CN115028714A - 一种检测冠状病毒的抗体及其应用 - Google Patents
一种检测冠状病毒的抗体及其应用 Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2469/00—Immunoassays for the detection of microorganisms
- G01N2469/10—Detection of antigens from microorganism in sample from host
Abstract
本发明公开了一种检测冠状病毒的抗体及其应用，所述抗体包括三个重链互补决定区和三个轻链互补决定区，所述重链互补决定区CDR1、CDR2、CDR3的氨基酸序列如SEQ ID NO：2、3、4所示，轻链互补决定区CDR1、CDR2、CDR3的氨基酸序列如SEQ ID NO：10、11、12所示。所述抗体还包括四个重链可变框架区和四个轻链可变框架区，所述重链可变框架区FR1、FR2、FR3、FR4的氨基酸序列分别如SEQ ID NO：5、6、7、8所示，所述轻链可变框架区FR1、FR2、FR3、FR4的氨基酸序列分别如SEQ ID NO：13、14、15、16所示。所述抗体能与冠状病毒抗原或其变异株特异性结合，均具有较高的结合活性。
Description
技术领域
本发明属于细胞生物技术、免疫学领域，涉及一种检测冠状病毒的抗体及其应用。
背景技术
严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)是2019年新型冠状病毒肺炎(COVID-19)的病原体，而2019年新型冠状病毒肺炎(COVID-19)的特征是危及生命的急性呼吸窘迫综合征(ARDS)，目前新型冠状病毒肺炎已在全球范围内大流行，超2亿人确诊感染，死亡数量突破数百万例。
目前，新型冠状病毒SARS-CoV-2的主要检测方法有基因组测序、核酸检测法和免疫学检测法等。大多数患者的症状为肺炎，其特征是电子计算机断层扫描(computedtomography，CT)检查显示胸部双侧斑片状影和毛玻璃影。因此，对于疑似患者确诊时建议进行CT扫描。然而，SARS-CoV-2病毒携带者缺乏临床表现，有些RT-qPCR检测阳性的患者可能在发病时其胸部CT诊断结果正常。免疫学检测方法是SARS-CoV-2快速确诊的辅助检测手段，仅需要最低限度的设备来检测抗体，即可达到快速确诊的目的(夏永胜,朱红年,沈小俊,等.新型冠状病毒SARS-CoV-2的快速核酸检测技术[J].生命化学，2022,42(3):502-512)。
SARS-CoV-2基因组由大约30000个核苷酸组成，其编码四种结构蛋白，包括S蛋白、E蛋白、M蛋白和N(核衣壳)蛋白。其中，N蛋白是一种免疫原性强、在感染期间表达丰富的蛋白，常用于疫苗开发和血清学检测(Weihong Zeng,Guangfeng Liu,etal.Biochemicalcharacterization of SARS-CoV-2nucleocapsid protein[J],Biochemical andBiophysical Research Communications,2020,(3):618-623.)。此外N蛋白与病毒基因组RNA相互缠绕形成病毒核衣壳，在病毒RNA的合成过程中发挥着重要的作用。同时，N蛋白相对保守，在病毒的结构蛋白中所占比例最大，感染早期机体就能产生抗N蛋白的高水平抗体，可以利用N蛋白建立快速检测SARS-CoV-2血清抗体方法。
鉴于此，提出本发明。
发明内容
本发明的目的在于提供一种检测冠状病毒的抗体及其应用，具体为抗SARS-CoV-2N蛋白的抗体及其应用。具体的方案如下：
本发明的第一方面提供了一种抗体，所述抗体包括3个重链互补决定区和3个轻链互补决定区；所述3个重链互补决定区的氨基酸序列分别如SEQ ID NO:2、3、4所示；所述3个轻链互补决定区的氨基酸序列分别如SEQ ID NO:10、11、12所示。
进一步，所述抗体还包括4个重链可变框架区，所述4个重链可变框架区的氨基酸序列分别如SEQ ID NO:5、6、7、8所示或与其具有至少90％的同一性；所述抗体还包括4个轻链可变框架区，所述4个轻链可变框架区的氨基酸序列分别如SEQ ID NO:13、14、15、16所示或与其具有至少90％的同一性。
