CN113683687A - 抗新型冠状病毒Spike蛋白抗体及其应用 - Google Patents
抗新型冠状病毒Spike蛋白抗体及其应用 Download PDFInfo
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Abstract
本发明提供一种抗新型冠状病毒Spike蛋白抗体及其应用。利用基因工程和噬菌体表面展示文库技术，从非免疫的全人源序列的单链抗体库中筛选出抗新冠病毒S蛋白的特异性抗体。它们与病毒S蛋白的亲和力在1nM‑50nM之间，抗体对新冠病毒S蛋白与人受体ACE2的结合有抑制作用，表明本发明的抗病毒S蛋白抗体具有良好地结合S蛋白的能力及潜在的中和抑制作用。本发明为研发针对新冠病毒(2019‑nCoV)的诊断试剂、预防和治疗抗体药物，以及其它疾病如冠状病毒引起的肺炎治疗等提供了特异性抗体候选分子。
Description
技术领域
本发明涉及基因工程及免疫学领域，具体地说，涉及一种抗新型冠状病毒Spike蛋白抗体及其应用。
背景技术
新型冠状病毒(2019-nCoV)是一种新的冠状病毒，与SARS-CoV同属于网巢病毒目冠状病毒科的β-CoV，为一种不分节段的单股正链RNA病毒，其每组基因组长度约30000个核苷酸左右。与中东呼吸综合征冠状病毒(MERS-CoV)和严重急性呼吸综合征冠状病毒(SARS-CoV)不同，新型冠状病毒是感染人类的冠状病毒家族中的第7个。根据基因序列同源性，新型冠状病毒基因组与SARS具有80％的相似性，新型冠状病毒与MERS-CoV的基因序列有40％的相似性。
新型冠状病毒2019-nCoV表现出典型的冠状病毒属结构(图4)，包括：5个未翻译区(UTR)、复制酶复合体(orf1ab)、S基因、E基因、M基因、N基因、3个UTR，以及几个未识别的非结构开放阅读框。
在冠状病毒中有一个关键的S蛋白(棘突蛋白，spike protein)，包含2个亚单位：S1和S2。S1能够促进病毒与宿主细胞受体的结合，其含有一个重要的C端RBD结构域，正是这个区域负责和受体结合。新型冠状病毒RBD结构域与SARS有高度的同源性。其中SARS感染的5个关键位点中，有1个被新型冠状病毒保留，其余4个有氨基酸的替换和变化。
冠状病毒的S蛋白(spike)组合成一个三聚体，约含有1300个氨基酸，属于第一类膜融合蛋白(Class I viral fusion protein)，同类的病毒膜融合蛋白还包括HIV的Env蛋白，流感的HA蛋白，以及埃博拉病毒的Gp蛋白等。S蛋白决定了病毒的宿主范围和特异性，也是宿主中和抗体的重要作用位点。同时也是疫苗设计的关键靶点。
与其它第一类病毒膜融合蛋白类似，S蛋白含有两个亚基(subunit)，S1和S2。S1主要包含有受体结合区(receptorbinding domain，RBD)，负责识别细胞的受体。S2含有膜融合过程所需的基本元件，包括一个内在的膜融合肽(fusion peptide)，两个7肽重复序列(heptad repeat，HR)，一个富含芳香族氨基酸的膜临近区域(membrane proximalexternal region，MPER)，以及跨膜区(transmembrane，TM)。S1蛋白可进一步分成两个区域(domain)，即N-端区域(N-terminal domain,NTD)和C-端区域(C-terminal domain，CTD)，其中NTD的构象与galectin蛋白非常相似。大部分的冠状病毒S蛋白的RBD都位于CTD，例如SARS病毒和中东呼吸道综合症病毒(Middle East respiratory syndrome，MERS)等。只有少部分β冠状病毒的RBD则位于NTD，例如小鼠肝炎病毒(mouse hepatitisvirus,MHV)。另外，牛冠状病毒(bovine coronavirus,BCoV)和人冠状病毒OC43的NTD能结合特异的糖分子(唾液酸等)，它们也参与了冠状病毒的入侵过程。同一家族病毒包膜蛋白需要两个不同的区域识别宿主受体，并有效介导病毒与细胞的膜融合过程。这是冠状病毒S蛋白与其它类病毒膜融合蛋白的重要区别之一。
目前已发现的冠状病毒受体主要包括以下几种：氨基肽酶N(animopeptidase N，APN)，血管紧张素转换酶2(angiotensin converting enzyme II，ACE2)，二肽基肽酶4(dipeptidylpeptidase 4,DPP4)，以及CEACAM1(carcinoembryonicantigen-related celladhesion molecule)。其中，具有种属特异性的APN蛋白是人冠状病毒229E，猫冠状病毒(FCoV)和猪冠状病毒TGEV的受体。人类ACE2是SARS病毒和NL63的受体。人类DPP4是MERS病毒的受体。小鼠CEACAM1蛋白的α亚型是MHV的受体。许多冠状病毒RBD与宿主受体结合的复合物晶体结构已经获得解析，主要包括SARS-RBD-ACE2复合物,NL63-RBD-ACE2复合物，MERS-RBD-DPP4复合物，HKU4-RBD-DPP4复合物，和MHV-RBD-mCEACAM1α复合物晶体结构。
