CN114835805A - 抗SARS-CoV-2 spike蛋白的单克隆抗体及应用 - Google Patents
抗SARS-CoV-2 spike蛋白的单克隆抗体及应用 Download PDFInfo
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- CN114835805A CN114835805A CN202210657559.6A CN202210657559A CN114835805A CN 114835805 A CN114835805 A CN 114835805A CN 202210657559 A CN202210657559 A CN 202210657559A CN 114835805 A CN114835805 A CN 114835805A
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Abstract
本发明属于单克隆抗体领域，具体涉及一种抗SARS‑CoV‑2spike蛋白的单克隆抗体及应用。该单克隆抗体包含氨基酸序列如SEQ ID NO:1‑3所示的VHCDR1、VHCDR2和VHCDR3，和氨基酸序列如SEQ ID NO:4‑6所示的VLCDR1、VLCDR2和VLCDR3。本发明提供的抗SARS‑CoV‑2spike蛋白的单克隆抗体，可特异性识别并结合S蛋白的464FERDISTEIYQA475区域，特异性好；多序列比对分析表明该表位是保守的，因而基于该表位的单克隆抗体在检测SARS‑CoV‑2上具有良好的应用前景。
Description
技术领域
本发明属于单克隆抗体领域，具体涉及一种抗SARS-CoV-2 spike蛋白的单克隆抗体及应用。
背景技术
冠状病毒属(Coronavirus)的病毒是具有包膜的正链RNA病毒。国际病毒分类委员会(International Committee on Taxonomy of Viruses，ICTV)将新型冠状病毒(2019-nCoV)的正式名字为严重急性呼吸综合征冠状病毒2(severe acute respiratorysyndrome coronavirus 2,SARS-CoV-2)。COVID-2019(2019冠状病毒病)是一种由SARS-CoV-2引起的严重呼吸窘迫综合征为特征的呼吸道传染病，人感染新型冠状病毒(COVID-19)的一般症状是发热、乏力、干咳，一些严重的临床症状有急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒、出凝血功能障碍等。
SARS-CoV-2的基因组长为29.9kb，主要编码刺突纤突蛋白(Spike，S)、小包膜蛋白(Envelope，E)、囊膜蛋白(Membrance，M)、核蛋白(Nucleocapsid，N)等4种结构蛋白，以及几种辅助蛋白。S蛋白介导病毒侵入靶细胞，诱导免疫应答。S蛋白有两个亚基：S1和S2，受体结合位点(RBD)位于S1亚基上。
冠状病毒通过其RBD与宿主细胞表面的血管紧张素转换酶2(ACE2)结合，诱导病毒囊膜与宿主细胞膜发生融合，实现病毒对宿主细胞的侵染。RBD与ACE2结合的表位在遗传上相对保守，是病毒的弱点和广谱性中和抗体的重要作用位点以及抗体药物筛选的关键靶点。
表位是蛋白质抗原性的基础，是抗原分子中决定抗原特异性的特殊化学基团，也是抗原分子诱导特异性免疫反应的基本结构和功能单位。准确细致地绘制抗原表位对疾病诊断、对蛋白质分子进行针对性修饰以降低蛋白质药物的免疫原性、设计无副作用的人工疫苗以及免疫干预治疗都具有积极意义。
发明内容
本发明的目的是提供一种抗SARS-CoV-2 spike蛋白的单克隆抗体，该单克隆抗体能够特异性地识别S蛋白RBD区域的464FERDISTEIYQA475序列区域，对该病的诊断和多肽疫苗的研制具有重要价值。
