CN115028713A - 一种抗冠状病毒n蛋白的抗体及其应用 - Google Patents
一种抗冠状病毒n蛋白的抗体及其应用 Download PDFInfo
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Abstract
本发明公开了一种抗冠状病毒N蛋白的抗体及其应用，所述抗体包括重链可变区的三个CDR和三个CDR的轻链可变区；其中，所述重链可变区CDR1、CDR2、CDR3的氨基酸序列如SEQ ID NO：2、3、4所示，轻链可变区CDR1、CDR2、CDR3的氨基酸序列如SEQ ID NO：10、11、12所示，同时公开了重链可变区的四个框架区和轻链可变区的四个框架区的氨基酸序列，及与所述抗体相关的核酸分子、表达载体、宿主细胞及药物组合物及应用。本发明所述的抗体与冠状病毒具有较高的结合活性，可以准确检测冠状病毒或其变异株。
Description
技术领域
本发明属于细胞生物技术、免疫学领域，涉及一种抗冠状病毒N蛋白的抗体及其应用。
背景技术
SARS-CoV-2在持续传播中不断发生进化和变异，目前已出现多种变异株，其中Alpha(B.1.1.7)变异株、Beta(B.1.351)变异株、Gamma(P.1)变异株、Delta(B.1.617.2)变异株和Omicron (B.1.1.529)变异株传染性更强，且对疫苗和治疗的抵抗力更高，为COVID-19 防治带来新难点和新挑战，被世界卫生组织认定为值得关注的变异株。SARS- CoV-2主要通过呼吸道飞沫和密切接触传播，传染能力极强，部分患者无症状却具备感染他人的能力。新冠肺炎的确诊对于疫情的防控、病患的早发现、早隔离、早治疗尤为关键。
目前核酸检测是最常用的新冠病毒。检测方法依据临床取样难度和患者接受程度，目前临床最常用的标本是口咽拭子，其次是鼻咽拭子。核酸检测的是新冠病毒的遗传物质RNA，如果检测结果为阳性，可直接确诊为感染病例。实时荧光 RT-PCR是核酸检测最常用的方法，是确诊新冠肺炎的“金标准”。RT-PCR因其快速简便、成本低、特异性高等特点是疫情期间使用最多最广泛的核酸检测方法，但检测结果容易受到诸多因素影响，可能造成核酸检测结果“假阴性”而出现漏诊。
由于核酸检测存在较高的假阴性，且耗时较长，对场地设备和技术人员要求较高，免疫学检测因其快速可满足现场检测、诊断较为准确，可辅助临床确诊，高滴度抗体血浆对重症COVID-19患者的治疗有所帮助，因此得到了越来越多的人重视。《新型冠状病毒传染的肺炎诊疗方案(试行第七版)》首次将血清学检测作为确诊依据之一，因此血清免疫学检测作为新冠病毒的诊断指标具有一定的临床意义。
发明内容
为了弥补现有技术的不足，本发明的目的在于提供一种抗冠状病毒N蛋白的抗体，所述抗体具有较高的结合N蛋白的活性。本发明是通过以下方案实现的：
本发明第一方面提供了一种抗体或其抗原结合片段，所述抗体或其抗原结合片段包括重链可变区的互补决定区CDR1、CDR2、CDR3和/或轻链可变区的互补性决定区域CDR1、CDR2、CDR3；重链可变区CDR1、CDR2、CDR3的氨基酸序列分别如SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4所示；轻链可变区 CDR1、CDR2、CDR3的氨基酸序列分别如SEQ ID NO:10、SEQID NO:11、SEQ ID NO:12所示。
优选地，所述抗体或其抗原结合片段为抗冠状病毒N蛋白的抗体或其抗原结合片段。
优选地，冠状病毒选自SARS-CoV-2、MERS-CoV、SARS-CoV。
优选地，所述冠状病毒为SARS-CoV-2。
优选地，所述抗体的重链可变区的氨基酸序列包括如SEQ ID NO:9所示的序列或与其具有至少90％的同一性的序列；轻链可变区的氨基酸序列包括如 SEQ ID NO:17所示的序列或与其具有至少90％的同一性的序列。