由新型冠状病毒2019-nCoV感染以及由其感染所致相关疾病目前没有相应的疫苗和特异性药物，因此开发2019-nCoV诊疗药物成为当务之急。
发明内容
本发明的目的是提供一种抗新型冠状病毒Spike蛋白抗体及其应用。
为了实现本发明目的，第一方面，本发明提供一种抗新型冠状病毒Spike蛋白抗体或其活性片段，其重链可变区的CDR1包含如SEQ ID NO:1所示的氨基酸序列或由其组成，重链可变区的CDR2包含如SEQ ID NO:2或3所示的氨基酸序列或由其组成，重链可变区的CDR3包含如SEQ ID NO:4-7任一所示的氨基酸序列或由其组成；其轻链可变区的CDR1包含如SEQID NO:8-12任一所示的氨基酸序列或由其组成，轻链可变区的CDR2包含如SEQ ID NO:13-16所示的氨基酸序列或由其组成，轻链可变区的CDR3包含如SEQ ID NO:17-19任一所示的氨基酸序列或由其组成。
本发明提供的抗体可变区氨基酸序列，其模式为：
FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。本发明中，FR和CDR的区域划分基于Kabat命名系统。在此，FR1～FR4代表4个框架区域，CDR1～CDR3代表3个高变区。FR1～FR4可以是从恒定区序列分离而来(例如人免疫球蛋白轻重链类、亚类或亚家族最常用的氨基酸)，也可以是从个人抗体框架区分离而来或从不同的框架区基因组合而来。
本发明的抗新型冠状病毒Spike蛋白抗体，其为：
i)、重链可变区包含如SEQ ID NO:20-25任一所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:26-33任一所示的氨基酸序列或由其组成；
ii)、i)的抗体经取代、缺失或添加一个或几个氨基酸且具有同等功能的由i)衍生的抗体；
iii)、与i)的抗体具有70％、80％、85％、90％或97％以上序列同源性且具有同等功能的由i)衍生的抗体。
优选CS1～CS8中的任一条抗体：
CS1：重链可变区包含如SEQ ID NO:20所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:26所示的氨基酸序列或由其组成；
CS2：重链可变区包含如SEQ ID NO:21所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:27所示的氨基酸序列或由其组成；
CS3：重链可变区包含如SEQ ID NO:22所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:28所示的氨基酸序列或由其组成；
CS4：重链可变区包含如SEQ ID NO:22所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:29所示的氨基酸序列或由其组成；
CS5：重链可变区包含如SEQ ID NO:23所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:30所示的氨基酸序列或由其组成；
CS6：重链可变区包含如SEQ ID NO:22所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:31所示的氨基酸序列或由其组成；
CS7：重链可变区包含如SEQ ID NO:24所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:32所示的氨基酸序列或由其组成；
CS8：重链可变区包含如SEQ ID NO:25所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:33所示的氨基酸序列或由其组成。
第二方面，本发明提供上述抗新型冠状病毒Spike蛋白抗体或其活性片段经改造得到的抗体，所述抗体包括但不限于单链抗体、Fab、微型抗体、嵌合抗体、全抗体免疫球蛋白IgG1、IgG2、IgA、IgE、IgM、IgG4或IgD等。
本发明提供的抗新型冠状病毒Spike蛋白抗体以1nM-50nM的亲和力结合于新型冠状病毒(2019-nCoV)Spike蛋白。该抗体抑制新型冠状病毒Spike蛋白结合人ACE2。
第三方面，本发明提供编码上述抗体的基因。
考虑到密码子的简并性，编码本发明所述抗体的基因可在其编码区，在不改变氨基酸序列的条件下，对编码上述抗体的基因序列进行修改，获得编码相同抗体的基因。本领域技术人员可以根据表达抗体宿主的密码子偏爱性，人工合成改造基因，以提高抗体的表达效率。
第四方面，本发明提供含有所述基因的生物材料，所述生物材料包括但不限于重组DNA、表达盒、转座子、质粒载体、噬菌体载体、病毒载体、工程菌或转基因细胞系等。
