CN114920834A - 抗SARS-CoV-2刺突蛋白S1的单克隆抗体及其应用 - Google Patents
抗SARS-CoV-2刺突蛋白S1的单克隆抗体及其应用 Download PDFInfo
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Abstract
本申请公开了一种抗SARS‑CoV‑2刺突蛋白S1的单克隆抗体及其应用。一个实施例中,该抗体包括:具有如SEQ ID NO:1~7任一所示的VHCDR1;具有如SEQ ID NO:8~14任一所示的VHCDR2;具有如SEQ ID NO:15~21任一所示的VHCDR3;具有如SEQ ID NO:22~28任一所示的VLCDR1;具有如SEQ ID NO:29~35任一所示的VLCDR2;具有如SEQ ID NO:36~42任一所示的VLCDR3。该抗体可用于SARS‑CoV‑2感染的快速检测或筛查。该抗体也可用于制备治疗或预防SARS‑CoV‑2感染相关疾病的药物中。
Description
技术领域
本申请涉及针对SARS-CoV-2的单克隆抗体(mAb)技术领域,尤其涉及抗SARS-cov-2刺突蛋白S1的单克隆抗体及其应用。
背景技术
新型冠状病毒2(SARS-CoV-2)利用包膜刺突(S)糖蛋白来介导以攻击和进入宿主细胞。S 糖体蛋白结构上包括一个亚基S1,即SpikeS1蛋白或S1。S1促进SARS-CoV-2通过其受体 结合域(RBD)附着在细胞表面受体,即血管紧张素转换酶2(ACE2)上。因此,可以通过阻断 SARS-CoV-2与RBD-ACE2相互作用,进而阻断或破坏SARS-CoV-2对宿主细胞的攻击和进入,从而提供潜在的治疗方法和应用方法。
发明内容
本申请发明人创造性地发现了一种识别SARS-CoV-2的抗体及其应用。该抗体可用于SARS- CoV-2感染的快速检测或筛查。该抗体也可用于制备治疗或预防SARS-CoV-2感染相关疾病的药物中。
第1方面,本申请实施例公开了一种抗体,包括:
具有如SEQ ID NO:1~7任一所示的氨基酸序列或其保守性修饰序列的VHCDR1;
具有如SEQ ID NO:8~14任一所示的氨基酸序列或其保守性修饰序列的VHCDR2;
具有如SEQ ID NO:15~21任一所示的氨基酸序列或其保守性修饰序列的VHCDR3;
具有如SEQ ID NO:22~28任一所示的氨基酸序列或其保守性修饰序列的VLCDR1;
具有如SEQ ID NO:29~35任一所示的氨基酸序列或其保守性修饰序列的VLCDR2;
具有如SEQ ID NO:36~42任一所示的氨基酸序列或其保守性修饰序列的VLCDR3。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:1所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:8所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:15所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:22所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:29所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 36所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:2所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:9所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:16所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:23所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:30所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 37所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:3所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:10所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:17所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:24所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:31所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 38所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:4所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:11所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:18所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:25所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:32所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 39所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:5所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:12所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:19所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:26所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:33所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 40所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:6所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:13所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:20所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:27所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:34所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 41所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第1方面所述的抗体中,所述VHCDR1具有如SEQ ID NO:7所示的氨基酸序列或其保守性修饰序列;所述VHCDR2具有如SEQ ID NO:14所示的氨基酸序列或其保守性修饰序列;所述VHCDR3具有如SEQ ID NO:21所示的氨基酸序列或其保守性修饰序列;所述VLCDR1具有如SEQ ID NO:28所示的氨基酸序列或其保守性修饰序列;所述VLCDR2具有如SEQ ID NO:35所示的氨基酸序列或其保守性修饰序列;所述VLCDR3具有如SEQ IDNO: 42所示的氨基酸序列或其保守性修饰序列。
第2方面,本申请实施例公开了一种抗体,包括:
具有如SEQ ID NO:43~49任一所示的氨基酸序列或其保守性修饰序列的VH;以及
具有如SEQ ID NO:50~56任一所示的氨基酸序列或其保守性修饰序列的VL。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:43所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:50所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:44所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:51所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:45所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:52所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:46所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:53所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:47所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:54所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:48所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:55所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第2方面所述的抗体中,所述VH具有如SEQ ID NO:49所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:56所示的氨基酸序列或其保守性修饰序列。
第3方面,本申请实施例公开了一种抗体,包括具有重链和轻链的Fab段,所述重链具有如 SEQ ID NO:57~63任一所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:6 4~70任一所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:57所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:64所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:58所示的氨基酸序列或其保守性修饰序列,所述具有如SEQ ID NO:65所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:59所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:66所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:60所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:67所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:61所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:68所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:62所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:69所示的氨基酸序列或其保守性修饰序列。
在本申请实施例提供的第3方面所述的抗体中,所述重链具有如SEQ ID NO:63所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:70所示的氨基酸序列或其保守性修饰序列。
本申请实施例中,第1~3任一方面所述的抗体还包含共价或非共价连接的缀合物。
本申请实施例中,其中所述缀合物包括酶,荧光团,生物素或链霉亲和素,或其组合。
本申请实施例中,第1~3任一方面所述的抗体是人源化或嵌合抗体。
第4方面,本申请实施例公开了一种用于诊断SARS-CoV-2或检测SARS-CoV-2刺突蛋白S 1的ELISA试剂盒,其包含如第1~3任一方面所述的抗体、或者其组合。
第5方面,本申请实施例公开了一种于体外诊断SARS-CoV-2或检测SARS-CoV-2刺突蛋S 1蛋白的方法,包括使用如第1~3任一方面所述的抗体、或者其组合。
本申请实施例中,第5方面所述的方法是直接ELISA。
本申请实施例中,第5方面所述的方法是是捕获ELISA。
本申请实施例中,第5方面所述的方法是夹心ELISA。
第6方面,第1~3任一方面所述的抗体或者其组合在制备治疗或预防SARS-CoV-2感染药物中的应用,所述药物以第1~3任一方面所述的抗体或者其组合为有效成分。
附图说明
图1为本申请实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的结构示意图。
图2A为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链CDR1 区进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图2B为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链CDR2 区进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图2C为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链CDR3 区进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图3A为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻链CDR1 区进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图3B为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻链CDR2 区进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图3C为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻链CDR3 区进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图4为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链可变区 (VH)进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E 1、7G5、9A5和9H1。
图5为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻可变区(V H)进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7 G5、9A5和9H1。
图6为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链Fab段进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、 9A5和9H1。
图7为本申请多个实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻链Fab段进行序列比对示意图,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、 9A5和9H1。
图8A为本申请多个实施例提供的兔单克隆抗体基于直接抗原ELISA法检测的SARS-CoV-2 刺突蛋白S1的结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、 9A5和9H1。