本发明的第二个目的是提供编码上述单克隆抗体的核酸分子。
本发明的第三个目的是提供上述单克隆抗体的应用。
为了实现以上目的，本发明所采用的技术方案是：
抗SARS-CoV-2 spike蛋白的单克隆抗体，其包含氨基酸序列如SEQ ID NO:1-3所示的VHCDR1、VHCDR2和VHCDR3，和氨基酸序列如SEQ ID NO:4-6所示的VLCDR1、VLCDR2和VLCDR3。
本发明提供的抗SARS-CoV-2 spike蛋白的单克隆抗体，可特异性识别并结合S蛋白的464FERDISTEIYQA475区域，特异性好；多序列比对分析表明该表位是保守的，因而基于该表位的单克隆抗体在检测SARS-CoV-2上具有良好的应用前景。
优选地，所述抗SARS-CoV-2 spike蛋白的单克隆抗体的重链可变区氨基酸序列如SEQ ID NO:7所示，轻链可变区氨基酸序列如SEQ ID NO:8所示。进一步优选地，所述抗SARS-CoV-2spike蛋白的单克隆抗体的重链为IgG2b型，轻链为Kappa型。
编码上述抗SARS-CoV-2 spike蛋白的单克隆抗体的核酸分子。
利用上述核酸分子编码得到的单克隆抗体能够特异性识别SARS-CoV-2的保守表位，在检测或诊断SARS-CoV-2上具有良好的应用前景。
优选地，编码所述抗SARS-CoV-2 spike蛋白的单克隆抗体的重链可变区的基因核苷酸序列如SEQ ID NO:9所示，编码所述抗SARS-CoV-2 spike蛋白的单克隆抗体的轻链可变区的基因核苷酸序列如SEQ ID NO:10所示。
上述抗SARS-CoV-2 spike蛋白的单克隆抗体在制备诊断、检测或预防SARS-CoV-2试剂中的应用。
优选地，所述抗SARS-CoV-2 spike蛋白的单克隆抗体特异性识别SARS-CoV-2splike蛋白的RBD区域，识别位点的氨基酸序列为464FERDISTEIYQA475(SEQ ID NO:11)。所述识别位点与所述单克隆抗体结合的关键基氨基酸为D467、I468、E471、Q474、A475。
进一步优选地，利用所述识别位点制备诊断或预防SARS-CoV-2的试剂。以上识别位点为Spike蛋白的B细胞表位，利用偶联后的表位肽可以作为包被原通过ELISA检测SARS-CoV-2抗体，也可以作为标记抗原或捕获抗原用于免疫层析试纸等。
附图说明
图1为本发明的目的基因构建的策略；
图2为本发明的SDS-PAGE鉴定RBD；图中自左至右编号为1～4，其中1为蛋白Marker，2为RBD细胞上清，3为RBD细胞沉淀，4为RBD纯化后；
图3为本发明的Western Blot鉴定RBD蛋白表达；图中自左至右编号为1～2，1为蛋白Marker，2为RBD纯化后孵育HRP标记的His单抗；
图4为本发明的RBD蛋白免疫小鼠融合前血清效价；
图5为本发明制备的6-4B单抗的腹水效价；
图6为本发明制备的单抗6-4B抗体可变区序列；
图7为本发明中IFA实验验证RBD蛋白与其制备的单抗6-4B可以特异性结合；
图8为本发明制备的单抗6-4B与设计的肽池、肽及截短肽Dot-Blot实验反应结果；
图9为本发明制备的单抗6-4B与丙氨酸突变的序列peptide-Elisa和Dot-Blot实验结果。
具体实施方式
本发明提供的SARS-CoV-2 spike蛋白单克隆抗体，是基于设计并构建能够表达具有良好空间构象的RBD蛋白。以RBD蛋白作为免疫原免疫小鼠，利用细胞融合技术，以RBD蛋白作为检测原，通过间接ELISA，筛选得到了抗SARS-CoV-2RBD蛋白的单克隆细胞株6-4B。该细胞株产生的单克隆抗体可特异性识别并结合S蛋白的464FERDISTEIYQA475区域。该S蛋白RBD免疫显性表位区域的确认，对该病的诊断和多肽疫苗的研制具有重要价值。