优选地，所述抗体的抗原结合片段包括Fab、Fab′、F(ab′)2、Fv或单链抗体。
本发明第二方面提供了一种分离的核酸分子，所述核酸分子编码本发明第一方面所述的抗体或其抗原结合片段。
本发明第三方面提供了一种表达载体，所述表达载体包括本发明第二方面所述的核酸分子。
优选地，所述载体还包含与本发明第一方面所述的抗体或其抗原结合片段可操作性地连接的信号肽。
本发明第四方面提供了一种宿主细胞，所述宿主细胞包括本发明第二方面所述的核酸分子或本发明第三方面所述的表达载体。
优选地，所述宿主细胞选自原核生物或真核生物。
优选地，所述宿主细胞选自真核生物。
优选地，所述宿主细胞选自哺乳动物细胞。
优选地，所述宿主细胞选自HEK293细胞。
本发明第五方面提供了一种药物组合物，所述该药物组合物包含本发明第一方面所述的抗体或其抗原结合片段、本发明第二方面所述的核酸分子、本发明第三方面所述的表达载体、本发明第四方面所述的宿主细胞和/或药学上可接受的载体。
本发明第六方面提供了一种检测产品，所述检测产品包括本发明第一方面所述的抗体或其抗原结合片段、本发明第二方面所述的核酸分子、本发明第三方面所述的表达载体和/或本发明第四方面所述的宿主细胞。
优选地，所述产品包括试剂盒。
优选地，所述试剂盒包括胶体金免疫试剂盒、化学发光试剂盒、放射免疫试剂盒、酶联免疫试剂盒(ELISA)、荧光免疫试剂盒或微流体芯片。
本发明第七方面提供了一种方法，所述方法包括以下任一种：
1)一种产生本发明第一方面所述的抗体或其抗原结合片段的方法，所述方法包括培养本发明第四方面所述的宿主细胞，并且回收得到所述的抗体或其抗原结合片段；
2)一种检测冠状病毒感染的方法，所述方法包括将待测样本与本发明第一方面所述的抗体或其抗原结合片段接触，观察待测样本与抗体或其抗原结合片段的免疫反应，以确定样本中N蛋白的表达水平或冠状病毒感染情况。
优选地，所述方法是非诊断目的检测方法。
本发明第八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或其抗原结合片段、本发明第二方面所述的核酸分子、本发明第三方面所述的表达载体、本发明第四方面所述的宿主细胞、第六方面所述的检测产品在检测冠状病毒感染中的应用；
2)本发明第一方面所述的抗体或其抗原结合片段、本发明第二方面所述的核酸分子、本发明第三方面所述的表达载体、本发明第四方面所述的宿主细胞、本发明第五方面所述的药物组合物在抑制冠状病毒感染中的应用；
3)本发明第一方面所述的抗体或其抗原结合片段、本发明第二方面所述的核酸分子、本发明第三方面所述的表达载体、本发明第四方面所述的宿主细胞、第六方面所述的检测产品在制备诊断冠状病毒感染相关疾病的产品中的应用；
4)本发明第一方面所述的抗体或其抗原结合片段、本发明第二方面所述的核酸分子、本发明第三方面所述的表达载体、本发明第四方面所述的宿主细胞、本发明第五方面所述的药物组合物在制备预防/治疗与冠状病毒感染相关疾病的药物中的应用。
优选地，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。
优选地，所述冠状病毒选自SARS-CoV-2病毒。
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，该抗体具有高纯度、高表达量的特点，与N蛋白或冠状病毒变异株具有较好的结合活性，能作为筛查冠状病毒的有效检测手段，对感染冠状病毒原蛋白或其变异株均具有较高的检测准确率。
附图说明
图1是检测单克隆抗体OP2的电泳图；
图2是检测单克隆抗体OP2的HPLC图；
图3是ELISA检测单克隆抗体OP2的结合活性图。
具体实施方式