图8B为本申请多个实施例提供的兔单克隆抗体基于直接抗原ELISA法检测的SARS-CoV-2 刺突蛋白S1 RBD结构域的结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、 5E1、7G5、9A5和9H1。
图9A为本申请多个实施例提供的兔单克隆抗体基于ELISA捕获法检测的SARS-CoV-2刺突蛋白S1的结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、9A5 和9H1。
图9B为本申请多个实施例提供的兔单克隆抗体基于ELISA捕获法检测的SARS-CoV-2刺突蛋白S1 RBD结构域的结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、 7G5、9A5和9H1。
图10为本申请多个实施例提供的兔单克隆抗体与SARS-CoV-2刺突蛋白S1、SARS蛋白S 1、SARS蛋白S2、MERS-CoV刺突蛋白、HKU1蛋白S1、HKU1蛋白S2、HCoV-NL63蛋白S、 HCoV-OC43蛋白S和HCoV-229E蛋白S的特异性其中,多个实施例提供的兔单克隆抗体包括1 A3、1D2、1H1、5E1、7G5、9A5和9H1。
图11为本申请多个实施例提供的兔单克隆抗体在假病毒感染试验中的中和能力的结果,其中,多个实施例提供的兔单克隆抗体包括1H1(左上)、9H1(右上)、5E1(左下)和7G5(右下)。
图12为本申请多个实施例提供的兔单克隆抗体对ACE2-S1的阻断活性检测结果,其中,多个实施例提供的兔单克隆抗体包括1H1、9H1、5E1和7G5。
图13A为本申请实施例提供的基于ELISA双抗夹心法检测结果,1H1作为捕获抗体,1A3 作为检测抗体。
图13B为本申请实施例提供的基于ELISA双抗夹心法检测结果,5E1作为捕获抗体,1D2 作为检测抗体。
图13C为本申请实施例提供的基于ELISA双抗夹心法检测结果,7G5作为捕获抗体,1H1 作为检测抗体。
图13D为本申请实施例提供的基于ELISA双抗夹心法检测结果,9A5作为捕获抗体,5E1 作为检测抗体。
图13E为本申请实施例提供的基于ELISA双抗夹心法检测结果,9A5作为捕获抗体,9H1 作为检测抗体。
图13F为本申请实施例提供的基于ELISA双抗夹心法检测结果,9H1作为捕获抗体,9A5 作为检测抗体。
具体实施方式
为了使本申请的目的、技术方案及优点更加清楚明白,以下结合实施例对本申请进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本申请,并不用于限定本申请。本申请中未详细单独说明的试剂均为常规试剂,均可从商业途径获得;未详细特别说明的方法均为常规实验方法,可从现有技术中获知。
需要说明的是,本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序,也不对其后的技术特征起到实质的限定作用。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
术语“一”或“一个”涵盖单数和复数引用,除非上下文有其他方面。术语“包括”、“具有”、“拥有”和“包含”是开放式术语,表示“包括但不限于”,除非另有说明。
本申请主要公开了抗SARS-CoV-2的抗体。具体地说,本申请公开了涉及抗SARSCoV-2 刺突蛋白S1的兔单克隆抗体(mAbs)及其应用。
在申请中,术语“抗体”应作最广泛的意义上的解释,具有各种抗体结构,包括但不限于Y 型抗体、所谓的全长抗体、Y型抗体的抗原结合部分,以及它们的遗传学或化学修饰。其中,“抗原结合部分”是指Y型抗体的一个或多个部分或片段,可以保留该抗体与SARS-CoV-2S1特异性结合的能力。
在本申请中,术语“单克隆抗体”(mAb)包括具有基本相同的抗原决定簇的高度同质的抗体群。即在该抗体群中,单个抗体基本上是相同的,除了可能自然发生的少量突变。单克隆抗体可以对抗原上的特定表位显示出单一的结合特异性和亲和力。与通常包含针对不同表位的多克隆抗体相比,每个单克隆抗体可以针对抗原上相同或基本相同的表位。修饰词“单克隆”表示抗体的特性是从一个基本同质的抗体群体中获得的,并且不能被解释为需要通过任何特定的方法制得的抗体。该抗体可以通过多种方法制备,包括但仅限于杂交瘤法、重组DNA法、噬菌体抗体库以及类似的方法制得。
在本申请中,术语“抗SARS-CoV-2S1单抗”,“抗对SARS-CoV-2的刺突蛋白S1单抗”和“抗 S1单抗”互换使用,指单克隆抗体具有特异性地结合SARS-CoV-2的S1蛋白有足够的亲和力,以致使其可以用于制备SARS-CoV-2的检测、诊断剂、治疗剂和/或药物中。术语“亲和力”是指单个分子(例如一个抗体)与其结合物(例如一个抗原)的单个结合位点之间的全部非共价分子间相互作用的结合强度。其中,“分子间相互作用”可以包括氢键作用、静电相互作用、疏水作用和范德华力。
在本申请中,术语“兔抗体”或“抗SARS-CoV-2Sl兔单克隆抗体”或者类似术语中的修饰词“兔”表示该抗体的互补决定区(CDR)来源于兔源免疫球蛋白序列。在一个实施例中,抗SARS-Co V-2S1的兔单克隆抗体可以包含来自兔源免疫球蛋白序列的抗体的CDR和骨架区(FR)。在一个实施例中,针对SARS-CoV-2的刺突蛋白S1的兔抗体或兔单克隆抗体可以包含来自兔源免疫球蛋白序列的抗体的CDR。在一个实施例中,针对SARS-CoV-2S1的兔单克隆抗体可以为CDR区来源于兔源免疫球蛋白序列、而FR来自于其他哺乳动物的种系免疫球蛋白序列(如小鼠或人类) 的一种抗体。术语“抗SARS-CoV-2S1的兔单克隆抗体”也可能包含具有非兔源免疫球蛋白序列编码的氨基酸残基的抗体,例如,由体外随机突变或点特异性突变引入的、或体内体细胞突变引入的突变。然而,术语“抗SARS-CoV-2S1的兔单克隆抗体”并不包括CDR区来自其他哺乳动物的种系(如老鼠)的抗体。
在本申请实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以具有Y型分子结构(如图1所示)。参阅图1,其详细示出了一个具体的抗SARS-CoV-2S1的兔单克隆抗体的Y型结构。在一个实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以包括一对重链2和一对轻链3。重链2可以包括一个重链可变区(VH)和一个或多个重链恒定区(CHS)。在一个实施例中,重链2可以包括一个VH和三个CHS(分别命名为CH1、CH2和CH1)。与三个CHS相比,VH更接近重链的N端。与CHS相比,VH在氨基酸序列上表现出更高的多态性。VH可以在不同抗体之间有所不同,并且赋予每种抗体所具有的特异性。CHS的氨基酸序列在同型(类)的所有抗体中可以是相同的,也可在不同型抗体之间有所不同。术语“同型”是指由重链恒定区域基因编码的同类抗体(例如同为 IgG)。哺乳动物的抗体一般包括五种类型的重链:γ、δ、α、μ和ε,相对应组成的抗体就称为I gG,IgD,IgA,IgM和IgE五种抗体。
轻链3可以是一个相对于重链2更小的一个多肽亚基。轻链3可以包括一个轻链可变区(VL) 和一个轻链恒定区(CL)。VL通常是轻链3的N端部分,在氨基酸序列上表现出更高的变异性。不同抗体之间的VL具有特异的氨基酸序列。
在一个实施例中,重链可变区VH和轻链可变区VL可均用于识别和结合S1蛋白。在一个实施例中,CHS和CL不与刺突蛋白S1的残基结合。
上述图1中的一对重链2和一轻链3可以形成一个Y形结构。该“Y型结构”包括两个Fa b段7(抗原结合片段)、一个Fc段8(可标记片段)和铰链区10。两个Fab段7类似于“Y”型结构的两个臂,而Fc段8类似于“Y”型结构的底部。铰链区域10将Fc段8与两个Fab段7连接起来。
每一Fab段7可以包含一个重链可变区VH、来自于重链2的重链恒定区CH1、一个轻链可变区VL和来自于轻链3的轻链恒定区CL。Fab段7包含一个由轻链可变区VL和重链可变区VH形成的可变段(Fv)。Fv段9容纳抗原结合位点,即抗原配位。抗原配位可以位于兔单克隆抗体Y型结构的手臂顶端。
每个可变区域(VH和VL),可以包括互补性决定区(CDR)和骨架区(FR)。CDR决定了Y型兔单克隆抗体的特异性和亲和力。CDR包含与抗原结合的残基,并具备识别和接触S1蛋白的功能。Y型兔单克隆抗体可包括6个CDR,其中3个位于VH中,即VHCDR1、VHCDR2和VHC DR3,另外3个位于VL中,即VLCDR1、VLCDR2和VLCDR3。
在一些实施例中,位于VH和VL区域中的CDR,相互之间可被都FR分隔开。FR是序列结构中的保守区域。FR通常可以作为一个支架,以使得CDR形成能够特异性地结合抗原(例如SARS-CoV-2刺突蛋白S1)的三维结构。FR的三维结构可以在不同的抗体中呈现保守性。Y型兔单克隆抗体的CDR可以被移植到来自其他物种的另一种抗体的FR之间,同时保留其与SARS-CoV-2刺突蛋白S1结合的能力,形成一种融合抗体。在一个实施例中,将Y型兔单克隆抗体的CDR移植到人抗体的FR之间,形成一个抗SARS-CoV-2刺突蛋白S1的人源化抗体。
在一些实施例中,Fc段8可以由来自不同重链2的CH2和CH3形成。在一个实施例中,Fc段8可以包含3个恒定区。由于Fc段8可以由来自于重链的恒定区组成,因此Fc段8可以用于对抗体进行分类。Y型兔单克隆抗体1的Fc段8一般不涉及与抗原的结合。在一个实施例中,Fc段8可以在调节免疫细胞活性方面发挥作用,例如通过结合特定的Fc受体或其它免疫分子如补体蛋白实现免疫调节。在一个实施例中,当CDR与抗原结合时,Fc段8可以发挥产生适当的免疫反应的作用。在一些实施例中,Fc段8可以介导不同的生理反应;这些生理反应包括但不限于与结合FcγR时介导识别的调理素粒子,与Fcε受体结合时介导肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞的脱粒反应,溶胞作用或补体依赖性细胞毒性反应,抗体依赖性细胞毒性效应(ADC C),抗体依赖性细胞吞噬效应(ADCP),以及通过与新生儿Fc受体(FcRn)反应以减缓抗体的降解作用并延长抗体的半衰期。
图2A、图2B和图2C分别显示了本申请实施例公开的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链可变区(VH)的CDR1、CDR2和CDR3的序列比对,其中,本申请实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、9A5和9H1。
参阅图2A,1A3、1D2、1H1、5E1、7G5、9A5和9H1的VH的CDR1区的长度约为9~10 个氨基酸。1A3的VHCDR1区可以包含或具有FSFSSYHMG(SEQ ID NO:1所示)的氨基酸序列。 1D2的VH的CDR1区可以包含或具有IDIETYWMS(SEQ ID NO:2所示)氨基酸序列。1H1的V H的CDR1区可以包含或具有FSFSSGYDMC(SEQ ID NO:3所示)的氨基酸序列。5E1的VH的C DR1区可以包含或具有IDLSSYAMG(SEQ ID NO:4所示)的氨基酸序列。7G5的VH的CDR1区可以包含或具有FSFSSAYYMC(SEQ ID NO:5所示)的氨基酸序列。9A5的VH的CDR1区可以包含或具有FSLSAYQMI(SEQ ID NO:6所示)的氨基酸序列。9H1的VH的CDR1区可以包含或具有FSLSRYAMS(SEQ ID NO:7所示)的氨基酸序列。1A3、1D2、1H1、5E1、7G5、9A5和9H 1的VH的CDR1区具有一个一致性的序列公式为:FSLSS[]Y[]MC。该序列公式中,一对方括号“[]”表示蛋白质序列中的单个氨基酸,该处的氨基酸残基可以缺失也可以为任一氨基酸残基,或者如图2A中对应的所示氨基酸残基。
参阅图2B,1A3、1D2、1H1、5E1、7G5、9A5和9H1的VH的CDR2区的长度约为18~2 0个氨基酸。1A3的VH的CDR2区的氨基酸序列可以包含或具有WIGTLIGIAGNTYYASWAK(S EQ IDNO:8所示)。1D2的VH的CDR2区的氨基酸序列可以包含或具有WIAIITSHDHSGYAN WAE(SEQ IDNO:9所示)。1H1的VH的CDR2区的氨基酸序可以包含或具有WIACIGTGSSGN IYYASWAK(SEQ IDNO:10所示)。5E1的VH的CDR2区的氨基酸序列可以包含或具有YIGIIY ISGLTYYASWAK(SEQID NO:11所示)。7G5的VH的CDR2区的氨基酸序列可以包含或具有W IACIGVDSGGNSYYASWAK(SEQ ID NO:12所示)。9A5的VH的CDR2区的氨基酸序列可以包含或具有YIGIMHTGTSAYYANWAK(SEQ ID NO:13所示)。9H1的VH的CDR2区的氨基酸序列可以包含或具有WIGIIVDSGHTAYASWAK(SEQ ID NO:14所示)。1A3、1D2、1H1、5E1、7 G5、9A5和9H1的VH的CDR2区的氨基酸序列具有一个一致性的序列,其公式为:WIG[][]II[] SSG[]TYYASWAK。该序列公式中,方括号“[]”表示蛋白质序列中的单个氨基酸,该处的氨基酸残基可以缺失也可以为任一氨基酸残基,或者如图2B中对应的所示氨基酸残基。
参阅图2C,1A3、1D2、1H1、5E1、7G5、9A5和9H1的VH的CDR3区的长度约为12~2 2个氨基酸。1A3的VH的CDR3的氨基酸序列区可以包含或具有YWCARIVTATFEFWG(SEQ I D NO:15所示)。1D2的VH的CDR3区的氨基酸序列可以包含或具有YFCAKDVGHSTYDLWG(S EQ ID NO:16所示)。1H1的VH的CDR3区的氨基酸序列可以包含或具有YFCARDDADYAGP DYFNLWG(SEQ IDNO:17所示)。5E1的VH的CDR3区的氨基酸序列可以包含或具有YFCAR GEYNSHSHYLLWG(SEQID NO:18所示)。7G5的VH的CDR3区可以包含或具有YFCTRSFSL WG(SEQ ID NO:19所示)的氨基酸序列。9A5的VH的CDR3区的氨基酸序列可以包含或具有Y FCGRNLNEGFTGAYPFNLWG(SEQID NO:20所示)。9H1的VH的CDR3区的氨基酸序列可以包含或具有YFCARETGGGAFYVFEFWG(SEQ ID NO:21所示)。1A3、1D2、1H1、5E1、7G5、 9A5和9H1的VH的CDR3区的氨基酸序列具有一个一致性的序列公式为:YFCAR[][][][][][][][] [][][]F[]LWGI。该序列公式中,方括号“[]”表示蛋白质序列中的单个氨基酸,该处的氨基酸残基可以缺失也可以为任一氨基酸残基,或者如图2C中对应的所示氨基酸残基。
图3A、图3B和图3C分别显示了抗SARSCoV-2S1的兔单克隆抗体的轻链可变区(VL)的C DR1、CDR2和CDR3的序列比对,其中,本申请实施例提供的兔单克隆抗体包括包括1A3、1D 2、1H1、5E1、7G5、9A5和9H1。
参阅图3A,1A3、1D2、1H1、5E1、7G5、9A5和9H1的VL的CDR1区的长度约为9~11 个氨基酸。1A3的VL的CDR1区的氨基酸序列可以包含或具有QSVNMNLLSW(SEQ ID NO:22 所示)。1D2的VL的CDR1区的氨基酸序列可以包含或具有ESVLSNNRLSW(SEQ ID NO:23所示)。1H1的VL的CDR1区的氨基酸序列可以包含或具有ESISNWLAW(SEQ ID NO:24所示)。5 E1的VL的CDR1区的氨基酸序列可以包含或具有QNIYSNLAW(SEQ ID NO:25所示)。7G5的 VL的CDR1区的氨基酸序列可以包含或具有QSVYNNDNLAW(SEQ ID NO:26所示)。9A5的V L的CDR1区的氨基酸序列可以包含或具有WSIGSNLAW(SEQ ID NO:27所示)。9H1的VL的C DR1区的氨基酸序列可以包含或具有EDIYDNLVW(SEQ ID NO:28所示)。1A3、1D2、1H1、5 E1、7G5、9A5和9H1的VL的CDR1区的氨基酸序列具有一个一致性的序列公式为:QSI[][]NL [][][]W的序列一致公式,该序列公式中,方括号“[]”表示蛋白质序列中的单个氨基酸,该处的氨基酸残基可以缺失也可以为任一氨基酸残基,或者如图3A中对应的所示氨基酸残基。
参阅图3B,1A3、1D2、1H1、5E1、7G5、9A5和9H1的VL的CDR2区的长度约为12个氨基酸。1A3的VL的CDR2区的氨基酸序列可以包含或具有LIYQASNLASGV(SEQ ID NO:29 所示)。1D2的VL的CDR2区的氨基酸序列可以包含或具有LIYAASTLASGV(SEQ ID NO:30所示)。1H1的VL的CDR2区的氨基酸序列可以包含或具有LIYAAFTLASGV(SEQ ID NO:31所示)。 5E1的VL的CDR2区可以包含或具有LIYDASQLASGV(SEQ ID NO:32所示)。7G5的VL的C DR2区的氨基酸序列可以包含或具有LIYLASNLASGV(SEQ ID NO:33所示)。9A5的VL的CD R2区的氨基酸序列可以包含或具有LIYQASNLASGV(SEQ ID NO:34所示)。9H1的VL的CDR 2区的氨基酸序列可以包含或具有LIYDASTLAFGV(SEQ ID NO:35所示)。1A3、1D2、1H1、5 E1、7G5、9A5和9H1的VL的CDR2区的氨基酸序列具有一个一致性的序列公式为:LIY[]ASN LASGV,该序列公式中,方括号“[]”表示蛋白质序列中的单个氨基酸,该处的氨基酸残基可以缺失也可以为任一氨基酸残基,或者如图3B中对应的所示氨基酸残基。