第五方面，本发明提供所述抗体、编码抗体的基因或含有基因的生物材料的以下任一应用：
1)在制备以新型冠状病毒Spike蛋白为靶标的疾病治疗药物或组合物中的应用；优选所述药物为新型冠状病毒2019-nCoV Spike蛋白引起疾病的诊断和治疗药物；
2)在制备预防或治疗新型冠状病毒2019-nCoV感染或由其感染所致相关疾病的药物或组合物中的应用；
3)在制备预防或治疗新型冠状病毒2019-nCoV感染或由其感染所致相关疾病的细胞治疗药物或组合物中的应用；
4)在制备新型冠状病毒2019-nCoV检测及诊断试剂或试剂盒中的应用；
5)在制备以新型冠状病毒Spike蛋白为靶标的CAR-T疗法的相关制剂中的应用；
6)用于新型冠状病毒2019-nCoV的检测(含非诊断目的)；
7)用于预防或治疗新型冠状病毒2019-nCoV感染或由其感染所致相关疾病；
8)用于CAR-T治疗。
第六方面，本发明提供含有所述抗新型冠状病毒Spike蛋白抗体或其活性片段的药物或组合物。
第七方面，本发明提供含有所述抗新型冠状病毒Spike蛋白抗体或其活性片段的检测试剂或试剂盒。
本发明提供的抗体为全抗体或各种其他形式的基因工程抗体。例如，抗新型冠状病毒Spike蛋白抗体可以是全抗体或抗体片段。抗体分子本身可用于治疗和诊断。抗体可以被标记、交联或偶联及与其他蛋白或多肽分子融合表达形成复合物(如细胞毒性物质、放射性毒素和/或化学分子等)用于诊断和治疗。
进一步地，本发明提供编码抗体的独立基因，表达载体，载体转染宿主细胞相关控制技术及宿主细胞，抗体表达流程及在细胞培养上清中回收抗体。本发明同样提供含有抗体的组分和药理学上可接受的递送分子或溶液。治疗用组分为无菌，可低温冻干。
本发明提供一种抗新型冠状病毒(2019-nCoV)Spike蛋白的抗体，该抗体也通过阻碍新型冠状病毒(2019-nCoV)Spike蛋白与ACE2结合发挥作用。新型冠状病毒(2019-nCoV)Spike蛋白拮抗剂所具有的干扰功能均落入本发明的保护范围。
本发明中SEQ ID NO:1-33所示序列包括“保守序列修饰”，即不明显影响和改变所述抗体或含有所述氨基酸序列抗体的结合特征的核苷酸和氨基酸序列修饰。所述保守序列修饰包括核苷酸或氨基酸替换、添加或缺失。本领域中，已经定义了具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链的氨基酸(如赖氨酸、精氨酸、组氨酸)，具有酸性侧链的氨基酸(如天冬氨酸、谷氨酸)，具有不带电的极性侧链的氨基酸(如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)，具有非极性侧链的氨基酸(如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)，具有β分支侧链的氨基酸(如苏氨酸、缬氨酸、异亮氨酸)和具有芳香侧链的氨基酸(如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此，优选用来自于同一侧链家族的另一种氨基酸残基代替人抗新型冠状病毒(2019-nCoV)Spike蛋白抗体中的非必须氨基酸残基。
含有本发明特定氨基酸组成的抗体包括基本上由经保守序列修饰的相似序列编码的，或含有经保守序列修饰的相似序列的抗体，均落入本发明的保护范围。
本发明提供一种双特异性或多特异性分子，包含本发明提供的上述抗体或抗体的抗原结合部位的分子。
本发明提供一种抗体与其他蛋白和/或多肽的融合蛋白，包含本发明提供的上述抗体和具有某种功能的其他蛋白或多肽分子的复合物。
进一步地，所述的融合蛋白为将抗体基因与免疫毒素或细胞因子基因连接构建重组表达载体，通过哺乳动物细胞或其他表达系统获得重组融合蛋白分子。
本发明提供的新型冠状病毒(2019-nCoV)Spike蛋白抗体具有良好的治疗应用前景，主要表现为与新型冠状病毒(2019-nCoV)Spike蛋白具有特异性结合活性。该抗体经ELISA检测及流式细胞仪检测，结果表明靶标特异性良好。
本发明利用基因工程和噬菌体表面展示文库技术，从非免疫的全人源序列的单链抗体库中筛选出抗新冠病毒S蛋白的特异性抗体。经Octet Blitz测定，它们与病毒S蛋白的表观亲和力为1nM-50nM之间，而且对新冠病毒S蛋白与人受体ACE2的结合有抑制作用，表明本发明的抗病毒S蛋白抗体具有良好地结合S蛋白的能力及潜在的中和抑制作用。本发明为研发针对新冠病毒(2019-nCoV)的诊断试剂、预防和治疗抗体药物，以及其它疾病如冠状病毒引起的肺炎治疗等提供了特异性抗体候选分子。
附图说明
图1A-图1K为本发明较佳实施例中抗体结合过表达新型冠状病毒(2019-nCoV)细胞ID8的流式细胞图。以Beckman流式细胞仪CytoFlex进行分析，FACS检测抗体对ID8的结合；抗体转化为scFv-Fc形式并表达纯化，按10μg/ml终浓度加入到200,000个ID8细胞中孵育。荧光二抗是PE-标记的抗人Fc，FITC-标记的抗鼠Fc。