在描述本发明方法之前，应当理解本发明不限于所描述的具体方法和实验条件，因为此类方法和条件可以变化。还应理解，本发明所使用的术语仅出于描述具体实施例的目的，而不旨在是限制性的，因为本发明的范围仅受所附权利要求限制。
除非另外定义，否则本发明所使用的所有技术术语和科学术语均具有与本发明所属领域普通技术人员通常所理解的含义相同的含义。尽管在本发明的实践或测试中可以使用类似于或等同于本发明所描述的方法和材料的任何方法和材料，但现在描述优选的方法和材料。本发明所提到的所有出版物均通过全文引用的方式并入本发明中。
本发明中使用的术语“抗体”包括能够与靶多肽的抗原部分结合的全抗体分子及其功能片段，例如Fab，F(ab')2，Fv，单链抗体(“SCA”或ScFv)或其任何组合。抗体优选是单特异性的，例如单克隆抗体或其抗原结合片段。术语“单特异性抗体”是指对特定靶标(例如表位)显示单一结合特异性和亲和力的抗体。该术语包括“单克隆抗体”或“单克隆抗体组成”，其在本发明中是指单分子组成的抗体或其片段的制备。抗体可以是人抗体、嵌合抗体、重组抗体、人源化抗体，单克隆抗体或多克隆抗体。抗体可以是完整的免疫球蛋白，例如IgA、IgG、Ig、IgD、IgM或其亚型，也可以是具有全抗体分子的功能片段(例如，具有生物或化学功能的化合物。本发明使用的抗N蛋白的抗体命名为OP2， OP2可以与具有N蛋白或者冠状病毒抗原任何变异株特异性结合。冠状病毒变异株包括但不限于Alpha(B.1.1.7)变异株、Beta(B.1.351)变异株、Gamma(P.1) 变异株、Delta(B.1.617.2)变异株和Omicron(B.1.1.529)变异株。
“抗体片段”、“抗体或其抗原结合片段”、“抗体的抗原活性片段”、以及“多个抗体片段”在本发明中可以互换，是指包括抗原结合位点或可变区域的完整抗体的部分。该部分不包括完整抗体的Fc区域的恒定重链结构域(例如，CH2、 CH3、或CH4，这取决于抗体同种型)。抗体片段的实例包括但不限于，Fab片段、Fab’片段、Fab’-SH片段、F(ab’)2片段、Fd片段、Fv片段、双价抗体、单链Fv(scFv)分子、仅包含一个轻链可变结构域的单链多肽、包含轻链可变结构域的三个CDR的单链多肽、仅包含一个重链可变区的单链多肽、以及包含重链可变区的三个CDR的单链多肽。“CDR”在本发明中是指在抗体可变序列内的“互补决定区”。在重链和轻链的每个可变区均有三个CDR，其对于每个可变区分别被特定为“CDR1”、“CDR2”和“CDR3”。
“框架”(FR)或“框架序列”在本发明中是指可变区减去CDR的序列。因为CDR序列的精确定义可由不同系统确定，框架序列的意思受制于相应地不同说明。重链可变区的三个互补决定区CDR1、CDR2、CDR3、轻链可变区的互补性决定区域CDR1、CDR2、CDR3六个CDR(也将在重链和轻链上的框架区域划分为在每个链上的四个子区域(FR1、FR2、FR3和FR4)，其中CDR1位于 FR1和FR2之间，CDR2位于FR2和FR3之间，并且CDR3位于FR3和FR4之间。在没有将特定子区域指定为FR1、FR2、FR3和FR4的情况下，如由其他指出的框架区域表示在单一、自然发生地免疫球蛋白链的可变区之内组合的FR。如本发明中使用的，FR表示四个子区域之一，FR表示构成框架区域的四个子区域中的两个或更多个。
冠状病毒
本发明所用的术语“冠状病毒(Coronaviruses)”是单股正链RNA病毒，属于巢病毒目Nidovirales)冠状病毒科(Coronaviridae)正冠状病毒亚科 (Orthocoronavirinae)。该病毒可以感染人、蝙蝠、猪、老鼠、牛、马、山羊、猴子等多种物种。已知感染人的冠状病毒(HCoV)有7种，包括中东呼吸综合征相关冠状病毒(MERSr-CoV)和严重急性呼吸综合征相关冠状病毒(SARSr-CoV)，具体为HCoV-229E、HCoV-OC43、SARS-CoV、HCoV-NL63、HCoV-HKU1、MERS- nCoV和SARS-CoV-2。在具体的实施方式中，本发明所述的冠状病毒是SARS- CoV-2。