参阅图3C,1A3、1D2、1H1、5E1、7G5、9A5和9H1的VL的CDR3区的长度的长度约为11~14个氨基酸。1A3的VL的CDR3区的氨基酸序列可以包含或具有GDMGGWMFPFG(SE Q ID NO:36所示)。1D2的VL的CDR3区的氨基酸序列可以包含或具有GAFSGSSDTRAFG(SE Q ID NO:37所示)。1H1的VL的CDR3区的氨基酸序列可以包含或具有QTYSSRDVDNVFG(S EQ ID NO:38所示)。5E1的VL的CDR3区的氨基酸序列可以包含或具有QGFESSDIFNVFG(SE Q ID NO:39所示)。7G5的VL的CDR3区的氨基酸序列可以包含或具有GGYDCSNADCHAFG(S EQ ID NO:40所示)。9A5的VL的CDR3区的氨基酸序列可以包含或具有MNYYISSSYTYTFG(S EQ ID NO:41所示)。9H1的VL的CDR3区的氨基酸序列可以包含或具有GEFSCSSGDCTAFG(S EQ ID NO:42所示)。1A3、1D2、1H1、5E1、7G5、9A5和9H1的VL的CDR3区的氨基酸序列具有一个一致性的序列公式为:G[]F[][]SS[][][][][]FG,该序列公式中,方括号“[]”表示蛋白质序列中的单个氨基酸,该处的氨基酸残基可以缺失也可以为任一氨基酸残基,或者如图3C中对应的所示氨基酸残基。
图4示了本申请实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链可变区V H的序列比对结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、9 A5和9H1。
1A3的VH的氨基酸序列可以包含或具有QSLEESGGRLVTPGTPLTLTCTVSGFSFSSYHMGWVRQAPGEGLEWIGTLIGIAGNTYYASWAKGRFSISKTSTTVDLKMTSPTTEDTATYWCARIVTATFEFWGPGTLVTVSS,SEQ ID NO:43所示。
1D2的VH的氨基酸序列可以包含或具有QSVEESGGRLVTPGTSLTLTCTVSGIDIETYWMSWVRQAPGKGLEWIAIITSHDHSGYANWAEGRETISKTSTTVTLTITDLQPSDTGTYFCAKDVGHSTYDLWGPGTLVTVSS,SEQ ID NO:44所示。
1H1的VH的氨基酸序列可以包含或具有QSLEESGGDLVKPGASLTLTCTASGFSFSSGYDMCWVRQAPGKGLEWIACIGTGSSGNIYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAR DDADYAGPDYFNLWGPGTLVTVSS,SEQ ID NO:45所示。
5E1的VH的氨基酸序列可以包含或具有QSVEESGGRLVTPGTPLTLTCTVSGIDLSSYAMGWVRQAPGKGLEYIGIIYISGLTYYASWAKGRFTISKTSTTVDLKIPSPTTEDTATYFCARGEYNSHS HYLLWGPGTLVTVSS,SEQ ID NO:46所示。
7G5的VH的氨基酸序列可以包含或具有QEQLEESGGDLVKPGASLTLTCTASGFSFSSAYYMCWVRQAPGKGLEWIACIGVDSGGNSYYASWAKGRFTISTTSSTTVTLQMTSLTAADKATYFCTRSFSLWGPGTLVTISS,SEQ ID NO:47所示。
9A5的VH的氨基酸序列可以包含或具有QSVEESGGRLVTPGTPLTLTCTVSGFSLSAYQMIWVRQTPGKGLEYIGIMHTGTSAYYANWAKGRFTISKTSSTTVDLKMTSPTTEDTATYFCGRNLNEGFTGAYPFNLWGPGTLVAVSS,SEQ ID NO:48所示。
9H1的VH的氨基酸序列可以包含或具有QSVEESGGRLVTPGTPLTLTCTVSGFSLSRYAMSWVRQAPGKGLEWIGIIVDSGHTAYASWAKGRFTISRTSTTVDLKMTSLTTEDTATYFCARETGGGAFYVFEFWGPGTVVTVSS,SEQ ID NO:49所示。
图5示了本申请实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻链可变区V L的序列比对结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、9 A5和9H1。
1A3的VL的氨基酸序列可以包含或具有AQVLTQTPSPVSAAVGGTVTISCQASQSVNMNL LSWFQQKPGQPPKLLIYQASNLASGVSARFKGSGSGTQFTLTINEIQCDDAATYYCQGDMGGW MFPFGGGTEVVVT,SEQ ID NO:50所示。
1D2的VL的氨基酸序列可以包含或具有AAVLTQTPSPVSAAVGGTVTISCQSSESVLSNNRLSWYQQKPGQPPKLLIYAASTLASGVPSRFKGRGSGTQFTLTISDVQCDDAAMYVCAGAFSGSSDTRAFGGGTEVVVK,SEQ ID NO:51所示。
1H1的VL的氨基酸序列可以包含或具有ADIVMTQTPASVSEPVGGTVTIKCQASESISNWLAWYQQKPGQPPKLLIYAAFTLASGVPSRFKGSGSGTQFTLTINGVECADAATYYCQQTYSSRDVDNVFGGGTEVVVK,SEQ ID NO:52所示。
5E1的VL的氨基酸序列可以包含或具有AYDMTQTPSSVSEPVGGTVSIKCQASQNIYSNLAWYQQKPGQRPKLLIYDASQLASGVPSRFKGSGSGTEYTLTISGVECADAATYYCQQGFESSDIFNVFGGGTEVVVK,SEQ ID NO:53所示。
7G5的VL的氨基酸序列可以包含或具有WRKWLTQTASSVSAAVGGTVTISCQASQSVYNN DNLAWFQQRPGQPPKLLIYLASNLASGVPPRFSGSGSGTQFTLTISDVQCDDAATYYCLGGYDCSNADCHAFGGGTEVVVK,SEQ ID NO:54所示。
9A5的VL的氨基酸序列可以包含或具有ADVVMTQTPASVEAAVGGTVTIKCQASQSIGSNLAWYQKKPGQPPKLLIYQASNLASGVPSRFKGSGSGTQFTLTISDLECADAATYYCQMNYYISSSYTYTFGGGTEVVVK,SEQ ID NO:55所示。
9H1的VL的氨基酸序列可以包含或具有AQVLTQTPSSVSAAVGGTVTINCQASEDIYDNLVWYQQKPGQPPKLLIYDASTLAFGVSSRFRGSGSGTHFTLTMRDVQCDDAATYYCQGEFSCSSGDCTAFGGGTEVVVK,SEQ ID NO:56所示。
参阅图6,其示出了本申请实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的重链Fab段的序列比对结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、 7G5、9A5和9H1。
1A3的重链Fab段的氨基酸序列可以包含或具有QSLEESGGRLVTPGTPLTLTCTVSGFSFSSYHMGWVRQAPGEGLEWIGTLIGIAGNTYYASWAKGRFSISKTSTTVDLKMTSPTTEDTATYW CARIVTATFEFWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNS GTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQ ID NO:57所示。
1D2的重链Fab段的氨基酸序列可以包含或具有QSVEESGGRLVTPGTSLTLTCTVSGIDIETYWMSWVRQAPGKGLEWIAIITSHDHSGYANWAEGRFTISKTSTTVTLTITDLQPSDTGTYFCA KDVGHSTYDLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWN SGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQ ID NO:58 所示。
1D2的重链Fab段的氨基酸序列可以包含或具有QSLEESGGDLVKPGASLTLTCTASGFSFSS GYDMCWVRQAPGKGLEWIACIGTGSSGNIYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATY FCARDDADYAGPDYFNLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEP VTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQ I DNO:59所示。
5E1的重链Fab段的氨基酸序列可以包含或具有QSVEESGGRLVTPGTPLTLTCTVSGIDLSS YAMGWVRQAPGKGLEYIGIIYISGLTYYASWAKGRFTISKTSTTVDLKIPSPTTEDTATYFCARGE YNSHSHYLLWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSG TLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQIDNO:60所示。
7G5的重链Fab段的氨基酸序列可以包含或具有QEQLEESGGDLVKPGASLTLTCTASGFSFS SAYYMCWVRQAPGKGLEWIACIGVDSGGNSYYASWAKGRFTISTTSSTTVTLQMTSLTAADKA TYFCTRSFSLWGPGTLVTISSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSG TLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQIDNO:61所示。
9A5的重链Fab段的氨基酸序列可以包含或具有QSVEESGGRLVTPGTPLTLTCTVSGFSLSA YQMIWVRQTPGKGLEYIGIMHTGTSAYYANWAKGRFTISKTSSTTVDLKMTSPTTEDTATYFCG RNLNEGFTGAYPFNLWGPGTLVAVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTV TWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQIDNO:62所示。
9H1的重链Fab段的氨基酸序列可以包含或具有QSVEESGGRLVTPGTPLTLTCTVSGFSLSR YAMSWVRQAPGKGLEWIGIIVDSGHTAYASWAKGRFTISRTSTTVDLKMTSLTTEDTATYFCAR ETGGGAFYVFEFWGPGTVVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVT WNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV,SEQIDNO:6 3所示。
参阅图7,其示出了本申请实施例提供的抗SARS-CoV-2刺突蛋白S1的兔单克隆抗体的轻链 Fab段的序列比对结果,其中,多个实施例提供的兔单克隆抗体包括1A3、1D2、1H1、5E1、7G 5、9A5和9H1。
1A3的轻链Fab段的氨基酸序列可以包含或具有AQVLTQTPSPVSAAVGGTVTISCQASQSVNMNLLSWFQQKPGQPPKLLIYQASNLASGVSARFKGSGSGTQFTLTINEIQCDDAATYYCQG DMGGWMFPFGGGTEVVVTGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDG TTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC,SEQI DNO:64所示。
1D2的轻链Fab段的氨基酸序列可以包含或具有AAVLTQTPSPVSAAVGGTVTISCQSSESVLSNNRLSWYQQKPGQPPKLLIYAASTLASGVPSRFKGRGSGTQFTLTISDVQCDDAAMYVCAG AFSGSSDTRAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDG TTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC,SEQI DNO:65所示。
1H1的轻链Fab段的氨基酸序列可以包含或具有ADIVMTQTPASVSEPVGGTVTIKCQASESISNWLAWYQQKPGQPPKLLIYAAFTLASGVPSRFKGSGSGTQFTLTINGVECADAATYYCQQT YSSRDVDNVFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDG TTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC,SEQI DNO:66所示。
5E1的轻链Fab段的氨基酸序列可以包含或具有AYDMTQTPSSVSEPVGGTVSIKCQASQNIYSNLAWYQQKPGQRPKLLIYDASQLASGVPSRFKGSGSGTEYTLTISGVECADAATYYCQQGF ESSDIFNVFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTT QTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC,SEQIDN O:67所示。
7G5的轻链Fab段的氨基酸序列可以包含或具有WRKWLTQTASSVSAAVGGTVTISCQASQSVYNNDNLAWFQQRPGQPPKLLIYLASNLASGVPPRFSGSGSGTQFTLTISDVQCDDAATYYC LGGYDCSNADCHAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTW EVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGD C,SEQIDNO:68所示。
9A5的轻链Fab段的氨基酸序列可以包含或具有ADVVMTQTPASVEAAVGGTVTIKCQASQSIGSNLAWYQKKPGQPPKLLIYQASNLASGVPSRFKGSGSGTQFTLTISDLECADAATYYCQM NYYISSSYTYTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVD GTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC,SE QIDNO:69所示。
9H1的轻链Fab段的氨基酸序列可以包含或具有AQVLTQTPSSVSAAVGGTVTINCQASEDIYDNLVWYQQKPGQPPKLLIYDASTLAFGVSSRFRGSGSGTHFTLTMRDVQCDDAATYYCQGE FSCSSGDCTAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDG TTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC,SEQI DNO:70所示。