其中，图1A-图1B为在细胞系ID8分别仅加入PE-标记的抗人Fc和FITC-标记的抗鼠Fc结果。
图1C-图1K上进行流式细胞仪检测抗体及对结合过表达新型冠状病毒(2019-nCoV)细胞ID8的结果。
图2A-图2E为本发明较佳实施例中Octet Blitz检测抗体对新型冠状病毒(2019-nCoV)Spike蛋白的结合结果。
其中，图2A为ACE2结合RBD和全长三聚体S蛋白的结果。
图2B为抗体CS1与RBD结合，并能与ACE2竞争结合的结果。
图2C为抗体CS1和CS2可同时结合到RBD的结果。
图2D为抗体CS1和CS8竞争结合RBD的结果。
图2E为抗体CS1可与CS2-CS7同时结合到RBD的结果。
图3A为本发明较佳实施例中抗体CS1在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3B为本发明较佳实施例中抗体CS2在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3C为本发明较佳实施例中抗体CS3在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3D为本发明较佳实施例中抗体CS4在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3E为本发明较佳实施例中抗体CS5在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3F为本发明较佳实施例中抗体CS6在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3G为本发明较佳实施例中抗体CS7在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图3H为本发明较佳实施例中抗体CS8在不同浓度梯度下竞争抑制ACE2结合过表达新型冠状病毒(COVID-19)细胞ID8的结果。
图4为新型冠状病毒2019-nCoV的结构示意图。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例均按照常规实验条件，如Sambrook等分子克隆实验手册(Sambrook J&Russell DW,Molecular Cloning:a Laboratory Manual,2001)，或按照制造厂商说明书建议的条件。实施例1从天然人抗体噬菌体表面呈现文库中筛选抗新型冠状病毒(2019-nCoV)Spike蛋白抗体
为了获得新型冠状病毒(2019-nCoV)Spike蛋白特异性的人抗体，用固相筛选法进行淘选。首先包被Spike的RBD蛋白(mFc tag，Sino biological，货号40592-V05H)包。解冻一份人抗体库，其中包含100亿个表达有不同抗体的噬菌体颗粒。PBS洗涤过夜包被的RBD蛋白靶孔，250ul/孔，洗2次；噬菌体颗粒加至RBD蛋白靶孔，室温(RT)，1h。加洗脱液0.2M甘氨酸-HCl(pH 2.2)，100ul/孔，静置10min左右，期间用枪吸吹混匀2次；加入中和液1M Tris-HCl pH 8.0)，42ul/孔，混匀。取中和后的混合物，分别加至10ml TG1(OD600约0.6-0.8)，混匀，于37℃，30min静置孵育浸染。取phage-TG1侵染混合物，约20ul，加至180ul 2YT，混匀，记为20ul-人；从20ul-人中取出20ul菌液，加至180ul 2YT中，混匀，记为2ul-人；分别从20ul-人、2ul-人取出100ul菌液涂布90mm平皿，记为10ul-人、1ul-人；于37℃培养过夜，用于统计人天然抗体库第一轮output phage。其余TG1菌液，于2400g，10min，弃上清，用约600ul 2YT重悬，涂布180mm平皿(2YTAG)，30℃过夜。次日，统计90mm小平皿上，10ul、1ul标记平皿的菌落数，计算人天然抗体库的第一轮output；同时，用约2.5ml 2YT将大平皿上的output菌苔刮落，吸出至5ml离心管，混匀，吸出900ul菌液加入300ul 50％甘油，混匀，保存菌种至-80℃，即1st output-人-菌液；另外，吸出300ul菌液，补充100ul左右2YT，混匀，暂时保存于4℃，用于接菌及制备第一轮筛选后的phage。