同一性
如本发明所用的术语“同一性”指与本发明所用氨基酸序列的序列相似性。同一性可以用肉眼或计算机软件进行评价。使用计算机软件，两个或多个序列之间的同一性可以用百分比(％)表示，其可以用来评价相关序列之间的同一性。本发明提供的如SEQ ID NO:1-18所示的氨基酸序列的功能等价变体，所述变体与SEQ ID NO:1-18所示氨基酸序列具有一个或几个氨基酸的置换、缺失或添加 (如1个，2个，3个，4个，5个，6个，7个，8个或9个氨基酸的置换、缺失或添加)，或与SEQ ID NO:1-18所示氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、或100％序列同一性均在本发明的保护范围内。
表达载体
术语“表达载体”指本领域熟知的细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒、慢病毒或其他载体，如质粒pcDNA、pcDNA3.3 TOPO(Life Technologies,New York)、质粒pTT3、质粒pEF- BOS、质粒pEM5.1载体等。总之，只要能在宿主体内复制和稳定，任何质粒和载体都可以用。表达载体的一个重要特征是通常含有复制起点、启动子、标记基因和翻译控制元件。在本发明的具体实施方式中，使用了pEM5.1载体。
本发明提供了一种分离的核酸分子，本发明中，术语“核酸分子”包括核糖核苷酸和脱氧核糖核苷酸的序列，如经修饰的或未经修饰的RNA或DNA，各自为单链和/或双链形式的线性或环状，或它们的混合物(包括杂合分子)。因此，根据本发明的核酸包括DNA(比如dsDNA、ssDNA、cDNA)、RNA(比如dsRNA、 ssRNA、mRNA、ivtRNA)，它们的组合或衍生物(比如PNA)。优选地，所述核酸是DNA或RNA。术语“分离的”通常是指大体上不含其天然存在的环境中通常伴随或与之相互作用的组分(例如病毒、核酸或蛋白质)。术语“分离的核酸分子”通常是指从其天然环境中分离的或人工合成的任何长度的分离形式的核苷酸、脱氧核糖核苷酸或核糖核苷酸或其类似物，其已与至少约50％的当从来源细胞分离总核酸时与核酸分子一起被天然发现的多肽、肽、脂质、糖类、多核苷酸或其他材料分离。在一些实施方式中，分离的核酸分子大体上不含任何其他污染性核酸分子或在核酸的天然环境中发现的可干扰其在多肽产生中的用途或其治疗性、诊断性、预防性或研究用途的其他分子。
本发明提供了一种包含表达载体的宿主细胞，在本发明中，“重组宿主细胞”、“宿主细胞”、“细胞”、“细胞系”、“细胞培养物”和其他表示微生物或作为单细胞实体培养的更高级别真核细胞系可以互换使用，其能够用作，或已经用作重组载体或其他转染的DNA的接受者，并且包括已转染的原始细胞的原始子代。所述表达载体用于表达本发明所述的针对N蛋白的抗体或本发明描述的抗体或其功能片段。在本发明中有用的宿主细胞包括但不限于真核宿主细胞。优选的真核宿主细胞包括但不限于哺乳动物宿主细胞、昆虫宿主细胞、植物宿主细胞、真菌宿主细胞、真核藻类宿主细胞、线虫宿主细胞、原生动物宿主细胞和鱼宿主细胞。优选地，哺乳动物宿主细胞包括但不限于中国仓鼠卵巢(CHO)细胞、COS细胞、Vero细胞、SP2/0细胞、NS/0骨髓瘤细胞、人胚胎肾(HEK293)细胞、幼仓鼠肾(BHK)细胞、HeLa细胞、人B细胞、CV-1/EBNA细胞、L细胞、3T3 细胞、HEPG2细胞、PerC6细胞或MDCK细胞。优选的真菌宿主细胞包括曲霉菌属(Aspergillus)、脉孢菌属(Neurospora)、酵母属(Saccharomyces)、毕赤酵母属(Pichia)、汉逊酵母属(Hansenula)、裂殖酵母属(Schizosaccharomyces)、克鲁维酵母属(Kluyveromyces)、子囊菌酵母属(Yarrowia)和假丝酵母属 (Candida)。在本发明的实施方式中，宿主细胞是HEK293细胞。