本发明将表达SARS-CoV-2RBD蛋白作为免疫原免疫小鼠，结果显示获得的单克隆抗体效价高的可达1:1024000，并具有良好的特异性。利用重叠多肽方法鉴定到了抗原抗体的作用位点，多序列比对分析表明该表位均是保守的，因此该单克隆抗体在检测SARS-CoV-2上具有良好的应用前景。
下面结合附图和具体实施例对本发明作进一步描述，但本发明的保护范围并不仅限于此；
以下实施例中所涉及的仪器设备如无特别说明，均为常规仪器设备；所涉及的试剂如无特别说明，均为市售常规试剂；所涉及的试验方法，如无特别说明，均为常规方法。
实施例1抗SARS-CoV-2 spike蛋白的单克隆抗体
本实施例的抗SARS-CoV-2 spike蛋白的单克隆抗体，其包含氨基酸序列如SEQ IDNO:1-3所示的VHCDR1、VHCDR2和VHCDR3，和氨基酸序列如SEQ ID NO:4-6所示的VLCDR1、VLCDR2和VLCDR3。该单克隆抗体的重链可变区氨基酸序列如SEQ ID NO:7所示，轻链可变区氨基酸序列如SEQ ID NO:8所示。抗体可变区序列图如图6所示。
本实施例的抗SARS-CoV-2 spike蛋白的单克隆抗体的制备过程如下：
(1)免疫原制备
针对S蛋白的胞外区设计并构建了RBD区域，并利用真核表达系统HEK293F细胞来制备抗原蛋白。RBD区域氨基酸序列如SEQ ID NO:12所示。
具体的，免疫原的制备包括如下步骤：
1.1引物设计
根据NCBI(http://www.ncbi.nlm.nih.gov)上的SARS-CoV-2S蛋白的基因序列信息(GenBank accession number MN908947.3)，设计引物，选择BamHⅠ/XbaⅠ两个酶切位点(划线部分)，添加保护性碱基(斜体部分)，扩增SARS-CoV-2RBD，基因，并构建至pcDNA3.1(+)载体上，构建示意图如图1，引物序列如表1所示：
表1引物序列表
1.2 RBD基因的PCR扩增
以合成的RBD基因序列为模板进行PCR扩增。PCR扩增体系如下：
表2 PCR扩增体系
1.3纯化回收PCR产物
扩增目的基因完成之后，用1％的核酸凝胶对PCR产物进行核酸电泳鉴定。最后利用DNA胶回收试剂盒选择和目的条带位置的PCR产物切胶进行纯化回收。使用Nano Drop测定回收的DNA溶液浓度，-20℃保存备用。
1.4目的基因和载体的双酶切
1.4.1将RBD基因/pcDNA3.1(+)载体进行双酶切，酶切反应体系如下表所示：
表3双酶切反应体系
1.4.2各组分混匀后放置于37℃恒温仪上3h酶切。
1.5酶切产物的回收
使用DNA胶回收纯化试剂盒回收双酶切产物并吸取1.5μL的回收产物测定DNA的浓度，放于-20℃备用。
1.6重组质粒的构建
1.6.1 RBD基因与pcDNA3.1(+)载体连接
在小EP管中加入下列组分：
表4连接体系
将离心管中的上述溶液混匀后，置于16℃连接仪中进行过夜连接。
1.6.2转化
将10μL连接产物都加入100μL DH5α感受态细胞中，冰浴30min后，42℃热激90s后，冰浴2-5min，加入500μL无抗性LB液体培养基，37℃，220r/min震荡培养45min；复苏后吸取150μL菌液均匀涂布在含有氨苄抗性的LB固体平板上，倒置于37℃恒温培养箱中培养12h。
1.6.3菌液PCR筛选阳性克隆
挑取圆滑的单个菌落，并将其接种在含有氨苄抗性的LB液体培养基中，37℃，220r/min培养4-6h，吸取浑浊的菌液作为PCR的模板。
按照下列组分加入EP管中：
表5菌液PCR反应体系
将上述反应组分混匀后，置于PCR仪中进行PCR扩增。菌液PCR结束后将产物用1％的核酸凝胶进行鉴定，选择条带大小与SARS-CoV-2RBD目的基因相符的单克隆菌株送至上海生工生物有限公司测序。