为了进一步收获亲和力比较高的特异性抗体克隆，需要进行更多轮淘选。为此，以第一轮淘选洗脱的噬菌体抗体溶液感染对数期的、能被M13噬菌体侵染的大肠杆菌(如TG1菌株)，得到感染液，取少量进行一系列10倍梯度稀释(通常稀释至原液的百万分之一，并取最后三个梯度进行涂布)以测定第一轮产出洗脱液output的滴度(titer)，该titer又称为第一轮最大多样性，通常第一轮淘选后的产出滴度在10E6个cfu以下。将其余感染液全部涂布于含有相应抗生素的细菌培养板上过夜培养，以获取菌落；刮下菌落层并以培基重悬，取足量包含第一轮output多样性的重悬液至含足量液体培基(2YT-CG，2YT培基中加入Carbenicillin和葡萄糖，终浓度分别是100μg/ml和2％)的摇瓶中，使重悬液稀释至OD600＝0.1以下并开始培养，直到对数期，即OD600达到0.5左右。为使第一轮淘选获取的这些抗体再次呈现于噬菌体颗粒表面，取10ml菌液，加入辅助噬菌体M13K07，使感染复数MOI为20:1，静置于37℃，保持30分钟(该阶段为噬菌体拯救)。离心，以50ml表达培养基(2YT-AK，2YT培基中加入Carbenicillin和Kanamycin，终浓度分别是100μg/ml和30μg/ml)重悬菌体，置于30℃，200转/分培养过夜。次日离心收获培养上清，加入1/5体积的PEG8000/NaCl(PEG-800020％，NaCl 2.5M)，充分混匀，置于冰上孵育1小时。高速离心(11500×g)30分钟以收获噬菌体抗体颗粒。以1ml PBS溶液重悬沉淀，再次进行高速离心以去除细菌碎片。上清液即为第一轮淘选后的扩增液，其中包含的每个抗体克隆都被扩增了上万倍以上。这个扩增液即可用于第二轮的淘选实验。第二轮淘选的操作除了在用PBST/PBS洗涤时，增加至各做6次(6/6)之外，其余和第一轮操作方法完全相同。在第三轮中，可以进一步增加洗涤次数至10/10。多轮淘选通常会有效地富集特异性的克隆，多样性明显减少但它们的亲和力比较高，便于后续的单克隆筛选。
为了获取特异性的单克隆抗体，需要进行单克隆噬菌体酶联实验(MonophageELISA)。为此，将在第二轮和/或第三轮的梯度稀释中会得到分离良好的单菌落单独地接种这些菌落至含2YT-AG的96-孔培养板中(每板接种93个菌落，留下三个孔作为阴性对照)，过夜培养，即母板(master plate)。将母板中每孔的菌液接种至新的培养板中生长至对数期，进行噬菌体拯救，使每个克隆的抗体表达于噬菌体表面。在普通的96-孔酶联板上包被BCMA抗原(1μg/ml)，同时以同样浓度的人Fc包被另一块酶联板。每个单独表达的单克隆噬菌体抗体菌液分别加入到RBD板和mFc板对应孔，然后加入合适的二抗及辣根过氧化物酶(HRP)偶联的三抗，底物显色，读取吸光值(450nM)。RBD阳性克隆的判断方法是：在mFc板上为阴性(不超过其所在板阴性孔吸收值1.5倍)，在RBD板上为阳性(高于所在板阴性孔吸收值3倍以上)，并且其孔吸收值高于mFc板上对应孔之吸收值上的克隆。经过分析，88个孔对应的克隆显示仅对RBD抗原阳性，而对mFc为阴性，这些克隆统称为hits。
从母板对应孔上将这些hist菌液分别接种至3ml 2YT-CG，置于37℃，200转/分培养过夜。次日抽提噬菌粒DNA，以特异性引物测定包含每个hit的单链抗体区的序列。取编码区DNA序列翻译成氨基酸序列，对它们进行多重序列比较(CLUSTALW，网站链接https://www.genome.jp/tools-bin/clustalw)以判断克隆特异性。经过分析，这88个hits在序列上属于26个不同的克隆，其中8个抗体与新型冠状病毒(2019-nCoV)Spike蛋白结合活性良好，由此获得了抗新型冠状病毒(2019-nCoV)Spike蛋白的全人抗体可变区序列。其重链可变区的CDR1包含如SEQ ID NO:1所示的氨基酸序列或由其组成，重链可变区的CDR2包含如SEQID NO:2或3所示的氨基酸序列或由其组成，重链可变区的CDR3包含如SEQ ID NO:4-7任一所示的氨基酸序列或由其组成；其轻链可变区的CDR1包含如SEQ ID NO:8-12任一所示的氨基酸序列或由其组成，轻链可变区的CDR2包含如SEQ ID NO:13-16所示的氨基酸序列或由其组成，轻链可变区的CDR3包含如SEQ ID NO:17-19任一所示的氨基酸序列或由其组成。
进一步地，重链可变区包含如SEQ ID NO:20-25任一所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:26-33任一所示的氨基酸序列或由其组成。
实施例2抗体功能验证
为了验证获得的新型冠状病毒(2019-nCoV)Spike蛋白抗体克隆是否结合新型冠状病毒(2019-nCoV)Spike蛋白抗原以及细胞膜表面表达的新型冠状病毒(2019-nCoV)Spike蛋白，新型冠状病毒(2019-nCoV)Spike蛋白单链抗体的基因被克隆至真核表达载体pFH。在该载体中，scFv基因和人IgG的Fc基因融合，表达出scFv-Fc形式的蛋白，它可以用Potein-A进行亲和纯化，也可以用(HRP或荧光素)标记抗人Fc抗体进行检测。
