 415
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
420 425 430
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
435 440 445
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
450 455 460
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
465 470 475 480
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
485 490 495
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
500 505 510
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
515 520 525
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
530 535 540
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
545 550 555 560
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
565 570 575
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
580 585 590
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
595 600 605
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
610 615 620
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
625 630 635 640
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
645 650 655
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
660 665 670
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
675 680 685
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
Lys
705
<210> 21
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg Val
1 5 10 15
Thr Ile Ser Cys Thr Gly Ser His Ser Asn Phe Gly Ala Gly Thr Asp
20 25 30
Val His Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile
35 40 45
His Gly Asp Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala
65 70 75 80
Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Tyr Gly Leu Arg
85 90 95
Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
130 135 140
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
145 150 155 160
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
165 170 175
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
180 185 190
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
195 200 205
Val Ala Pro Thr Glu Cys Ser
210 215
<210> 22
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Trp Ser Gly Gly Gly Thr Asp Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Ile Ser Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gln Leu Gly Leu Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 23
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 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 Arg Val Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Claims (14)
1.抗PDL1×KDR的双特异性抗体,其特征在于,包含两条多肽链和两条轻链,其中:
(a)所述的多肽链从N末端至C末端包含VH-PDL1-CH1-CH2-CH3-linker2-VL-KDR-linker1-VH-KDR或VH-PDL1-CH1-CH2-CH3-linker2-VH-KDR-linker1-VL-KDR,所述的轻链从N末端至C末端包含VL-PDL1-CL;或
(b)所述的多肽链从N末端至C末端包含VL-PDL1-linker1-VH-PDL1-linker2-VH-KDR-CH1-CH2-CH3,所述的轻链从N末端至C末端包含VL-KDR-CL;
其中,所述的VH-PDL1为结合PD-L1的重链可变区,所述的VL-PDL1为结合PD-L1的轻链可变区,所述的VH-KDR为结合KDR的重链可变区,所述的VL-KDR为结合KDR的轻链可变区,所述的linker1为4个G4S,所述的linker2为3个G4S,所述的CH1-CH2-CH3为重链恒定区,所述的CL为轻链恒定区,所述的VH-PDL1与所述的VL-PDL1形成特异性结合PD-L1的抗原结合位点,所述的VH-KDR与所述的VL-KDR形成特异性结合KDR的抗原结合位点。
2.如权利要求1所述的双特异性抗体,其特征在于,所述的VH-PDL1包含氨基酸序列如SEQ ID NO:1-3所示的重链CDR,所述的VL-PDL1包含氨基酸序列如SEQ ID NO:4-6所示的轻链CDR,所述的VH-KDR包含氨基酸序列如SEQ ID NO:7-9所示的重链CDR,所述的VL-KDR包含氨基酸序列如SEQ ID NO:10-12所示的轻链CDR。
3.如权利要求2所述的双特异性抗体,其特征在于,所述的VH-PDL1具有如SEQ ID NO:13所示的氨基酸序列,所述的VL-PDL1具有如SEQ ID NO:14所示的氨基酸序列,所述的VH-KDR具有如SEQ ID NO:15所示的氨基酸序列,所述的VL-KDR具有如SEQ ID NO:16所示的氨基酸序列。
4.如权利要求3所述的双特异性抗体,其特征在于,所述的多肽链具有如SEQ ID NO:17或SEQ ID NO:18所示的氨基酸序列,所述的轻链具有如SEQ ID NO:19所示的氨基酸序列;或所述的多肽链具有如SEQ ID NO:20所示的氨基酸序列,所述的轻链具有如SEQ ID NO:21所示的氨基酸序列。
5.如权利要求1所述的双特异性抗体,其特征在于,所述的重链恒定区包括IgG1、IgG2、IgG3或IgG4重链恒定区,所述的轻链恒定区包括κ或λ轻链恒定区。
6.一种分离的核苷酸,其特征在于,所述的核苷酸编码如权利要求1-5中任一项所述的双特异性抗体。
7.一种表达载体,其特征在于,所述的表达载体含有如权利要求6所述的核苷酸。
8.一种宿主细胞,其特征在于,所述的宿主细胞含有如权利要求7所述的表达载体。
9.如权利要求1-5中任一项所述的双特异性抗体的制备方法,其特征在于,所述方法包含以下步骤:
(a)在表达条件下,培养如权利要求8所述的宿主细胞,从而表达所述的双特异性抗体;
(b)分离并纯化(a)所述的双特异性抗体。
10.一种药物组合物,其特征在于,所述药物组合物含有如权利要求1-5中任一项所述的双特异性抗体和药学上可接受的载体。
11.如权利要求1-5中任一项所述的双特异性抗体或如权利要求10所述的药物组合物在制备治疗癌症的药物中的用途。
12.如权利要求11所述的用途,其特征在于,所述癌症选自由以下组成的组:结直肠癌、非小细胞肺癌、胃癌、胃食管连接部腺癌、黑色素瘤、肺癌、肝癌、淋巴癌、白血病、前列腺癌、骨髓癌及其它赘生性恶性疾病。
13.一种治疗癌症的方法,其特征在于,包括向有需要的受试者施用如权利要求1-5中任一项所述的双特异性抗体或如权利要求10所述的药物组合物。
14.如权利要求13所述的方法,其特征在于,所述癌症选自由以下组成的组:结直肠癌、非小细胞肺癌、胃癌、胃食管连接部腺癌、黑色素瘤、肺癌、肝癌、淋巴癌、白血病、前列腺癌、骨髓癌及其它赘生性恶性疾病。
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PCT/CN2021/097783 WO2021244552A1 (zh) | 2020-06-02 | 2021-06-01 | 抗pdl1×kdr的双特异性抗体 |
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CN (2) | CN113754772A (zh) |
TW (1) | TW202146461A (zh) |
WO (1) | WO2021244552A1 (zh) |
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EP3411068A4 (en) * | 2016-02-02 | 2020-01-29 | Kadmon Corporation, LLC | BISPECIFIC BINDING PROTEINS FOR PD-L1 AND KDR |
WO2020177627A1 (zh) * | 2019-03-02 | 2020-09-10 | 上海一宸医药科技有限公司 | 一种双特异抗体 |
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2020
- 2020-06-02 CN CN202010487531.3A patent/CN113754772A/zh active Pending
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2021
- 2021-06-01 WO PCT/CN2021/097783 patent/WO2021244552A1/zh active Application Filing
- 2021-06-01 CN CN202180038933.8A patent/CN115698087A/zh active Pending
- 2021-06-02 TW TW110119996A patent/TW202146461A/zh unknown
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CN115698087A (zh) | 2023-02-03 |
WO2021244552A1 (zh) | 2021-12-09 |
TW202146461A (zh) | 2021-12-16 |
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