1.6.4重组质粒的提取
选则测序成功的阳性菌株，接种至500ml氨苄抗性的LB液体培养基中，37℃，220rpm培养12h。用康为去内毒素质粒大量提取试剂盒，按试剂盒说明书操作步骤提取pcDNA3.1-RBD重组质粒。
1.7目的蛋白的表达
瞬时转染HEK293F细胞。以20ml培养体系(100ml培养瓶)举例如下：
a.材料准备
新鲜的SMM293-TⅡ培养基；转染试剂(义翘神州Sinofection，货号STF02)；携带目的基因的质粒DNA；150mM NaCl(无菌过滤，用于制备转染复合物)；处在对数生长期且活率高于90％的HEK293F细胞；
b.转染前一天，取样计数细胞密度，计算细胞活率；
c.以2×106cell/ml的密度将细胞密度接种到新鲜培养基中，至于37℃，5％CO2，175rpm转速的恒温摇床中培养；
d.转染当天，取样计数细胞密度和活率。细胞密度应该在3-5×106cell/ml，活率高于90％。调整细胞密度至3×106cell/ml，每瓶细胞液体体积为20ml；
e.转染液的配制：
用150mM的NaCl稀释20ug DNA至总体积为0.5ml，温和混匀；
用150mM的NaCl稀释100ul Sinofection转染试剂至总体积为0.5ml，温和混匀；
将稀释好的DNA和转染试剂同时单独静置约5分钟后温和混匀，总体积1ml，室温静置10min。
f.将转染试剂逐滴加入到细胞培养液中，滴加的同时轻轻摇动培养瓶，摇匀后放回摇床继续培养；
g.转染24h后悬松瓶后满足后续细胞密度生长的溶氧以及CO2的排放需求，防止因CO2累积导致培养液PH值过低(溶液呈黄色)，影响细胞生长。
h.转染后48-72h可用WB检测目的基因的表达。
1.8目的蛋白的鉴定及纯化
收集转染后72h的细胞，12000rpm，20min，收取沉淀，用缓冲Buffer(20mM Tris，150mM NaCl，pH 8.0)重悬细胞(按1:100加入蛋白酶抑制剂)，超声破碎后，12000rpm，20min，收取上清，取100μL破碎后上清液加入5×SDS上样缓冲液15μL，煮沸10min后进行SDS-PAGE及WesternBlot鉴定。WB鉴定中使用HRP标记的Goat-Mouse 6×His单抗以1：5000的比例进行稀释，室温孵育1h。孵育结束后，用PBST洗涤PVDF膜5遍，使用ECL化学发光液(新赛美)对PVDF膜进行曝光。
破碎后上清液经0.45μm滤膜过滤后采用镍离子亲和层析法进行纯化。纯化条件为：以20mM Tris+150mM NaCl，pH 8.0为平衡液，20mM Tris+150mM NaCl+20mM咪唑，pH 8.0为洗涤液，20mM Tris+150mM NaCl+200mM咪唑，pH 8.0为目的蛋白洗脱液。依次收集破碎后上清原液、柱穿出液、平衡液、洗涤液以及目的蛋白洗脱液，各取100μL，加入5×SDS上样缓冲液15μL，煮沸10min后进行SDS-PAGE，如图2所示。SDS-PAGE结果显示洗脱液中纯化的目的蛋白纯度约达到90％。
收集洗脱液，使用透析袋，以，20mM Tris+150mM NaCl为透析液对其进行过夜透析处理，透析后12000rpm离心1min收集上清液并取其100μL，加5×SDS上样缓冲液15μL，煮沸0min后进行SDS-PAGE及Western Blot鉴定，如图2，图3所示。Western Blot鉴定中使用HRP标记的Goat-Mouse 6×His单抗1:5000作为一抗，室温孵育1h。孵育结束后，用PBST洗涤PVDF膜5遍，使用ECL化学发光液(新赛美)对PVDF膜进行曝光。SDS-PAGE及Western Blot结果显示，透析后的SARS-CoV-2RBD重组蛋白纯度可达98％。
(2)SARS-CoV-2RBD重组蛋白小鼠免疫及免疫效果分析
2.1小鼠免疫及免疫效果初步评价