进一步，所述抗体的序列包括：具有如SEQ ID NO:9所示的氨基酸序列或与其具有至少90％的同一性的氨基酸序列的重链可变区；和/或具有如SEQ ID NO:17所示的氨基酸序列或与其具有至少90％的同一性的氨基酸序列的轻链可变区。
本发明第二方面提供了一种核酸分子，所述核酸分子编码本发明第一方面所述的抗体。
本发明第三方面提供了一种生物材料，所述生物材料包括表达本发明第一方面所述的抗体的重组表达载体、重组微生物或重组细胞系。
本发明第四方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的抗体、本发明第二方面所述的核酸分子和/或本发明第三方面所述的生物材料。
进一步，所述药物组合物还包括药学上可接受的载体。
本发明第五方面提供了一种制备本发明第一方面所述抗体的方法，所述方法包括将本发明第二方面所述的核酸分子或本发明第三方面中所述的重组表达载体转入宿主细胞内培养，得到所述抗体；或培养本发明第三方面中所述的重组微生物或重组细胞系，得到所述抗体。
本发明第六方面提供了一种检测冠状病毒N蛋白或冠状病毒感染的产品，所述产品包括以下任一种：
1)由本发明第一方面所述的抗体制备而成的产品；
2)由本发明第二方面所述的核酸分子制备而成的产品；
3)由本发明第三方面所述的生物材料制备而成的产品。
本发明第七方面提供了一种应用，所述应用包括以下任一种：
1)本发明第一方面所述的抗体、本发明第二方面所述的核酸分子、本发明第三方面所述的生物材料、本发明第六方面所述的产品在检测冠状病毒N蛋白/检测冠状病毒感染/抑制冠状病毒感染中的应用；
2)本发明第一方面所述的抗体、本发明第二方面所述的核酸分子、本发明第三方面所述的生物材料、本发明第六方面所述的产品在制备诊断冠状病毒感染相关疾病的产品中的应用；
3)本发明第一方面所述的抗体、本发明第二方面所述的核酸分子、本发明第三方面所述的生物材料、本发明第四方面所述的药物组合物在制备预防/治疗冠状病毒感染相关疾病的药物中的应用。
进一步，所述冠状病毒为SARS-CoV-2病毒；所述冠状病毒感染相关疾病包括高烧、干咳、呼吸短促、肺炎、胃肠道症状(如腹泻)、器官衰竭(肾衰竭和肾功能障碍)、脓毒性休克。
进一步，所述冠状病毒感染相关疾病选自肺炎。
本发明的有益效果：
本发明提供了一种冠状病毒SARS-CoV-2的抗体，该抗体与N蛋白具有较好的结合活性，能作为临床上冠状病毒检测的有效辅助手段，提高冠状病毒检测的准确率，从而实现早诊断、早预防、早治疗。
附图说明
图1是检测单克隆抗体OP1的电泳图；
图2是检测单克隆抗体OP1的HPLC图；
图3是ELISA检测单克隆抗体OP1的结合活性图。
具体实施方式
本发明通过广泛而深入的研究，发现了一个抗冠状病毒N蛋白的抗体，所述抗体具有较高的亲和活性。
抗体
术语“抗体”是指通过至少一个位于免疫球蛋白分子的可变区内的抗原识别位点，识别和特异性结合(诸如蛋白、多肽、肽、糖类、多核苷酸、脂质或上述物质的组合等靶标)的免疫球蛋白分子。可用于本发明的抗体包括不同的抗体结构，包括但不限于单克隆抗体、多克隆抗体、多特异性抗体(例如双特异性抗体)以及抗体片段，只要它们展示所要的抗原结合活性。抗体是由免疫系统生成的能够识别并结合特定抗原的蛋白质。抗体可以是人的、人源化的、鼠的、嵌合的或衍生自其他物种，只要所述抗体显示所需的生物活性即可。基于分别称为α、δ、ε、γ和μ的抗体重链恒定域的同一性，抗体可以是五个主要种类免疫球蛋白中的任一种：IgA、IgD、IgE、IgG和IgM，或其亚类(例如，IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)。不同种类的免疫球蛋白具有不同的亚基结构和三维构造。免疫球蛋白可以源自任何物种，包括鼠、人或兔。抗体可以是裸露的或与诸如毒素、放射性同位素等其它分子缀合。在本发明中，N蛋白抗体不仅包括完整的抗体，还包括具有免疫活性的抗体的片段或抗体与其他序列形成的融合蛋白。因此，本发明还包括所述抗体的片段、衍生物和类似物。本发明优选的是单克隆抗体。
可变区
如本发明所用，“抗体”由两个相同的轻链(L)和两个相同的重链(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)，其后是多个恒定区。每条轻链的一端有可变区(VL)，另一端有恒定区；轻链的恒定区与重链的第一个恒定区相对，轻链的可变区与重链的可变区相对。特殊的氨基酸残基在轻链和重链的可变区之间形成界面。