本申请实施例提供的抗SARS-CoV-2S1的兔单克隆抗体也可以是上述实施例所公开的Y 型抗体的抗原结合部分。在一个实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以是一个Fab段 7形成,由VH、VL、CH1和CL形成的一个单一亚基。在一个实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以是F(ab’)2段形成的,该F(ab’)2段由两个亚基通过连接形成(例如通过铰链区10 的二硫键连接),其中每一亚基均为一个Fab段7。在一个实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以是由VH和CH1结构域形成的Fd段。在一个实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以是VL和VH结构域形成的Fv片段9。在一个实施例中,抗SARSCoV-2S1的兔单克隆抗体可以是一个孤立的互补决定区。
本申请实施例提供的抗SARS-CoV-2S1的兔单克隆抗体还可以包括来自上述实施例提供的结构或通过基因修饰获得的其抗原结合部分。在一些实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以具有不同的转基因抗体结构,包括但不限于人源化抗体和嵌合抗体。在一个实施例中,抗 SARS-CoV-2S1的兔单克隆抗体可以是一种人源化抗体,该人源化抗体的蛋白序列具有与适应人体自然变异抗体的高度同源性。其中,“人源化抗体”的蛋白质序列可以与人类变异抗体的蛋白质序列基本相同,并同时使得其兔源的CDR区保持与SARS-CoV-2刺突蛋白S1的结合能力。在一个实施例中,可以通过插入非人源抗体的CDR区来创建所述的“人源化抗体”,例如,将一个兔抗体的CDR区插入一个人源抗体支架中以制得一种人源化抗体。在一个实施例中,抗SAR S-CoV-2S1的兔单克隆抗体可以是一种嵌合抗体。在一个实施例中,该嵌合抗体可以是通过将不同来源的Y型抗体的重链和轻链的可变区移植到另一动物(比如人体)的恒定区而制成的抗体。在一个实施例中,该嵌合抗体是通过将本申请公开的抗SARS-CoV-2S1的兔单克隆抗体的Fab段与人源Fc段融合而形成。在一个实施例中,抗SARS-CoV-2S1的兔单克隆抗体可以是一个单链F v(scFv)。尽管Fv段的两个结构域,即VL和VH,是由两个单独的基因编码的,但可以通过重组方法将两个单独的编码基因连接形成的一个连接子,从而编码表达scFv。在一个实施例中,可以根据本领域技术人员熟知的方法进行相关基因修饰和转基因操作,并且可以以与筛选全长抗体相同的方式筛选转基因抗体结构。
本申请实施例提供的抗SARS-CoV-2S1的兔单克隆抗体还可以具有从上述实施例提供的抗体衍生形成的结构及其通过化学修饰产生的抗原结合部分。在一个实施例中,所述化学修饰可以是化学交联。在一个实施例中,一个或多个缀合物可以共价连接到抗体或非共价连接到抗体上。在一个实施例中,该缀合物可以是共价附着到该抗体上的分子标记,以便于检测其抗原。该缀合物可以是任何合适的小分子。所述小分子可以包括但不限于,例如,生物素、链霉亲和素,和/ 或荧光染料。所述荧光染料可以是任何合适的荧光染料,包括但不限于Alexa Flour染料、氨基香豆素(AMCA)、Atto染料、花菁染料、DyLight染料、FITC、荧光探针647H、罗丹明和德克萨斯红。所述Alexa Flour染料包括但不限于AlexaFlour488、Alexa Flour 555、Alexa Flour568、 Alexa Flour594、Alexa Flour647和AlexaFlour700。所述Atto染料可以包括但不限于Atto390、 Atto488、Atto565、Atto633和Atto700。所述花菁染料可以包括但不限于Cy3、Cy5和Cy5.5。D yLight染料可以包括但不限于DyLight350、DyLight405、DyLight488、DyLight550、DyLight594、 DyLight633、DyLight650、DyLight680、DyLight755和DyLight800。在一个实施例中,所述缀合物可以是具有两个共价连接的荧光分子的串联染料。在实施例中,一个荧光分子作为供体,另一个作为受体。在一个实施例中,所述供体具有供体激发特性,而所述受体具有受体发射特性,二者可以进行独特荧光激发和发射反应。所述串联染料可包括但不限于异藻蓝蛋白-Cy5.5、异藻蓝蛋白-Cy7、PE-Atto594、PE-Cy5、PE-Cy5.5、PE-Cy7、PE-德克萨斯红、PE-AlexaFluor647、PE- AlexaFluor700,PE-AlexaFluor750、APC-AlexaFluor750和PerCP-Cy5.5。
上述实施例中的缀合物也可以是大分子。在一个实施例中,该大分子可以是一种酶。该酶可包括但不限于碱性磷酸酶(AP)、葡萄糖氧化酶(Gox)、辣根过氧化酶(HRP)。在一个实施例中,该大分子可以是荧光蛋白。该荧光蛋白可包括但不限于异藻蓝蛋白(APC)、B-藻红蛋白(BPER- 藻红蛋白(R-PE)、PerCP和R-藻蓝蛋白(RPC)。在一个实施例中,大分子也可以是一种具有不同抗SARS-CoV-2S1兔单克隆抗体特异性的抗体,形成一个具有多种特异性的多价抗体。
本申请实施例提供的抗SARS-CoV-2S1的兔单克隆抗体具有于体内和于体外的用途。该用途包括但不限于制备免疫分析的试剂盒、制备免疫染色的试剂盒、制备免疫化学的试剂盒、制备 SARS-CoV-2病毒感染的诊断试剂盒、制备免疫肿瘤治疗药物和制备SARS-CoV-2引起的一些感染性疾病的治疗药物,以及于体外进行免疫分析、免疫染色、免疫化学反应、SARS-CoV-2病毒感染诊断。其中,所述的免疫分析方法可以包括酶联免疫吸附剂分析方法(ELISA),本申请实施例提供的抗SARS-CoV-2S1的单抗可用于不同形式的ELISA。在一个实施例中,所公开的抗SA RS-CoV-2S1的兔单克隆抗体可用于直接ELISA。所述直接ELISA可以是一种基于平板的免疫吸附试验,用于检测和量化来自复杂生物样本或在复杂生物样本内的特定抗原,可以采用多种方法实现直接ELISA。在一个实施例中,所述抗原,例如,SARS-CoV-2的刺突蛋白S1可以被固定化或吸附在塑料板的表面上。在一个实施例中,所述塑料板可以是一个多孔微量滴定板。在一个实施例中,多孔微量滴定平面可以是96孔聚苯乙烯板。在实施例中,可以在表面添加过量的阻断蛋白以阻断所有其他结合位点。在一个实施例中,阻断蛋白是牛血清白蛋白。在一个实施例中,针对抗原(例如,SARS-CoV-2的刺突蛋白S1)的抗体,可以与偶联在表面上的抗原形成复合物。在一个实施例中,该抗体可以与一种酶偶联。在一个实施例中,该酶可以是HRP。在多余的缀合抗体被洗去后,与抗原结合的缀合抗体继续停留在表面上。在一个实施例中,共轭抗体催化与添加的底物的反应,以产生可由分光光度计或吸光度酶标仪测量的可见比色输出。直接ELISA检测由于仅使用了一种抗体,使得其相较于其他形式的ELISA检测具有更少的检测步骤和更高的检测效率。在一个实施例中,直接ELISA可以测试特异性抗体-抗原反应,并有助于消除与其他抗体之间的交叉反应。直接ELISA适用于目标样本的定性和定量应用于抗原检测、抗体筛选和抗原表位定位。
表1示出了本申请实施例提供的多个兔单克隆抗体分别与SARS-CoV-2S结合动力学参数,其中,多个兔单克隆抗体包括1A3、1D2、1H1、5H1E1、7G5、9A5、9H5和9H1。如表1所示,1A3、1D2、1H1、5E1、7G5、9A5和9H1对SARS-CoV-2S1表现出高度亲和性和特异性,其解离常数(KD)分别为5.37E-10、3.55E-09、2.06E-09、1.38E-10、2.14E-09、8.70E-10、7.69E-10。
表1与SARS-CoV-2S结合动力学参数
克隆 | K<sub>off</sub>(1/s) | K<sub>on</sub>(1/Ms) | K<sub>D</sub>(M) |
1A3 | 9.34E-05 | 1.74E+05 | 5.37E-10 |
1D2 | 2.59E-04 | 7.29E+04 | 3.55E-09 |
1H1 | 2.73E-04 | 1.33E+05 | 2.06E-09 |
5E1 | 1.00E-05 | 7.23E+04 | 1.38E-10 |
7G5 | 2.61E-04 | 1.22E+05 | 2.14E-09 |
9A5 | 1.15E-04 | 1.32E+05 | 8.70E-10 |
9H1 | 2.50E-04 | 3.25E+05 | 7.69E-10 |
参阅图8A,其显示了多个实施例分别提供的抗SARS-CoV-2S1兔单克隆抗体基于直接EL ISA检测SARS-CoV-2S1抗原的曲线,其中,多个兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、9A5和9H1。图中,X轴表示在ng/ml单位处的抗体浓度,Y轴表示在波长为450nm(OD45 0)处的光密度。如图8A所示,所有兔单克隆抗体都能特异性地与SARS-CoV-2S1结合,其结合曲线在从约1ng/ml到约1000ng/ml的抗体浓度范围内表现出近似于“S”形状。检测过程设置了阴性对照组,在与抗SARS-CoV-2S1的兔单克隆抗体相同的检测步骤下,使用空白缓冲液代替抗S ARS-CoV-2S1的兔单克隆抗体。空白缓冲液是用于稀释兔单克隆抗体的缓冲液。与几乎无OD45 0吸光值的阴性对照相比,1A3、1D2、1H1、5E1、7G5、9A5和9H1表现出良好的检测信号,即表明在OD450处的吸光值能够检测较宽浓度范围的SARS-CoV-2S1。
参阅图8B,其示出了多个实施例分别提供的抗SARS-CoV-2S1兔单克隆抗体基于直接EL ISA法对SARS-CoV-2S1的RBD的检测曲线,其中,多个兔单克隆抗体包括1A3、1D2、1H1、5E1、7G5、9A5和9H1。图中,X轴表示以ng/ml为单位的抗体浓度,Y轴表示450nm(OD450) 处的光密度。阴性对照采用与兔抗SARS-CoV-2S1的单克隆抗体按照相同的步骤进行,使用空白缓冲液代替抗SARS-CoV-2S1的兔单克隆抗体。空白缓冲液是用于稀释兔单克隆抗体的缓冲液。阴性对照组的OD450值接近零,几乎没有检测信号。与阴性对照相比,1H1、5E1、7G5、9A5和9H1可产生显著的OD450值。由图8B可知,1H1、5E1、7G5、9A5和9H1在0.5ng/ml到10 00ng/ml的抗体浓度范围内形成的结合曲线呈现近似“S”形状,由此说明1H1、5E1、7G5、9A5 和9H1可以特异性地结合SARS-CoV-2S1的RBD。而与1H1、5E1、7G5、9A5和9H1相比,1 A3和1D2的在OD450的检测值接近零,由此说明1A3和1D2不能特异性地与SARS-CoV-2S1 的RBD结合。
为验证本申请实施例提供的兔单克隆抗体能够在自然状态下与S1蛋白结合,本申请还进行了基于捕获ELISA的检测试验。该试验中,兔单克隆抗体被涂在平板上的Fc捕获,然后将处于自然状态的S1或RBD添加到平板中。结果如图9A和9B所示。
图9A示出了1A3、1D2、1H1、5E1、7G5、9A5和9H1与S1结合的捕获ELISA结果。如图9A所示,除1D2和1A3外,1H1、5E1、7G5、9A5和9H1都可以以自然状态与S1结合。
参阅图9B,其示出了1A3、1D2、1H1、5E1、7G5、9A5和9H1在自然状态下与RBD结合的捕获ELISA结果。如图9B所示,除1D2和1A3外,1H1、5E1、7G5、9A5和9H1都可以以自然状态与RBD结合。而1A3和1D2可在ELISA中作为全长S1蛋白而不是RBD的检测抗体。
参阅图10,其示了1A3、1D2、1H1、1H1、5E1、7G5、9H1、9A5对SARS-CoV-2(SARS- CoV-2)蛋白S1、SARS蛋白S1、SARS蛋白S2、MERS-CoV刺突蛋白S1、HKU1蛋白S1、HK U1蛋白S2、HCoV-NL63蛋白S、HCoV-OC43蛋白S和HCoV-229E蛋白S的特异性。图10中, Y轴显示直接ELISA在450nm处的检测光密度。图10中,每组列包含7个组别,沿X轴方向依次为1A3、1、1D2、1H1、5E1、7G5、9A5和9H1,分别显示了对SARS-CoV-2S1、SARS S1、 MERS S1和HCoV-NL63S1的特异性。如图10所示,本申请实施例提供的抗体对SARS-CoV-2 S1表现出最高的特异性。在本申请实施例提供的抗体中,1A3、1H1、7G5和9A5对SARS-CoV- 2S1具有独特的特异性,对SARS蛋白S1和SARS蛋白S2、MERS-CoV刺突蛋白、HKU1蛋白 S1、HKU1蛋白S2、HCoV-NL63蛋白S、HCoV-OC43蛋白S和HCoV-229E蛋白S没有明显的特异性。相较而言,1D2、5E1和9H1对SARS-CoV-2蛋白S1、SARS蛋白S1、SARS蛋白S2、 MERS-CoV刺突蛋白表现出较高的特异性,而对KU1蛋白S1、HKU1蛋白S2表现出较低的特异性。然而,1D2、5E1和9H1对HCoV-NL63蛋白S、HCoV-OC43蛋白S和HCoV-229E蛋白 S无特异性。
为了评价1H1、9H1、5E1和7G5的中和能力,分别进行了假病毒中和试验和活病毒中和试验。假病毒中和试验结果如11所示。图11中,1H1、9H1、5E1和7G5可以中和SARS-CoV- 2野生型假病毒。活病毒中和试验结果如表2所示,1H1、9H1、5E1和7G5可以中和SARS-Co V-2活病毒,结果与假病毒中和试验一致。
表2 SARS-CoV-2活病毒中和试验结果
如表2所示,1H1、9H1、5E1和7G5分别对于野生型SARS-CoV-2活病毒的半最大抑制浓度(半抑制浓度)值分别为0.136μg/mL、0.026μg/mL、0.512μg/mL和0.261μg/mL。
为了评估1H1、9H1、5E1和7G5是否能阻断S1与ACE2的结合,本申请进一步进行了阻断实验。重组的ACE2被涂在ELISA平板上,本申请实施例提供的不同兔单抗与不同浓度的RBD结构域蛋白预孵育,形成抗体-RBD混合物,然后加载到ACE2包被的ELISA板上。结果如图12所示,1H1、9H1、5E1和7G5可以阻断RBD结构域与ACE2的结合。
图13A示出了一个使用1H1作为捕获抗体、1A3作为检测抗体进行双抗夹心ELISA的实施例检测结果。如图13A所示,1A3可以结合或检测被1H1结合的S1。
图13B示出了一个使用5E1作为捕获抗体、1D2作为检测抗体进行双抗夹心ELISA的实施例检测结果。如图13B所示,1D2可以结合或检测被5E1捕获的S1。
图13C示出了一个使用7G5作为捕获抗体、1H1作为检测抗体进行双抗夹心ELISA的实施例检测结果。如图13C所示,1H1可以结合或检测被7G5捕获的S1。
图13D示出了一个使用9A5作为捕获抗体、5E1作为检测抗体进行双抗夹心ELISA的实施例检测结果。如图13D所示,5E1可以结合或检测被9A5捕获的S1。
图13E示出了一个使用9A5作为捕获抗体、9H1作为检测抗体进行双抗夹心ELISA的实施例检测结果。如图13E所示,9H1可以结合或检测被9A5捕获的S1。
图13F示出了一个使用9H1作为捕获抗体、作为9A5检测抗体进行双抗夹心ELISA的实施例检测结果。如图13F所示,9A5可以结合或检测被9H1捕获的S1。
参阅图11,其示出了1H1、9H1、5E1、H5和7G5的中和试验结果。X轴表示示抗体浓度,Y轴表示假病毒感染到宿主细胞的感染的百分比。
方法
1、制备、分离和纯化抗SARS-CoV-2S1的兔单抗
抗SARS-CoV-2S1的兔单抗可以通过多种技术手段制得,包括单克隆抗体制备方法,例如,体细胞杂交技术和其他技术,包括但不限于B淋巴细胞的杂交瘤技术。在一个实施例中,通过基于B细胞制得重组兔单克隆抗体。
在一个实施例中,将SARS-CoV-2(GenBank:MN908947.3)基因组位置22,553~23,312bp对应的RBD区,经过密码子优化后克隆至pcDNA3.4表达载体中,以构建表达载体;将该表达构建转入感受态大肠杆菌DH5a菌株中培养,筛选阳性克隆,并利用Qiagen PlasmidMega试剂盒(C atNO:10023)提取表达载体。将纳米金(AlphaAesar,Catalog NO:39817)用100mg/mL亚精胺(Si gma,Catalog NO:S2626)进行预包裹后,再取36μg纯化的表达载体对预包裹的100μL 100mg/ml 金粉对包裹。将经表达载体包裹的纳米金用无水乙醇洗涤多次后,转载至子弹制造器(Scientz S cientific)的弹丸管中,向其中缓慢滴入200μL 2.5MCaCl2溶液,以促进DNA与纳米金的结合;将装载包括表达载体的金粉的弹丸管在0.1MPa N2流下缓慢干燥10min,再将干燥的子弹管切成 DNA弹丸。