获得的scFv-Fc蛋白后，用Octet Blitz检测了抗体对新型冠状病毒(2019-nCoV)Spike蛋白及RBD的结合情况，证实了新型冠状病毒(2019-nCoV)Spike蛋白抗体的特异性结合(图2A-图2E)。CS1为含有SEQ ID NO:20和26可变区的单克隆抗体；CS2为含有SEQ ID NO:21和27可变区的单克隆抗体；CS3为含有SEQ ID NO:22和28可变区的单克隆抗体；CS4为含有SEQ ID NO:22和29可变区的单克隆抗体；CS5为含有SEQ ID NO:23和30可变区的单克隆抗体；CS6为含有SEQ ID NO:22和31可变区的单克隆抗体；CS7为含有SEQ ID NO:24和32可变区的单克隆抗体；CS8为含有SEQ ID NO:25和33可变区的单克隆抗体。CS1表观亲和力为1.2nM，CS2表观亲和力为2.1nM，CS3表观亲和力为23.2nM，CS4表观亲和力为48nM，CS5表观亲和力为4.1nM，CS6表观亲和力为35.2nM，CS7表观亲和力为12.3nM，CS8表观亲和力为2.6nM。
以流式细胞仪检测抗体对过表达新型冠状病毒(2019-nCoV)Spike蛋白的细胞系ID8，表明了抗体特异性结合细胞膜表面的过表达新型冠状病毒(2019-nCoV)Spike蛋白(图1A-图1K)。
以流式细胞仪检测抗体对抑制ACE2结合过表达新型冠状病毒(2019-nCoV)Spike蛋白的细胞系ID8，结果表明抗体均能部分抑制ACE2结合过表达新型冠状病毒(2019-nCoV)Spike蛋白的细胞系ID8，并随着浓度增加抑制效果增强(图3A-图3H)。
实施例3
基于FACS analysis的Cell binding法检测抗体与ACE2竞争结合到特异表达2019-nCoV Spike蛋白的细胞系ID8上。
经测定，饱和ID8细胞Spike蛋白的ACE2-mFC蛋白最低浓度为0.02μg/ml。
1、收集ID8细胞：收集0.5×106cells/tube。
2、漂洗细胞：用1ml staining buffer(含有1％w/v BSA的PBS)漂洗细胞一次，350xg离心5min 4℃，离心后用95μl staining buffer重悬。
3、Antibody binding:分别加入不同浓度梯度的抗体CS1-CS8(0-40μg/ml)，冰上孵育60min。
4、ACE2-mFC binding:分别加入人ACE2-mFC蛋白至浓度0.02μg/ml，冰上孵育30min。
5、漂洗细胞：在细胞悬液中加入1ml staining buffer，混匀后4℃350g离心5min，去上清，重新漂洗2次。离心后用100μl staining buffer重悬细胞。
6、样品管加入Biolegend直标抗体5μl(APC anti-Mousw IgG Fc Antibody,Biolegend,405308)，冰上避光孵育15-20min。
7、漂洗细胞：在细胞悬液中加入1ml staining buffer，混匀后4℃350g离心5min，去上清，重新漂洗一次。
8、上机检测：用100-200μl PBS重悬细胞后，用Beckman CytoFlex上机检测分析。
实验结果表明，不同抗体封阻ACE2与Spike蛋白的效果不同。在抗体浓度为20μg/ml时，CS1封阻效果为10.81％，CS2封阻效果为16.78％，CS3封阻效果为41.94％，CS4封阻效果为5.51％，CS5封阻效果为4.36％，CS6封阻效果为24.89％，CS7封阻效果为27.26％，CS8封阻效果为93.12％。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之做一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
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<110> 益科思特（北京）医药科技发展有限公司
<120> 抗新型冠状病毒Spike蛋白抗体及其应用
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Val Ile Ser Glu Val Arg Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
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85 90 95
Asp Thr Arg Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu
100 105 110
<210> 28
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
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20 25 30
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35 40 45
Met Val Ser Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Arg
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<210> 29