如本发明所用，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，它形成了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。它集中于轻链和重链可变区中称为互补决定区(CDR)或超变区中的三个片段中。可变区中较保守的部分称为构架区(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))。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，例如参与抗体的依赖于抗体的细胞毒性。
重链可变区与轻链可变区共同构成抗原结合域。术语“互补决定区”、“CDR”或“高变区”是指抗体的可变区内主要促成抗原结合的6个高变区之一。通常，每个重链可变区中存在三个CDR(HCDR1、HCDR2、HCDR3)，每个轻链可变区中存在三个CDR(LCDR1、LCDR2、LCDR3)。可以使用各种公知方案中的任何一种来确定CDR的氨基酸序列边界，包括“Kabat”编号规则(参见Kabat等(1991)，“Sequences of Proteinsof Immunological Interest”，第5版，Public Health Service，National Institutes ofHealth，Bethesda，MD)、“Chothia”编号规则(参见Al-Lazikani等人，(1997)JMB 273：927-948)和ImMunoGenTics(IMGT)编号规则(Lefranc M.P.，Immunologist，7，132-136(1999)；Lefranc，M.P.等，Dev.Comp.Immunol.，27，55-77(2003)等。例如，对于经典格式，遵循Kabat规则，所述重链可变区(VH)中的CDR氨基酸残基编号为31-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3)；轻链可变区(VL)中的CDR氨基酸残基编号为24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)。遵循Chothia规则，VH中的CDR氨基酸编号为26-32(HCDR1)、52-56(HCDR2)和95-102(HCDR3)；并且VL中的氨基酸残基编号为26-32(LCDR1)、50-52(LCDR2)和91-96(LCDR3)。通过组合Kabat和Chothia两者的CDR定义，CDR由人VH中的氨基酸残基26-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3)和人VL中的氨基酸残基24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)构成。遵循IMGT规则，VH中的CDR氨基酸残基编号大致为26-35(CDR1)、51-57(CDR2)和93-102(CDR3)，VL中的CDR氨基酸残基编号大致为27-32(CDR1)、50-52(CDR2)和89-97(CDR3)。遵循IMGT规则，抗体的CDR区可以使用程序IMGT/DomainGapAlign确定。
术语“框架”或“FR”指除了互补决定区(CDR)残基以外的可变区残基。可变区的FR一般由四个FR域组成：FR1、FR2、FR3和FR4。因而，CDR和FR序列一般以下面的次序在VH(或VL)中出现：
FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3-HCDR3(LCDR3)-FR4同一性
在本发明中，术语“同一性”、“同源性”可以互换使用，通常是指将本发明中的抗体序列中氨基酸残基与相应序列进行比较，经序列比对和必要情况下引入间隔以实现整段序列的最大相同百分数并且不把任何保守取代视为序列同一性的一部分后，二者碱基或残基相同的比例。无论N端或C端延伸或插入均不应理解为降低同一性或同源性。对于比对的方法和计算程序均可获得，并为本领域所熟知，例如，可以通过序列分析软件测定序列同一性。在本发明中，氨基酸序列变体中相同的残基的百分比，如果需要，达到最大百分比的同源性。用于比对的方法和计算机程序在本领域内是公知的。本发明所述的“至少90％的同一性”是指同源性为90％至100％任一值，例如90％、95％、99％等。
核酸分子