将上述制得的SARS-CoV-2RBD DNA弹丸用SJ-500基因枪(Scientz Scientific)的弹夹装载。用4MPa氦气发射SJ-500基因枪中的DNA弹丸,以注射于新西兰大白兔(4-6周龄)腹部皮肤(36μg/每次免疫),分别在第0、7、21天对每只家兔进行3次DNA免疫。并分别在第35天和第49天,用不完全弗氏佐剂制得的SARSCoV-2S1蛋白的乳化制剂肌肉注射2次,进行加强免疫。两周后,再次向兔皮下注射200μg S1蛋白,以进行加强免疫。分别于第0、14、28、4 2和69天收集免疫前和免疫后的血清。
取经过上述免疫后的兔脾脏,分离新鲜的单个脾细胞,并在B细胞培养基(例如,优睿赛思生物科技)中培养过夜。用含2%胎牛血清和1mM EDTA的PBS溶氧稀释脾细胞制得新鲜的单细胞悬液。
利用平台(优睿赛思生物科技)分离单细胞悬液中的单个B细胞,然后再使用FACS Aria II(BD Biosciences,美国)对单个B细胞进行分选,并置于96孔板的每一单孔中。具有S1 特异性的原代B细胞加入B细胞完全培养基(例如,一种兔B细胞培养基,优睿赛思生物科技) 中,于37℃、5%CO2条件下培养10~14天。在原代B细胞培养结束时,通过直接ELISA筛选抗 S1的原代B细胞培养上清液,以鉴定S1特异性的B细胞阳性克隆。一般而言,B细胞阳性克隆的OD450nm值是背景噪声的5倍以上。采用RT-PCR法检测,鉴原代B细胞上清液顶层的阳性克隆中IgG重链和轻链的可变区。将每个克隆的全长IgG重链和轻链共转染HEK293T细胞。将含转染HEK293T表达兔IgG重组蛋白的上清液用ELISA方法筛选对S1的特异性。
在本申请实施例中,将所选克隆的可变区PCR片段克隆到pcDNA3.4载体中,在HEK293F 细胞中表达抗体。
在本申请实施例中,兔单克隆抗体可以通过本领域技术人员所熟知的常规方法进行分离和纯化。
在一个实施例中,兔单克隆抗体可以从转染了兔抗体基因的哺乳动物细胞的培养上清中分离出来,通过蛋白A亲和层析充分纯化,纯化的兔单克隆抗体的纯度和功能可分别通过SDS-PAGE 和ELISA进行验证。
2、抗SARS-CoV-2S1的兔单克隆偶联抗体的制备
兔单克隆偶联抗体使用PierceEZ-Link Sulfo-NHS-生物素按照制造商手册进行生物素化。简单而言,即将本申请实施例提供的抗SARS-CoV-2S1兔源单克隆抗体在1倍稀释体积的PBS中与磺基-NHS生物素混合,在室温下孵育30min。
3、ELISA鉴定免疫兔血清和抗SARS-CoV-2S1的单克隆抗体
(1)将SARS-CoV-2蛋白S1或来自其他病毒的S1蛋白作为抗原包被至ELISA板上(例如, Corning,Cat.NO:9018),于4℃、pH7.4的1×PBS中过夜。
(2)包被后的孔板用洗涤缓冲液(添加0.5%(V/V)Tween-20(Sigma,Cat.NO:P96416)的1×P BS)洗涤3次后,用封闭缓冲液(1×PBS添加5%(W/V)脱脂牛奶)封闭。
(3)封闭后,向孔板中加入连续稀释的兔血清样品或单克隆抗体在室温下孵育1h,然后用洗涤缓冲液洗涤5次,然后与经过1:5000封闭缓冲液稀释的偶联有HRP(例如,Jackson Immun o Research公司的HRP,Cat.NO:111-035-045)的山羊抗兔IgG抗体孵育。
(4)用洗涤缓冲液洗涤孔板5次后,加入25μL TMB底物(MossINS,Cat.NO:TMBHK-1000),在室温黑暗中放置3min。
(5)随后用20μL 1M硫酸停止TMB底物的比色反应。用Epoch微孔板分光光度计(Biotek, USA)测定了在450nm和630nm处的光密度(OD)值,最终值用OD450减去OD630得到。血清滴度计算为稀释后血清OD450读数为对照样品2倍或以上的最大稀释度。
4、兔单克隆抗体应用于捕获ELISA法检测SARS-CoV-2S1
本申请涉及的抗SARS-CoV-2S1的兔单克隆抗体捕获ELISA法检测步骤大致包括:
包被:于4℃将抗兔IgGFc抗体添加至高结合ELISA的孔板中,于1倍稀释体积的pH7.4 P BS中包被过夜。
封闭:将包被后的孔板用洗涤缓冲液(添加0.5%(V/V)Tween-20的1×PBS)洗涤,并用封闭缓冲液(添加5%(W/V)脱脂牛奶1×PBS中)封闭。
孵育:向封闭后的孔板中加入抗SARS-CoV-2蛋白S1的兔抗体,于室温下孵育1h,洗涤,再用稀释3倍的生物素化SARS-CoV-2的S1蛋白孵育。最后再加入结合HRP的链霉亲和素孵育。
比色:将上述孵育后的孔板清洗后,使用HRP催化的比色反应,以检测单克隆抗体是否能够捕获S1。
本领域技术人员应当理解的是,可以采用与上述不同的步骤、试剂、实验参数来执行上述的捕获ELISA步骤。
5、兔单克隆抗体应用于双抗夹心ELISA法检测SARS-CoV-2S1
本申请涉及的抗SARS-CoV-2S1的兔单克隆抗体的双抗夹心ELISA法检测步骤大致包括:
包被:于4℃将捕获抗体添加至至高结合ELISA的孔板中,于pH9.4的0.02M碳酸氢盐缓冲液中包被过夜。
封闭:将包被后的孔板用洗涤缓冲液(添加0.5%(V/V)Tween-20的1×PBS)洗涤,并用封闭缓冲液(添加5%(W/V)脱脂牛奶1×PBS中)封闭。
孵育:向封闭后的孔板中加入SARS-CoV-2蛋白S1,于室温下孵育1h,洗涤,再加入抗SA RS-CoV-2S1的生物素化单克隆抗体。将平板再加入结合HRP的链霉亲和素孵育。
比色:将上述孵育后的孔板清洗后,使用HRP催化的比色反应,以观察用于捕获和用于检测的单克隆抗体是否能够同时或不能同时与SARS-CoV-2S1结合。
本领域技术人员应当理解的是,可以采用与上述不同的步骤、试剂、实验参数来执行上述的捕获ELISA步骤。
6、抗SARS-CoV-2蛋白S1的兔单克隆抗体结合动力学
使用具有蛋白A传感器芯片的Biacore仪器(GE Health,USA),通过表面等离子体共振(S PR)法分析兔mAbs对抗SARS-CoV-2S1的结合动力学。所有实验均在25℃条件下进行,流速为 40μL/min。用含0.005%Tween-20脱气的PBS作为运行缓冲液。通道1装载与SARS-CoV-2蛋白 S1没有特异性结合的参考抗体,通道2、3和4分别装载候选抗体。
一般而言,检测过程中,采用2μg/mL的抗体并进行20~30秒的快速注射至通道内进行上样,如此获得检测结果能够产生150~250反应单位(RU),并且具有高度重现性。因此,将2μg/mL的抗体以20~30s的速度快速注射至通道内后,再次将抗原注射到所有通道表面5min以便于抗体进行结合,然后将注入缓冲液冲10min以进入解离阶段。
使用1.2~100nM范围内的抗原稀释梯度以及空白缓冲液进行多次结合/解离循环。在每个周期结束时,通过30s注射甘氨酸缓冲液(pH2.0、10mM)再生通道,以便在每个通道再次装载抗体。动力学曲线采用BIA evaluation 3.2软件和1:1Langmuir模型进行双系数曲线进行分析,并计算结合合速率常数、解离速率常数和亲和常数。
7、抗SARS-CoV-2S1的兔单抗的中和试验
抗SARS-CoV-2的中和活性在认证的生物安全III级实验室进行。活SARS-CoV-2毒株分离子从中国江苏省一名感染患者的鼻咽拭子中分离出来。中和试验步骤包括:将Vero细胞接种于2 4孔板(200000个细胞/孔),孵育约16h,直到90~100%融合;用含有2%胎牛血清的DMEM分别稀释1H1和9H13倍,然后分别与病毒以1:1(vol/vol)的比例混合,生成含有100个聚焦形成单位(PFU)/ml病毒的混合物,然后在37℃孵育1h;将单抗和病毒复合物重复加入到Vero细胞单层 24孔板孔中,然后在37℃孵育1h。去除混合物,并在细胞上覆盖含1%低熔点琼脂糖(Promega) 和2%胎牛血清的DMEM,于37℃下孵育3d后,细胞用4%甲醛固定,并用0.2%结晶紫溶液(Si gma)染色。通过斑块数量可见感染SARS-CoV-2的细胞灶。单抗的50%抑制浓度(半抑制浓度) 定义为相对于无抗体的50%总斑块总数对应的抗体浓度(g/mL)。
8、ACE2受体阻断的ELISA试验
以1μg/mL重组ACE2(KactusBiosystems公司,Cat.NO:ACE-HM501)包被ELISA孔板。将抗体分别与不同浓度稀释的RBD结构域蛋白在室温下预孵育1h。然后将抗体-RBD复合物沉积在ACE2包覆的ELISA孔板上,在室温下放置1h。
以上所述,仅为本申请较佳的具体实施方式,但本申请的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本申请揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本申请的保护范围之内。因此,对于使用不超过常规实验的普通技能的人,可能会发生本领域披露的披露的进一步修改和等价物。本申请的这些修改和等效内容包括编码所公开的氨基酸序列的核酸序列。
序列表
<110> 优睿赛思(武汉)生物科技有限公司
<120> 抗SARS-CoV-2刺突蛋白S1的单克隆抗体及其应用
<150> US17399364
<151> 2021-08-11
<160> 70
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Glu Ser Val Leu Ser Asn Asn Arg Leu Ser Trp
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Gly Ala Phe Ser Gly Ser Ser Asp Thr Arg Ala Phe Gly
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Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Ser
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Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala
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Ile Ile Thr Ser His Asp His Ser Gly Tyr Ala Asn Trp Ala Glu Gly
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Arg Glu Thr Ile Ser Lys Thr Ser Thr Thr Val Thr Leu Thr Ile Thr
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Asp Leu Gln Pro Ser Asp Thr Gly Thr Tyr Phe Cys Ala Lys Asp Val
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Gly His Ser Thr Tyr Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val
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Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser
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Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
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Ala Cys Ile Gly Thr Gly Ser Ser Gly Asn Ile Tyr Tyr Ala Ser Trp
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Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr
65 70 75 80
Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys
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Ala Arg Asp Asp Ala Asp Tyr Ala Gly Pro Asp Tyr Phe Asn Leu Trp
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Gly Pro Gly Thr Leu Val Thr Val Ser Ser
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Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
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Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Ala
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Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
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Ile Ile Tyr Ile Ser Gly Leu Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
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Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Pro
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Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Glu
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Tyr Asn Ser His Ser His Tyr Leu Leu Trp Gly Pro Gly Thr Leu Val
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Thr Val Ser Ser
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Gln Glu Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala
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Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ala
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Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
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Ile Ala Cys Ile Gly Val Asp Ser Gly Gly Asn Ser Tyr Tyr Ala Ser
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Trp Ala Lys Gly Arg Phe Thr Ile Ser Thr Thr Ser Ser Thr Thr Val
65 70 75 80
Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Lys Ala Thr Tyr Phe
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Cys Thr Arg Ser Phe Ser Leu Trp Gly Pro Gly Thr Leu Val Thr Ile
100 105 110
Ser Ser
<210> 48
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Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ala Tyr Gln
20 25 30