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
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Val Ile Ser Glu Val Arg Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
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65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Arg
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Asp Thr Arg Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu
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<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
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Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
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Val Ile Ser Glu Val Arg Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
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<211> 110
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<213> 人工序列(Artificial Sequence)
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Gln Ala Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
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Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Val Ile Ser Glu Val Arg Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Arg
85 90 95
Asp Thr Arg Val Phe Gly Gly Gly Thr Gln Val Thr Val Leu
100 105 110
<210> 32
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Gln Ser Ala Leu Ala Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ala Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Arg
85 90 95
Asp Thr Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 33
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Gln Ala Val Leu Thr Gln Pro Ser Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Glu Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
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Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
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Claims (9)
1.抗新型冠状病毒Spike蛋白抗体或其活性片段，其特征在于，其重链可变区的CDR1包含如SEQ ID NO:1所示的氨基酸序列或由其组成，重链可变区的CDR2包含如SEQ ID NO:2或3所示的氨基酸序列或由其组成，重链可变区的CDR3包含如SEQ ID NO:4-7任一所示的氨基酸序列或由其组成；其轻链可变区的CDR1包含如SEQ ID NO:8-12任一所示的氨基酸序列或由其组成，轻链可变区的CDR2包含如SEQ ID NO:13-16所示的氨基酸序列或由其组成，轻链可变区的CDR3包含如SEQ ID NO:17-19任一所示的氨基酸序列或由其组成。