在本发明中，术语“核酸分子”是以核苷酸为单元所组成的分子，包含DNA、RNA等。核酸分子可为单链或双链，例如可以是双链DNA或单链mRNA或修饰的mRNA。当将核酸与另一个核酸序列置于功能关系中时，核酸是“有效连接的”。例如，如果启动子或增强子影响编码序列的转录，那么启动子或增强子有效地连接至所述编码序列。
重组表达载体
术语“重组表达载体”指用于表达例如编码所需多肽的多核苷酸的DNA结构。重组表达载体可包括，例如包含i)对基因表达具有调控作用的遗传元素的集合，例如启动子和增强子；ii)转录成mRNA并翻译成蛋白质的结构或编码序列；以及iii)适当的转录和翻译起始和终止序列的转录亚单位。重组表达载体以任何合适的方式构建。载体的性质并不重要，并可以使用任何载体，包括质粒、病毒、噬菌体和转座子。用于本发明的可能载体包括但不限于染色体、非染色体和合成DNA序列，例如病毒质粒、细菌质粒、噬菌体DNA、酵母质粒以及从质粒和噬菌体DNA的组合中衍生的载体，来自如慢病毒、逆转录病毒、牛痘、腺病毒、鸡痘、杆状病毒、SV40和伪狂犬病等病毒的DNA，在本发明的具体实施方案中，重组表达载体为真核生物表达载体。
重组微生物
术语“重组微生物”包括微生物(例如细菌、酵母、藻、真菌等)或微生物菌株，其已经被遗传改变、修饰或工程化(例如遗传工程化)以便其与其来源的天然发生微生物或“亲本”微生物相比显示改变的、修饰的或不同的基因型和/或表型(例如，当遗传修饰影响了微生物的编码核酸序列时)。
重组细胞系
术语“重组细胞系”指的是已经引入重组表达载体的细胞系。应当理解，“重组细胞系”不仅指特定的个体细胞系，也指该细胞系的后代。由于突变或者环境影响，而在后代中可能出现某些修饰，所以其后代事实上可能和母细胞不一致，但是仍然被包括在此处使用的术语“重组细胞系”的范围中。适用于本发明的重组细胞系包括但不限于大肠杆菌或枯草菌等的原核细胞，如酵母细胞或曲霉菌等的真菌细胞，如S2果蝇细胞或Sf9等的昆虫细胞，或者如纤维原细胞，CHO细胞、COS细胞、NSO细胞、HeLa细胞、BHK细胞、HEK293细胞或人细胞等的动物细胞。在本发明中的一些实施方案中，重组细胞系优选为真核细胞，更优选为哺乳动物细胞。在本发明中的具体实施方案中，所述的重组细胞系为HEK293细胞。
药学上可接受的载体
如本发明所用，“药学上可接受的”的成分是适用于人和/或哺乳动物而无过度不良副反应(如毒性、刺激和变态反应)的，即具有合理的效益/风险比的物质。术语“药学上可接受的载体”指用于治疗剂给药的载体，包括各种赋形剂和稀释剂。
本发明的药物组合物含有安全有效量的本发明的活性成分以及药学上可接受的载体。这类载体包括但并不限于：盐水、缓冲液、葡萄糖、水、甘油、乙醇、脂质体、脂质、蛋白、蛋白-抗体缀合物、肽类物质、纤维素、纳米凝胶及其组合。通常药物制剂应与给药方式相匹配，本发明的药物组合物的剂型为注射剂、口服制剂(片剂、胶囊、口服液)、透皮剂、缓释剂。例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。所述的药物组合物宜在无菌条件下制造。
本发明所述的活性成分为冠状病毒N蛋白抗体、及编码所述抗体的核酸分子、表达所述抗体的生物材料及上述抗体、核酸分子、生物材料的药物组合物的有效量可随给药的模式和待治疗的疾病的严重程度等而变化。优选的有效量的选择可以由本领域普通技术人员根据各种因素来确定(例如通过临床试验)。所述的因素包括但不限于：所述的活性成分的药代动力学参数例如生物利用率、代谢、半衰期等；患者所要治疗的疾病的严重程度、患者的体重、患者的免疫状况、给药的途径等。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。
冠状病毒
在本发明中，术语“冠状病毒”是指套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒属(Coronavirus)的病毒。冠状病毒通常是具囊膜(envelope)、基因组为线性单股正链的RNA病毒，是自然界广泛存在的一大类病毒。目前已知的7种可以感染人的冠状病毒分别是HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV、MERS-CoV和SARS-CoV-2(也被称为2019-nCoV)，其中SARS-CoV、MERS-CoV和SARS-CoV-2会引发严重的疾病。本发明的抗体适合于抗SARS-CoV、MERS-CoV和SARS-CoV-2，优选地，适合于抗SARS-CoV-2。