取3只6-8周龄的Balb/c小鼠，每只免疫10μg的RBD蛋白，共免疫三次，每隔两周免疫一次，首免用弗氏完全佐剂和蛋白/PBS混合乳化，二免和三免均用弗氏不完全佐剂和蛋白/PBS混合乳化。在首次免疫后14d、21d、28d、35d、42d尾静脉采血，以间接ELISA、评价免疫效果。
2.2间接ELISA测定RBD蛋白免疫小鼠血清效价
以2μg/mL的RBD重组蛋白CBS稀释后包被96孔反应板，每孔100μL，4℃包被过夜；弃去包被液，PBST洗涤三次，5％脱脂奶封闭，37℃孵育1h；弃去封闭液，PBST洗涤三次；首孔分别加入起始浓度为1:1000稀释的首次免疫42d的小鼠血清，同时以PBS免疫小鼠血清作为阴性对照，从左到右依次倍比稀释，37℃孵育1h；PBST洗涤三次，加入1:1000稀释的HRP标记的羊抗鼠为二抗，37℃孵育1h；PBST洗涤三次，加入TMB显色液，避光显色5min后加入2mol/LH2SO4终止显色；测定OD450nm值，评价免疫效果。如图4所示，针对RBD蛋白产生较高效价的特异性抗体。
(3)RBD重组蛋白单克隆抗体制备与鉴定
3.1细胞融合
细胞融合前3-4d进行超免，超免时直接进行腹腔注射：根据间接ELISA测定RBD免疫小鼠血清效价结果，选择效价最好的RBD-3号小鼠，吸取20μg RBD重组蛋白，不添加佐剂，进行腹腔注射超免。超免完成三天后进行细胞融合。取1.5mL EP管收集小鼠眼球血液，将血液放置37℃静置2h后，4000rpm，离心10min，吸取上清作为阳性血清，分装后﹣20℃储存备用。收集生长良好的小鼠骨髓瘤SP2/0细胞2～5×107个于50mL无菌的离心管中备用。超免后小鼠脱颈处死后用75％酒精浸泡消毒。在超净台内用无菌剪刀和镊子剪开表皮，更换第二套刀剪开腹膜，取出脾脏放在200目无菌尼龙网上，用剪刀研磨，加GNK洗液冲洗，使脾细胞单个滤入无菌烧杯中。将脾细胞悬液移入离心管中，补加GNK到40mL，与瘤细胞一起离心，1000rpm离心10min。弃上清，弹虚细胞团，各加GNK 10mL，将脾细胞悬液转入瘤细胞瓶中，加GNK至40mL，1000rpm离心10min，弃尽上清。将细胞团微微打散，滴加1mL 50％PEG1500，1min内加完，静置90s，然后慢慢滴加15mL GNK终止融合，37℃水浴稳定5min，补加GNK至40mL，1000rpm离心10min，弃上清，将细胞团微微打散，加500mL含HAT和10％胎牛血清的RPMI-1640培养基，轻轻混悬细胞，平均铺在96孔细胞培养板中，每孔加250μL细胞悬液，在培养箱中培养7天。
3.2杂交瘤细胞阳性孔的筛选
细胞融合后7天，观察到细胞团长至比较大时，用间接ELISA测其细胞上清。细胞融合前小鼠眼球采血血清为阳性对照，PBS免疫的小鼠血清为阴性对照。用2μg/mL RBD的蛋白作为检测用的抗原，CBS稀释后每孔包被100μL，4℃过夜。5％脱脂奶每孔加入200μL，37℃封闭2h；吸取细胞上清50μL作为一抗，37℃孵育30min；HRP标记羊抗鼠作为二抗1:1000稀释后每孔50μL，37℃孵育30min；PBST洗板3次后加入TMB显色液，100μL/孔，遮光反应5min；加入100μL 2mol/L H2SO4终止反应，选取显色反应最强的孔转至48孔板和24孔板中扩大培养，再以同样的方法对其测定，反复测定三次之后将能稳定反应的阳性杂交瘤细胞孔进行亚克隆。通过有限稀释法进行单克隆化，确保获得稳定分泌单克隆抗体的杂交瘤细胞株。
3.3单克隆抗体的大量制备及腹水的纯化
亚克隆后用间接ELISA以上述同样的方法再次进行筛选，将筛选出的阳性孔杂交瘤细胞孔6-4B扩大培养。对经产Balb/c小鼠腹腔中注射灭菌的液体石蜡，注射石蜡一周后，将阳性孔杂交瘤细胞用RPMI-1640基础培养基稀释后计数，每只小鼠注射细胞量约为1.0×106个。注射天小鼠腹部明显的增大，说明有腹水产生，将小鼠拖颈处死，收集腹水。