Met Ile Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Ile Met His Thr Gly Thr Ser Ala Tyr Tyr Ala Asn Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Gly Arg Asn
85 90 95
Leu Asn Glu Gly Phe Thr Gly Ala Tyr Pro Phe Asn Leu Trp Gly Pro
100 105 110
Gly Thr Leu Val Ala Val Ser Ser
115 120
<210> 49
<211> 117
<212> PRT
<213> Oryctolagus cuniculus
<400> 49
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Val Asp Ser Gly His Thr Ala Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Val Asp Leu Lys Met Thr
65 70 75 80
Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Glu Thr
85 90 95
Gly Gly Gly Ala Phe Tyr Val Phe Glu Phe Trp Gly Pro Gly Thr Val
100 105 110
Val Thr Val Ser Ser
115
<210> 50
<211> 109
<212> PRT
<213> Oryctolagus cuniculus
<400> 50
Ala Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Ser Cys Gln Ala Ser Gln Ser Val Asn Met Asn
20 25 30
Leu Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
35 40 45
Ile Tyr Gln Ala Ser Asn Leu Ala Ser Gly Val Ser Ala Arg Phe Lys
50 55 60
Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Asn Glu Ile Gln
65 70 75 80
Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Asp Met Gly Gly Trp
85 90 95
Met Phe Pro Phe Gly Gly Gly Thr Glu Val Val Val Thr
100 105
<210> 51
<211> 112
<212> PRT
<213> Oryctolagus cuniculus
<400> 51
Ala Ala Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Glu Ser Val Leu Ser Asn
20 25 30
Asn Arg Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
35 40 45
Leu Ile Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Lys Gly Arg Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val
65 70 75 80
Gln Cys Asp Asp Ala Ala Met Tyr Val Cys Ala Gly Ala Phe Ser Gly
85 90 95
Ser Ser Asp Thr Arg Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 52
<211> 111
<212> PRT
<213> Oryctolagus cuniculus
<400> 52
Ala Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val
1 5 10 15
Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Asn
20 25 30
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Ala Phe Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys
50 55 60
Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Asn Gly Val Glu
65 70 75 80
Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Ser Arg
85 90 95
Asp Val Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 53
<211> 110
<212> PRT
<213> Oryctolagus cuniculus
<400> 53
Ala Tyr Asp Met Thr Gln Thr Pro Ser Ser Val Ser Glu Pro Val Gly
1 5 10 15
Gly Thr Val Ser Ile Lys Cys Gln Ala Ser Gln Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Gln Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Gly Val Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Phe Glu Ser Ser Asp
85 90 95
Ile Phe Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 54
<211> 114
<212> PRT
<213> Oryctolagus cuniculus
<400> 54
Trp Arg Lys Trp Leu Thr Gln Thr Ala Ser Ser Val Ser Ala Ala Val
1 5 10 15
Gly Gly Thr Val Thr Ile Ser Cys Gln Ala Ser Gln Ser Val Tyr Asn
20 25 30
Asn Asp Asn Leu Ala Trp Phe Gln Gln Arg Pro Gly Gln Pro Pro Lys
35 40 45
Leu Leu Ile Tyr Leu Ala Ser Asn Leu Ala Ser Gly Val Pro Pro Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp
65 70 75 80
Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Gly Tyr Asp
85 90 95
Cys Ser Asn Ala Asp Cys His Ala Phe Gly Gly Gly Thr Glu Val Val
100 105 110
Val Lys
<210> 55
<211> 112
<212> PRT
<213> Oryctolagus cuniculus
<400> 55
Ala Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val
1 5 10 15
Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser
20 25 30
Asn Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Pro Pro Lys Leu Leu
35 40 45
Ile Tyr Gln Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Lys
50 55 60
Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu
65 70 75 80
Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Met Asn Tyr Tyr Ile Ser
85 90 95
Ser Ser Tyr Thr Tyr Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 56
<211> 111
<212> PRT
<213> Oryctolagus cuniculus
<400> 56
Ala Gln Val Leu Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Tyr Asp Asn
20 25 30
Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Thr Leu Ala Phe Gly Val Ser Ser Arg Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr His Phe Thr Leu Thr Met Arg Asp Val Gln Cys
65 70 75 80
Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Glu Phe Ser Cys Ser Ser
85 90 95
Gly Asp Cys Thr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
<210> 57
<211> 209
<212> PRT
<213> Oryctolagus cuniculus
<400> 57
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Phe Ser Ser Tyr His
20 25 30
Met Gly Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Ile Gly
35 40 45
Thr Leu Ile Gly Ile Ala Gly Asn Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Ser Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Trp Cys Ala Arg Ile
85 90 95
Val Thr Ala Thr Phe Glu Phe Trp Gly Pro Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala Pro Cys
115 120 125
Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys
130 135 140
Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Thr Leu
145 150 155 160
Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln Pro Val
180 185 190
Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys Thr
195 200 205
Val
<210> 58
<211> 209
<212> PRT
<213> Oryctolagus cuniculus
<400> 58
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Ser
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Ile Glu Thr Tyr Trp
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala
35 40 45
Ile Ile Thr Ser His Asp His Ser Gly Tyr Ala Asn Trp Ala Glu Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Thr Leu Thr Ile Thr
65 70 75 80
Asp Leu Gln Pro Ser Asp Thr Gly Thr Tyr Phe Cys Ala Lys Asp Val
85 90 95
Gly His Ser Thr Tyr Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala Pro Cys
115 120 125
Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys
130 135 140
Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Thr Leu
145 150 155 160
Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln Pro Val
180 185 190
Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys Thr
195 200 205
Val
<210> 59
<211> 217
<212> PRT
<213> Oryctolagus cuniculus
<400> 59
Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala Ser
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Gly Tyr
20 25 30
Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ala Cys Ile Gly Thr Gly Ser Ser Gly Asn Ile Tyr Tyr Ala Ser Trp
50 55 60
Ala Lys Gly Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Thr
65 70 75 80
Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asp Asp Ala Asp Tyr Ala Gly Pro Asp Tyr Phe Asn Leu Trp
100 105 110
Gly Pro Gly Thr Leu Val Thr Val Ser Ser Gly Gln Pro Lys Ala Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr
130 135 140
Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr
145 150 155 160
Val Thr Trp Asn Ser Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro
165 170 175
Ser Val Arg Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser
180 185 190
Val Thr Ser Ser Ser Gln Pro Val Thr Cys Asn Val Ala His Pro Ala
195 200 205
Thr Asn Thr Lys Val Asp Lys Thr Val
210 215
<210> 60
<211> 211
<212> PRT
<213> Oryctolagus cuniculus
<400> 60
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Ala
20 25 30
Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Ile Ile Tyr Ile Ser Gly Leu Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Pro
65 70 75 80
Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Glu
85 90 95
Tyr Asn Ser His Ser His Tyr Leu Leu Trp Gly Pro Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu
130 135 140
Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly
145 150 155 160
Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln
180 185 190
Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp
195 200 205
Lys Thr Val
210
<210> 61
<211> 209
<212> PRT
<213> Oryctolagus cuniculus
<400> 61
Gln Glu Gln Leu Glu Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Ala
20 25 30
Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Ala Cys Ile Gly Val Asp Ser Gly Gly Asn Ser Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Thr Thr Ser Ser Thr Thr Val
65 70 75 80
Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Lys Ala Thr Tyr Phe
85 90 95
Cys Thr Arg Ser Phe Ser Leu Trp Gly Pro Gly Thr Leu Val Thr Ile
100 105 110
Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala Pro Cys
115 120 125
Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys
130 135 140
Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Thr Leu
145 150 155 160
Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln Pro Val
180 185 190
Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys Thr
195 200 205
Val
<210> 62
<211> 215
<212> PRT
<213> Oryctolagus cuniculus
<400> 62
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ala Tyr Gln
20 25 30
Met Ile Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Tyr Ile Gly
35 40 45
Ile Met His Thr Gly Thr Ser Ala Tyr Tyr Ala Asn Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met
65 70 75 80
Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Gly Arg Asn
85 90 95
Leu Asn Glu Gly Phe Thr Gly Ala Tyr Pro Phe Asn Leu Trp Gly Pro
100 105 110
Gly Thr Leu Val Ala Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr
130 135 140
Leu Gly Cys Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr
145 150 155 160
Trp Asn Ser Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val
165 170 175
Arg Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr
180 185 190
Ser Ser Ser Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn
195 200 205
Thr Lys Val Asp Lys Thr Val
210 215
<210> 63
<211> 212
<212> PRT
<213> Oryctolagus cuniculus
<400> 63
Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr Ala
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Ile Ile Val Asp Ser Gly His Thr Ala Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Val Asp Leu Lys Met Thr
65 70 75 80
Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Glu Thr
85 90 95
Gly Gly Gly Ala Phe Tyr Val Phe Glu Phe Trp Gly Pro Gly Thr Val
100 105 110
Val Thr Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser
145 150 155 160
Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser
180 185 190
Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val
195 200 205
Asp Lys Thr Val
210
<210> 64
<211> 213
<212> PRT
<213> Oryctolagus cuniculus
<400> 64
Ala Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Ser Cys Gln Ala Ser Gln Ser Val Asn Met Asn
20 25 30
Leu Leu Ser Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
35 40 45
Ile Tyr Gln Ala Ser Asn Leu Ala Ser Gly Val Ser Ala Arg Phe Lys
50 55 60
Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Asn Glu Ile Gln
65 70 75 80
Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Asp Met Gly Gly Trp
85 90 95
Met Phe Pro Phe Gly Gly Gly Thr Glu Val Val Val Thr Gly Asp Pro
100 105 110
Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp Gln Val Ala
115 120 125
Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr Phe Pro Asp
130 135 140
Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr Thr Gly Ile
145 150 155 160
Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr Tyr Asn Leu
165 170 175
Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser His Lys Glu
180 185 190
Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val Gln Ser Phe
195 200 205
Asn Arg Gly Asp Cys
210
<210> 65
<211> 216
<212> PRT
<213> Oryctolagus cuniculus
<400> 65
Ala Ala Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Glu Ser Val Leu Ser Asn
20 25 30
Asn Arg Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
35 40 45
Leu Ile Tyr Ala Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Lys Gly Arg Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val
65 70 75 80
Gln Cys Asp Asp Ala Ala Met Tyr Val Cys Ala Gly Ala Phe Ser Gly
85 90 95
Ser Ser Asp Thr Arg Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
Gly Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp
115 120 125
Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr
130 135 140
Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr
145 150 155 160
Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr
165 170 175
Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser
180 185 190
His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val
195 200 205
Gln Ser Phe Asn Arg Gly Asp Cys
210 215
<210> 66
<211> 215
<212> PRT
<213> Oryctolagus cuniculus
<400> 66
Ala Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val
1 5 10 15
Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Glu Ser Ile Ser Asn
20 25 30
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Ala Phe Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys
50 55 60
Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Asn Gly Val Glu
65 70 75 80
Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Ser Arg
85 90 95
Asp Val Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Gly
100 105 110
Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp Gln
115 120 125
Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr Phe
130 135 140
Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr Thr
145 150 155 160
Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr Tyr
165 170 175
Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser His
180 185 190
Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val Gln
195 200 205
Ser Phe Asn Arg Gly Asp Cys
210 215
<210> 67
<211> 214
<212> PRT
<213> Oryctolagus cuniculus
<400> 67
Ala Tyr Asp Met Thr Gln Thr Pro Ser Ser Val Ser Glu Pro Val Gly
1 5 10 15
Gly Thr Val Ser Ile Lys Cys Gln Ala Ser Gln Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Gln Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Gly Val Glu Cys
65 70 75 80
Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Phe Glu Ser Ser Asp
85 90 95
Ile Phe Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Gly Asp
100 105 110
Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp Gln Val
115 120 125
Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr Phe Pro
130 135 140
Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr Thr Gly
145 150 155 160
Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr Tyr Asn
165 170 175
Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser His Lys
180 185 190
Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val Gln Ser
195 200 205
Phe Asn Arg Gly Asp Cys
210
<210> 68
<211> 218
<212> PRT
<213> Oryctolagus cuniculus
<400> 68
Trp Arg Lys Trp Leu Thr Gln Thr Ala Ser Ser Val Ser Ala Ala Val
1 5 10 15
Gly Gly Thr Val Thr Ile Ser Cys Gln Ala Ser Gln Ser Val Tyr Asn
20 25 30
Asn Asp Asn Leu Ala Trp Phe Gln Gln Arg Pro Gly Gln Pro Pro Lys
35 40 45
Leu Leu Ile Tyr Leu Ala Ser Asn Leu Ala Ser Gly Val Pro Pro Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp
65 70 75 80
Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Gly Tyr Asp
85 90 95
Cys Ser Asn Ala Asp Cys His Ala Phe Gly Gly Gly Thr Glu Val Val
100 105 110
Val Lys Gly Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala
115 120 125
Ala Asp Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn
130 135 140
Lys Tyr Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr
145 150 155 160
Gln Thr Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp
165 170 175
Cys Thr Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr
180 185 190
Asn Ser His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser
195 200 205
Val Val Gln Ser Phe Asn Arg Gly Asp Cys
210 215
<210> 69
<211> 216
<212> PRT
<213> Oryctolagus cuniculus
<400> 69
Ala Asp Val Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val
1 5 10 15
Gly Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Gly Ser
20 25 30
Asn Leu Ala Trp Tyr Gln Lys Lys Pro Gly Gln Pro Pro Lys Leu Leu
35 40 45
Ile Tyr Gln Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Lys
50 55 60
Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu
65 70 75 80
Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Met Asn Tyr Tyr Ile Ser
85 90 95
Ser Ser Tyr Thr Tyr Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys
100 105 110
Gly Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp
115 120 125
Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr
130 135 140
Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr
145 150 155 160
Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr
165 170 175
Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser
180 185 190
His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val
195 200 205
Gln Ser Phe Asn Arg Gly Asp Cys
210 215
<210> 70
<211> 215
<212> PRT
<213> Oryctolagus cuniculus
<400> 70
Ala Gln Val Leu Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Tyr Asp Asn
20 25 30
Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Thr Leu Ala Phe Gly Val Ser Ser Arg Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr His Phe Thr Leu Thr Met Arg Asp Val Gln Cys
65 70 75 80
Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Glu Phe Ser Cys Ser Ser
85 90 95
Gly Asp Cys Thr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Gly
100 105 110
Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp Gln
115 120 125
Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr Phe
130 135 140
Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr Thr
145 150 155 160
Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr Tyr
165 170 175
Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser His
180 185 190
Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val Gln
195 200 205
Ser Phe Asn Arg Gly Asp Cys
210 215
Claims (13)
1.一种抗体,包括:
具有如SEQ ID NO:1~7任一所示的氨基酸序列或其保守性修饰序列的VHCDR1;
具有如SEQ ID NO:8~14任一所示的氨基酸序列或其保守性修饰序列的VHCDR2;
具有如SEQ ID NO:15~21任一所示的氨基酸序列或其保守性修饰序列的VHCDR3;
具有如SEQ ID NO:22~28任一所示的氨基酸序列或其保守性修饰序列的VLCDR1;
具有如SEQ ID NO:29~35任一所示的氨基酸序列或其保守性修饰序列的VLCDR2;以及
具有如SEQ ID NO:36~42任一所示的氨基酸序列或其保守性修饰序列的VLCDR3。
2.如权利要求1所述的抗体,其中,所述VHCDR1具有如SEQID NO:1所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:8所示的氨基酸序列或其保守性修饰序列,所述V HCDR3具有如SEQ ID NO:15所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:22所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SEQ IDNO:29所示的氨基酸序列或其保守性修饰序列,所述VLCDR3具有如SEQ ID NO:36所示的氨基酸序列或其保守性修饰序列;或者
所述VHCDR1具有如SEQ ID NO:2所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:9所示的氨基酸序列或其保守性修饰序列,所述VHCDR3具有如SEQ ID NO:16所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:23所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SE Q ID NO:30所示的氨基酸序列或其保守性修饰序列,所述VLCDR3具有如SEQ ID NO:37所示的氨基酸序列或其保守性修饰序列;或者
所述VHCDR1具有如SEQ ID NO:3所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:10所示的氨基酸序列或其保守性修饰序列,所述VHCDR3具有如SEQ ID NO:17所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:24所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SEQ ID NO:31所示的氨基酸序列或其保守性修饰序列,所述VLCD R3具有如SEQ ID NO:38所示的氨基酸序列或其保守性修饰序列;或者
所述VHCDR1具有如SEQ ID NO:4所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:11所示的氨基酸序列或其保守性修饰序列,所述VHCDR3具有如SEQ ID NO:18所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:25所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SEQ ID NO:32所示的氨基酸序列或其保守性修饰序列,所述VLCD R3具有如SEQ ID NO:39所示的氨基酸序列或其保守性修饰序列;或者
所述VHCDR1具有如SEQ ID NO:5所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:12所示的氨基酸序列或其保守性修饰序列,所述VHCDR3具有如SEQ ID NO:19所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:26所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SEQ ID NO:33所示的氨基酸序列或其保守性修饰序列,所述VLCD R3具有如SEQ ID NO:40所示的氨基酸序列或其保守性修饰序列;或者
所述VHCDR1具有如SEQ ID NO:6所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:13所示的氨基酸序列或其保守性修饰序列,所述VHCDR3具有如SEQ ID NO:20所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:27所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SEQ ID NO:34所示的氨基酸序列或其保守性修饰序列,所述VLCD R3具有如SEQ ID NO:41所示的氨基酸序列或其保守性修饰序列;或者
所述VHCDR1具有如SEQ ID NO:7所示的氨基酸序列或其保守性修饰序列,所述VHCDR2具有如SEQ ID NO:14所示的氨基酸序列或其保守性修饰序列,所述VHCDR3具有如SEQ ID NO:21所示的氨基酸序列或其保守性修饰序列,所述VLCDR1具有如SEQ ID NO:28所示的氨基酸序列或其保守性修饰序列,所述VLCDR2具有如SEQ ID NO:35所示的氨基酸序列或其保守性修饰序列,所述VLCD R3具有如SEQ ID NO:42所示的氨基酸序列或其保守性修饰序列。
3.一种抗体,包括:
具有如SEQ ID NO:43~49任一所示的氨基酸序列或其保守性修饰序列的VH;以及
具有如SEQ ID NO:50~56任一所示的氨基酸序列或其保守性修饰序列的VL。
4.如权利要求3所述的抗体,其中,所述VH具有如SEQ ID NO:43所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQ ID NO:50所示的氨基酸序列或其保守性修饰序列;或者
所述VH具有如SEQ ID NO:44所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQID NO:51所示的氨基酸序列或其保守性修饰序列;或者
所述VH具有如SEQ ID NO:45所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQID NO:52所示的氨基酸序列或其保守性修饰序列;或者
所述VH具有如SEQ ID NO:46所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQID NO:53所示的氨基酸序列或其保守性修饰序列;或者
所述VH具有如SEQ ID NO:47所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQID NO:54所示的氨基酸序列或其保守性修饰序列;或者
所述VH具有如SEQ ID NO:48所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQID NO:55所示的氨基酸序列或其保守性修饰序列;或者
所述VH具有如SEQ ID NO:49所示的氨基酸序列或其保守性修饰序列,所述VL具有如SEQID NO:56所示的氨基酸序列或其保守性修饰序列。
5.一种抗体,包括具有重链和轻链的Fab段,所述重链具有如SEQ ID NO:57~63任一所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:64~70任一所示的氨基酸序列或其保守性修饰序列。
6.如权利要求5所述的抗体,其中,所述重链具有如SEQ ID NO:57所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SE Q ID NO:64所示的氨基酸序列或其保守性修饰序列;或者
所述重链具有如SEQ ID NO:58所示的氨基酸序列或其保守性修饰序列,所述具有如SEQ ID NO:65所示的氨基酸序列或其保守性修饰序列;或者
所述重链具有如SEQ ID NO:59所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:66所示的氨基酸序列或其保守性修饰序列;或者
所述重链具有如SEQ ID NO:60所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:67所示的氨基酸序列或其保守性修饰序列;或者
所述重链具有如SEQ ID NO:61所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:68所示的氨基酸序列或其保守性修饰序列;或者
所述重链具有如SEQ ID NO:62所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:69所示的氨基酸序列或其保守性修饰序列;或者
所述重链具有如SEQ ID NO:63所示的氨基酸序列或其保守性修饰序列,所述轻链具有如SEQ ID NO:70所示的氨基酸序列或其保守性修饰序列。
7.如权利要求1~2任一、或权利要求3~4任一、或权利要求5~6任一所述的抗体,所述抗体还包含共价或非共价连接的缀合物。
8.如权利要求7所述的抗体,所述包括酶,荧光团,生物素或链霉亲和素,或其组合。
9.如权利要求7所述的抗体,所述抗体是人源化或嵌合抗体。
10.于体外诊断SARS-CoV-2或检测SARS-CoV-2刺突蛋白S1的ELISA试剂盒,其包含如权利要求1~2任一所述的抗体;或者包含如权利要求3~4所述的抗体;或者包含如权利要求5~6任一所述的抗体,或者其组合。
11.于体外诊断SARS-CoV-2或检测SARS-CoV-2刺突蛋S1蛋白的方法,包括使用如权利要求1~2任一所述的抗体;或者包含如权利要求3~4任一所述的抗体;或者包含如权利要求5~6任一所述的抗体,或者其组合。
12.如权利要求11所述的方法,所述方法选自直接ELISA、捕获ELISA和双抗夹心ELISA中的一种。
13.如权利要求1~2任一所述的抗体、或者包含如权利要求3~4任一所述的抗体、或者包含如权利要求5~6任一所述的抗体,或者其组合在制备治疗或预防SARS-CoV-2感染药物中的应用,所述药物以如权利要求1~2任一所述的抗体、或者包含如权利要求3~4任一所述的抗体、或者包含如权利要求5~6所述的抗体,或者其组合作为有效成分。
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