冠状病毒感染
如本发明所使用的，术语“冠状病毒感染”或“CoV感染”是指感染冠状病毒，如SARS-CoV-2、MERS-CoV或SARS-CoV。在一个方面，所述术语包含了非诊断目的的在实验室内培养、分离冠状病毒，研究冠状病毒感染细胞的相关特征。在一个方面所述术语包含通常在体内的冠状病毒感染，一般是体内的下呼吸道中的冠状病毒呼吸道感染，包括有症状感染和无症状感染。有症状感染的症状可以包含高烧、干咳、呼吸短促、肺炎、胃肠道症状(如腹泻)、器官衰竭(肾衰竭和肾功能障碍)、脓毒性休克和严重病例的死亡。
冠状病毒感染相关疾病
在本发明中，术语“冠状病毒感染相关疾病”、“冠状病毒感染性疾病或病症”可以互换使用，是指由冠状病毒引起或导致的疾病或病症。适合于使用本发明的药物组合物进行预防或治疗的疾病是冠状病毒感染引起的相关疾病，包括：高烧、干咳、呼吸短促、肺炎、胃肠道症状(如腹泻)、器官衰竭(肾衰竭和肾功能障碍)、脓毒性休克和严重病例的死亡。
预防
在本发明中。术语“预防”指对冠状病毒感染性疾病或病症的预防性或防止性措施。
治疗
在本发明中，术语“治疗”指对冠状病毒感染性疾病或病症的治愈性或缓解性治疗。
EC50值
如本发明所用的，术语“EC50值”是指半数最大效应浓度(concentration for50％of maximal effect,EC50)，指能引起50％最大效应的浓度。
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1单克隆抗体的筛选
1、重组新冠N蛋白的合成
合成SARS-CoV-2病毒的N蛋白序列，构建至pEM5.1载体；抽提转染用质粒；转染至SP2/0细胞，培养细胞7天；收获上清，Ni柱纯化，经过浓缩置换缓冲液，得到重组新冠N蛋白，重组新冠N蛋白序列来源Uniprot P0DTC9，序列如表1所示。
表1重组新冠N蛋白的序列
2、免疫
第一次用福氏完全佐剂，每只100μg，腹腔注射小鼠，总剂量0.5ml/只，间隔3周进行第二次免疫；第二次起用福氏不完全佐剂，剂量为50μg/0.5ml/只，间隔2周进行第三次免疫；第三次注射后10天准备细胞融合；
取饲养细胞，可按105/孔使用，于融合前一天铺板105个/100μl/孔；取小鼠免疫脾细胞与准备好的骨髓瘤细胞用融合剂PEG进行融合，铺入已经加入饲养细胞的96细胞培养板，100μl/孔。
3、杂交瘤细胞的筛选和克隆
通过ELISA检测方法进行阳性孔筛选，铺入重组表达N蛋白过夜；洗板，加脱脂奶粉封闭，37℃，1h；洗板，加入100μl 96孔培养液上清，37℃，孵育1h；洗板，加入HRP标记羊抗鼠二抗，37℃，孵育30min；洗板，加入显色液，显色10min，加入终止液，读取OD450的数值；筛选高表达量细胞株进行亚克隆培养。
4、测序
收集细胞，采用Trizol抽提总RNA，用oligo(dT)20为引物，逆转录生成cDNA。然后利用特异性引物PCR分别扩增其重、轻链可变区基因。PCR产物经电泳纯化后，通过TA克隆插入载体，进行转化，挑选阳性克隆送测序。
5、结果
筛选出抗SARS-CoV-2的单克隆抗体OP1，序列如表2所示。
表2单克隆抗体OP1的序列
实施例2单克隆抗体OP1的功能性研究
1、单克隆抗体的表达和纯化
1)对筛选出的序列进行化学合成，并克隆至真核表达载体中；
2)对质粒扩增提取；
3)将编码抗体的质粒瞬时转染入哺乳动物细胞HEK293；
4)收集上清，利用亲和层析方法，纯化获得单克隆抗体；
5)结果，纯化后的抗体表达量是476mg/L。
2、单克隆抗体的理化性质检测
2.1凝胶电泳检测单克隆抗体的纯度
1)仪器设备
表3单克隆抗体OP1凝胶电泳纯度测定所用仪器设备
2)主要试剂
表4单克隆抗体OP1凝胶电泳纯度测定所用试剂
3)样品制备
取20μl的样品与5μl的5×还原buffer混合均匀，在95℃中加热5min，冷却。
4)电泳
配置胶，加适量的电泳缓冲液，加样，进行电泳。
5)染色与脱色
电泳结束后，取凝胶放入适量考马斯亮蓝染色液中，室温染色1h或更长时间；倒出染色液，加入适量考马斯亮蓝染色脱色液，室温脱色4-24h。完成脱色后，用ddH2O浸泡，参照Marker蛋白，与未染色凝胶对比，切下所需蛋白成分的凝胶，收集起来。然后把所要提纯的蛋白从凝胶中分离出来。
6)结果