3.4单克隆抗体的亚类鉴定
使用Mouse单克隆抗体亚型鉴定试剂盒(Proteintech)，按照说明书步骤对6-4B单抗进行亚型鉴定。结果表明本发明中的6-4B重链为IgG2b型，轻链为Kappa型。
3.5单抗效价测定
间接ELISA实验测定单克隆抗体的效价，用2μg/mL RBD蛋白包板CBS稀释后每孔包被100μL，4℃过夜。5％脱脂奶每孔加入200μL封闭，37℃，2h；以纯化后单克隆抗体1:1000稀释后加入首孔，然后从左至右依次倍比稀释，同时以PBS免疫小鼠血清作为阴性对照，37℃，1h；HRP标记羊抗鼠作为二抗1:1000稀释后每孔100μL，37℃，1h；PBST洗板3次后加入TMB显色液，100μL/孔，遮光反应5min；加入100μL 2mol/L H2SO4终止反应，最后读取OD450nm值。结果如图5所示。
3.6间接免疫荧光(IFA)试验
将HEK293T细胞铺于6孔板中，细胞密度在70-80％，共2mL。转染1.6制备的质粒，培养48小时，弃去上清，每孔加入1mL预冷甲醇，固定20min后小心吸出甲醇并晾干6孔板。吸取1mL PBS清洗6孔板后每孔加2mL 5％脱脂奶37℃封闭1h；单克隆抗体6-4B按照1:2000稀释后分别加入细胞孔，以融合小鼠眼眶血清1:1000稀释作为阳性对照，37℃，1h；AF488荧光二抗1:1000稀释，37℃，1h；PBS洗3次后每孔加入800μL DAPI孵育15min，弃去，PBS再洗3次，每孔加入1mL ddH2O，荧光显微镜下观察结果。如图7所示。结果表明，本发明中的单克隆抗体6-4B分别可与RBD重组蛋白发生特异性反应。
实施例2核酸分子
本实施例的核酸分子，能够编码得到实施例1的单克隆抗体，其重链可变区基因的核苷酸序列如SEQ ID NO:9所示，轻链可变区基因的核苷酸序列如SEQ ID NO:10所示。
实施例3 SARS-CoV-2Spike重组蛋白线性B细胞表位的定位
本实施例进行SARS-CoV-2Spike重组蛋白线性B细胞表位的定位，具体过程如下：
(1)SARS-CoV-2Spike蛋白全长RBD区域氨基酸序列截短合成及鉴定
对SARS-CoV-2Spike蛋白的胞外区(319-685aa)的氨基酸序列按照表6进行截短合成一系列连续重叠肽段(吉尔生化)，合成后的S13-S28共16条多肽稀释成4mg/mL，每条多肽按照每孔包被4μg分别包被9个孔(针对每个mAb，分别做3次重复实验)，RBD重组蛋白作为阳性对照包被原，PBS作为阴性对照。按照表7组合成肽池进行反应，Dot-blot显示肽池#5与单抗6-4B反应，(图8)。再将每个反应的肽池中的肽分别与抗体反应，发现S19是单抗6-4B的识别表位肽，结果如图8。进而将肽S19继续截短合成(表8)，同上述的方法，Dot-blot显示S19.2分别可与对应的单抗发生特异性结合(图8)。
表6 SARS-CoV-2Spike蛋白RBD区域重叠多肽设计序列
表7肽池设计
表8肽S19截短序列设计
(2)SARS-CoV-2Spike蛋白RBD区域线性B细胞表位关键氨基酸的确定
由上述实验可得S19.2为12个氨基酸的肽，分别为464FERDISTEIYQA475，我们采用了丙氨酸扫描法来确定肽S19.2的具体起作用的氨基酸残基。具体地，将每条多肽的每个氨基酸残基分别逐个替换成丙氨酸(A)，原来是丙氨酸的则替换为甘氨酸(G)，具体肽设计见表9，按照上述方法进行实验，结果显示D467,I468,E471,Q474,A475是肽S19.2与单抗6-4B反应的关键氨基酸(图9)。
表9肽S19.2丙氨酸突变序列设计
实施例4单克隆抗体及识别位点的应用