2.根据权利要求1所述的抗体，其特征在于，其为：
i)、重链可变区包含如SEQ ID NO:20-25任一所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:26-33任一所示的氨基酸序列或由其组成；
ii)、i)的抗体经取代、缺失或添加一个或几个氨基酸且具有同等功能的由i)衍生的抗体；
iii)、与i)的抗体具有70％、80％、85％、90％或97％以上序列同源性且具有同等功能的由i)衍生的抗体。
3.根据权利要求2所述的抗体，其特征在于，选自CS1～CS8中的任一条抗体：
CS1：重链可变区包含如SEQ ID NO:20所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:26所示的氨基酸序列或由其组成；
CS2：重链可变区包含如SEQ ID NO:21所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:27所示的氨基酸序列或由其组成；
CS3：重链可变区包含如SEQ ID NO:22所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:28所示的氨基酸序列或由其组成；
CS4：重链可变区包含如SEQ ID NO:22所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:29所示的氨基酸序列或由其组成；
CS5：重链可变区包含如SEQ ID NO:23所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:30所示的氨基酸序列或由其组成；
CS6：重链可变区包含如SEQ ID NO:22所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:31所示的氨基酸序列或由其组成；
CS7：重链可变区包含如SEQ ID NO:24所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:32所示的氨基酸序列或由其组成；
CS8：重链可变区包含如SEQ ID NO:25所示的氨基酸序列或由其组成，轻链可变区包含如SEQ ID NO:33所示的氨基酸序列或由其组成。
4.权利要求1所述抗体或其活性片段经改造得到的抗体，所述抗体为单链抗体、Fab、微型抗体、嵌合抗体、全抗体免疫球蛋白IgG1、IgG2、IgA、IgE、IgM、IgG4或IgD。
5.编码权利要求1-4任一项所述抗体的基因。
6.含有权利要求5所述基因的生物材料，所述生物材料为重组DNA、表达盒、转座子、质粒载体、噬菌体载体、病毒载体、工程菌或转基因细胞系。
7.权利要求1-4任一项所述抗体、权利要求5所述基因或权利要求6所述生物材料的以下任一应用：
1)在制备以新型冠状病毒Spike蛋白为靶标的疾病治疗药物或组合物中的应用；
2)在制备预防或治疗新型冠状病毒2019-nCoV感染或由其感染所致相关疾病的药物或组合物中的应用；
3)在制备预防或治疗新型冠状病毒2019-nCoV感染或由其感染所致相关疾病的细胞治疗药物或组合物中的应用；
4)在制备新型冠状病毒2019-nCoV检测及诊断试剂或试剂盒中的应用；
5)在制备以新型冠状病毒Spike蛋白为靶标的CAR-T疗法的相关制剂中的应用；
6)用于非诊断目的新型冠状病毒2019-nCoV的检测。
8.含有权利要求1-4任一项所述抗体的药物或组合物。
9.含有权利要求1-4任一项所述抗体的检测试剂或试剂盒。
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| CN114805562A (zh) * | 2022-05-07 | 2022-07-29 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化纳米抗体及其应用 |
| CN114805559A (zh) * | 2022-04-02 | 2022-07-29 | 浙江大学 | 全人源抗新冠病毒受体结合域单链抗体No4及其应用 |
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| CN116253797B (zh) | 2024-05-14 |
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| CN116444660A (zh) | 2023-07-18 |
| CN116063473A (zh) | 2023-05-05 |
| CN116162157A (zh) | 2023-05-26 |
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