结果如图1所示，从左至右条带分别是marker、还原条带；单克隆抗体的检测纯度大于95％。
2.2HPLC检测单克隆抗体的纯度
1)仪器设备
表5单克隆抗体OP1 HPLC纯度测定所用仪器设备
2)主要试剂
表6单克隆抗体OP1 HPLC纯度测定所用试剂
| 名称 | 生产厂家 | 规格 | 货号 |
| 磷酸氢二钾三水 | 国药集团化学试剂有限公司 | 500g/瓶 | 10017592 |
| 磷酸二氢钾 | 国药集团化学试剂有限公司 | 500g/瓶 | 10017692 |
| 氯化钾 | 国药集团化学试剂有限公司 | 500g/瓶 | 10016392 |
3)流动相配制
将磷酸氢二钾三水、磷酸二氢钾和氯化钾加入到约900ml纯化水中，搅拌溶解，定容至1L，用pH计测量，确定其pH在6.2±0.1之间。0.22μm滤膜过滤，室温保存。
4)样品制备
系统适用性样品：MIL62标准品用流动相稀释至2mg/ml
供试品：待测样品用流动相稀释至2mg/ml。
5)色谱条件
表7单克隆抗体OP1 HPLC纯度测定色谱条件设置
6)结果
结果如图2所示，单克隆抗体的检测纯度大于95％。
3、单克隆抗体的结合活性检测
1)仪器设备
表8单克隆抗体OP1结合活性测定所用仪器设备
| 名称 | 生产厂家 |
| 酶标仪 | Tecan |
| 洗板机 | Tecan |
| 96孔包被板 | costar |
| 96孔样品稀释板 | 广州洁特生物过滤制品有限公司 |
2)所用溶液、试剂
包被液：1.5g Na2C03、2.93g NaHCO3定容至1000ml；
DPBS(1x)：0.2g KCl、0.2g KH2PO4、8.0g NaCl、2.9g Na2HPO4·12H2O,定容至1L；
显色液：TMB(湖州英创生物科技有限公司TMB-S-001 1000ml)；
终止液：2N H2SO4(H2SO4 56ml+H2O 944ml)；
封闭液：5％高蛋白脱脂高钙奶粉溶于10ml DPBS；
洗涤液：含3‰吐温(TWEEN 20，Sigma试剂V900548-500ml)的DPBS
包被所用抗原：N-HIS6X-终止子(所述N为上述合成的N蛋白)、SARS-COV2-N-B1617(序列如表9所示)。
表9包被所用抗原及序列
3)实验步骤
①包被：用包被液将抗原N蛋白稀释成2μg/ml，混匀，加入96孔包被板，100μl/孔，封膜封闭，4℃过夜。
②洗板机洗涤3次，最后一次不能有液体残留在板子上，用吸水纸拍干板子表面的液体。
③封闭：加入封闭液，300μl/孔，37℃孵育1h，按照步骤2)洗板3次。
④将抗体进行梯度稀释，共分成11个浓度梯度，100μl/孔，37℃反应1h，按照步骤2)洗板3次。
⑤加二抗：用DPBS按照1:3000稀释，加入96孔板，100μl/孔，37℃反应1h，按照步骤2)洗板3次。
⑥显色：加入TMB，100μl/孔，室温避光显色10min。
⑦终止：加入2N H2SO4，100μl/孔。
⑧酶标仪测OD450，10min内检测。
⑨结果
具体的单克隆抗体结合活性检测所用物质及结果如表10所示。
表10单克隆抗体结合活性检测所用物质及结果
结合活性结果如图3所示，单克隆抗体OP1可以与抗原N蛋白特异性结合，EC50为0.01555μg/ml。且可以与冠状病毒SARS-COV2变异株B1617特异性结合，EC50为0.02359μg/ml。
综上，本发明中的抗体OP1可以与N蛋白抗原和冠状病毒变异株具有较好的结合活性，可以用于检测冠状病毒SARS-COV2。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也将落入本发明权利要求的保护范围内。
序列表
<110> 江苏东抗生物医药科技有限公司
<120> 一种检测冠状病毒的抗体及其应用
<141> 2022-06-22
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Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys
245 250 255
Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln
260 265 270
Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp
275 280 285
Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile
290 295 300
Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile
305 310 315 320
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Gly Ala
325 330 335
Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu
340 345 350
Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro
355 360 365
Lys Lys Asp Lys Lys Lys Lys Ala Tyr Glu Thr Gln Ala Leu Pro Gln
370 375 380
Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu
385 390 395 400
Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser
405 410 415
Thr Gln Ala
Claims (10)
1.一种抗体，其特征在于，所述抗体包括3个重链互补决定区和3个轻链互补决定区；所述3个重链互补决定区的氨基酸序列分别如SEQ ID NO:2、3、4所示；所述3个轻链互补决定区的氨基酸序列分别如SEQ ID NO:10、11、12所示。
2.根据权利要求1所述的抗体，其特征在于，所述抗体还包括4个重链可变框架区，所述4个重链可变框架区的氨基酸序列分别如SEQ ID NO:5、6、7、8所示或与其具有至少90％的同一性；所述抗体还包括4个轻链可变框架区，所述4个轻链可变框架区的氨基酸序列分别如SEQ ID NO:13、14、15、16所示或与其具有至少90％的同一性。
3.根据权利要求2所述的抗体，其特征在于，所述抗体的序列包括：具有如SEQ ID NO:9所示的氨基酸序列或与其具有至少90％的同一性的氨基酸序列的重链可变区；和/或具有如SEQ ID NO:17所示的氨基酸序列或与其具有至少90％的同一性的氨基酸序列的轻链可变区。
4.一种核酸分子，其特征在于，所述核酸分子编码权利要求1-3中任一所述抗体。
5.一种生物材料，其特征在于，所述生物材料包括表达权利要求1-3中任一所述抗体的重组表达载体、重组微生物或重组细胞系。
6.一种药物组合物，其特征在于，所述药物组合物包括权利要求1-3中任一所述的抗体、权利要求4所述的核酸分子和/或权利要求5所述的生物材料；
优选地，所述药物组合物还包括药学上可接受的载体。
7.一种制备权利要求1-3任一项所述抗体的方法，其特征在于，所述方法包括将权利要求4所述的核酸分子或权利要求5中所述的重组表达载体转入宿主细胞内培养，得到所述抗体；或培养权利要求5中所述的重组微生物或重组细胞系，得到所述抗体。
8.一种检测冠状病毒N蛋白或冠状病毒感染的产品，其特征在于，所述产品包括以下任一种：
1)由权利要求1-3中任一所述的抗体制备而成的产品；
2)由权利要求4所述的核酸分子制备而成的产品；
3)由权利要求5所述的生物材料制备而成的产品。
9.一种应用，其特征在于，所述应用包括以下任一种：
1)权利要求1-3中任一所述的抗体、权利要求4所述的核酸分子、权利要求5所述的生物材料、权利要求8所述的产品在检测冠状病毒N蛋白/检测冠状病毒感染/抑制冠状病毒感染中的应用；
2)权利要求1-3中任一所述的抗体、权利要求4所述的核酸分子、权利要求5所述的生物材料、权利要求8所述的产品在制备诊断冠状病毒感染相关疾病的产品中的应用；
3)权利要求1-3中任一所述的抗体、权利要求4所述的核酸分子、权利要求5所述的生物材料、权利要求6所述的药物组合物在制备预防/治疗冠状病毒感染相关疾病的药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述冠状病毒为SARS-CoV-2病毒；所述冠状病毒感染相关疾病包括高烧、干咳、呼吸短促、肺炎、胃肠道症状、器官衰竭、脓毒性休克；
优选地，所述冠状病毒感染相关疾病选自肺炎。
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