利用上述实施例的单克隆抗体检测SARS-CoV-2：以单克隆抗体作为检测抗体，通过Western blotting，ELISA，IFA，IPMA，免疫层析试纸等方法检测SARS-CoV-2抗原。具体的检测方法可在本发明公开的抗原表位肽的基础上参考现有技术常规构建，例如，参考“《免疫学实验》，余平等，2012”或“《免疫诊断试剂实用技术》，唐秋艳等，2009”记载的实验方法。
利用上述实施例确定的SARS-CoV-2表位的氨基酸序列作为抗原去检测SARS-CoV-2抗体。具体操作：将表位肽与载体蛋白偶联，偶联方法为利用水溶性的氨基-巯基交联剂Sulfo-SMCC进行偶联。Sulfo-SMCC具有sulfo-NHS酯和马来酰亚胺两个反应基团，可以在伯氨基与巯基之间发生反应。
首先，在pH7-9的条件下，Sulfo-SMCC与载体蛋白BSA的伯胺基发生反应，形成稳定的酰胺键，得到活化的载体蛋白BSA。
其次，活化的BSA经PBS(pH7.2-7.4)透析，换三次透析液，每次间隔6个小时。收集透析好的溶液，用PBS调整蛋白浓度至5mg/ml。
最后，在pH 6.5-7.5的条件下，活化好的BSA与阳性反应肽段的巯基发生反应，形成稳定的硫醚键，形成免疫原性载体蛋白BSA与阳性反应肽段偶联物，以用于抗体生产，偶联后的表位肽可以作为包被原通过ELISA检测SARS-CoV-2抗体，待检抗体作为一抗；作为固定原通过Westernblotting检测SARS-CoV-2抗体，此外，也可以作为标记抗原或捕获抗原用于免疫层析试纸等。
<110> 郑州大学 河南农业大学
<120> 抗SARS-CoV-2 spike蛋白的单克隆抗体及应用
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Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala
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Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val
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Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser
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<210> 35
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<213> 人工序列
<221> 465
<400> 35
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<210> 36
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<213> 人工序列
<221> 466
<400> 36
Phe Glu Ala Asp Ile Ser Thr Glu Ile Tyr Gln Ala
1 5 10
<210> 37
<211> 12
<212> PRT
<213> 人工序列
<221> 467
<400> 37
Phe Glu Arg Ala Ile Ser Thr Glu Ile Tyr Gln Ala
1 5 10
<210> 38
<211> 12
<212> PRT
<213> 人工序列
<221> 468
<400> 38
Phe Glu Arg Asp Ala Ser Thr Glu Ile Tyr Gln Ala
1 5 10
<210> 39
<211> 12
<212> PRT
<213> 人工序列
<221> 469
<400> 39
Phe Glu Arg Asp Ile Ala Thr Glu Ile Tyr Gln Ala
1 5 10
<210> 40
<211> 12
<212> PRT
<213> 人工序列
<221> 470
<400> 40
Phe Glu Arg Asp Ile Ser Ala Glu Ile Tyr Gln Ala
1 5 10
<210> 41
<211> 12
<212> PRT
<213> 人工序列
<221> 471
<400> 41
Phe Glu Arg Asp Ile Ser Thr Ala Ile Tyr Gln Ala
1 5 10
<210> 42
<211> 12
<212> PRT
<213> 人工序列
<221> 472
<400> 42
Phe Glu Arg Asp Ile Ser Thr Glu Ala Tyr Gln Ala
1 5 10
<210> 43
<211> 12
<212> PRT
<213> 人工序列
<221> 473
<400> 43
Phe Glu Arg Asp Ile Ser Thr Glu Ile Ala Gln Ala
1 5 10
<210> 44
<211> 12
<212> PRT
<213> 人工序列
<221> 474
<400> 44
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Ala Ala
1 5 10
<210> 45
<211> 12
<212> PRT
<213> 人工序列
<221> 475
<400> 45
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Gly
1 5 10
Claims (9)
1.抗SARS-CoV-2spike蛋白的单克隆抗体，其特征在于，其包含氨基酸序列如SEQ IDNO:1-3所示的VHCDR1、VHCDR2和VHCDR3，和氨基酸序列如SEQ ID NO:4-6所示的VLCDR1、VLCDR2和VLCDR3。
2.如权利要求1所述的抗SARS-CoV-2spike蛋白的单克隆抗体，其特征在于，所述抗SARS-CoV-2spike蛋白的单克隆抗体的重链可变区氨基酸序列如SEQ ID NO:7所示，轻链可变区氨基酸序列如SEQ ID NO:8所示。
3.如权利要求2所述的抗SARS-CoV-2spike蛋白的单克隆抗体，其特征在于，所述抗SARS-CoV-2spike蛋白的单克隆抗体的重链为IgG2b型，轻链为Kappa型。
4.编码如权利要求1～3中任一项所述的抗SARS-CoV-2spike蛋白的单克隆抗体的核酸分子。
5.如权利要求4所述的核酸分子，其特征在于，编码所述抗SARS-CoV-2spike蛋白的单克隆抗体的重链可变区的基因核苷酸序列如SEQ ID NO:9所示，编码所述抗SARS-CoV-2spike蛋白的单克隆抗体的轻链可变区的基因核苷酸序列如SEQ ID NO:10所示。
6.如权利要求1～3中任一项所述的抗SARS-CoV-2spike蛋白的单克隆抗体在制备诊断、检测或预防SARS-CoV-2试剂中的应用。
7.如权利要求6所述的应用，其特征在于，所述抗SARS-CoV-2spike蛋白的单克隆抗体特异性识别SARS-CoV-2splike蛋白的RBD区域，识别位点的氨基酸序列为464FERDISTEIYQA475。
8.如权利要求7所述的应用，其特征在于，所述识别位点与所述单克隆抗体结合的关键基氨基酸为D467、I468、E471、Q474、A475。
9.如权利要求7或8所述的应用，其特征在于，利用所述识别位点制备诊断或预防SARS-CoV-2的试剂。
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