本发明使用的术语“药学上可接受的载体”是指在药物生产领域中广泛采用的辅助物料。使用载体的主要目的在于提供一种使用安全、性质稳定和/或具有特定功能性的药物组合物，还在于提供一种方法，以便在为受试者施用药物之后，活性成分能够以所期望的速率溶出，或者促进活性成分在接受给药的受试者体内得到有效吸收。药学上可接受的载体可以是具有惰性的填充剂，也可以是为所述的抗N蛋白的抗体或其抗原结合片段、核酸分子、表达载体、宿主细胞等任一种药物组合物提供某种功能(例如稳定组合物的整体pH值或防止组合物中活性成分的降解)的功效成分。药学上可接受的载体的非限制性实例包括但不限于粘合剂、助悬剂、乳化剂、稀释剂(或填充剂)、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂、甜味剂等。
如本发明所使用的，术语“转化”、“转染”具有本领域技术人员普遍理解的意思，即将外源性的DNA导入宿主的过程。所述转化、转染的方法包括任何将核酸导入细胞的方法，这些方法包括但不限于电穿孔法、磷酸钙(CaPO4)沉淀法、氯化钙(CaCl2)沉淀法、微注射法、聚乙二醇(PEG)法、DEAE-葡聚糖法、阳离子脂质体法以及乙酸锂-DMSO法。
如本发明所使用的，“治疗”是指：在冠状病毒感染导致相关疾病之后，使受试者接触(例如给药)本发明的抗N蛋白抗体或其抗原结合片段、核酸分子、表达载体、宿主细胞、药物组合物等，从而与不接触时相比使该疾病的症状减轻，并不意味着必需完全抑制疾病的症状。在其中一个具体的示例中，新型冠状病毒感染相关疾病为新型冠状病毒肺炎(COVID-19)。
如本发明所使用的，“预防”是指：在冠状病毒感染之前，使受试者接触(例如给药)本发明的抗N蛋白抗体或其抗原结合片段、核酸分子、表达载体、宿主细胞等，从而与不接触时相比减少冠状病毒感染导致疾病的发生率，。在其中一个具体的示例中，新型冠状病毒感染相关疾病为新型冠状病毒肺炎(COVID-19)。
如本发明所述，术语“生物受试者”、“受试者”、“个体”在本发明中可互换使用来指动物受试者，特别是脊椎动物受试者，更特别是哺乳动物受试者。落在本发明的范围内的合适的脊椎动物包括但不限于脊索动物亚门的任何成员，包括灵长目动物(例如，人、猿、猴、黑猩猩)、啮齿动物(例如，小鼠、大鼠、豚鼠)、兔形目动物(例如，家兔、野兔)、牛科动物(例如，牛)、绵羊类动物(例如，绵羊)、山羊类动物(例如，20山羊)、猪类动物(例如，猪)、马科动物(例如，马)、犬科动物(例如，狗)、猫科动物(例如，猫)、鸟类动物(例如，鸡；鸭；鹅；陪伴鸟类，诸如金丝雀、虎皮鹦鹉等)、海洋哺乳动物(例如，海豚、鲸鱼)、爬行动物(例如，蛇、青蛙、蜥蜴等)和鱼。优选的受试者是灵长目动物(例如，人、猿、猴、黑猩猩)、和啮齿动物(例如，小鼠、大鼠、豚鼠)。
当在实验室环境中处理样本时，可能获得最可靠的结果。例如，可在医生办公室中从受试者获取样本，然后将其发送到医院或商业医学实验室进行进一步测试。然而，在许多情况下，可能希望在临床医生的办公室提供即时结果或允许受试者在家中进行测试。在一些情况下，对于便携式、预包装、一次性的、可由受试者在无协助或指导等的情况下即可使用等等的测试的需求比高度准确度更为重要。在许多情况下，尤其是在有医师随访的情况下，进行初步测试，甚至灵敏度和/或特异度降低的测试也可能就足够了。因此，以产品形式提供的测定可涉及检测和测量相对少量的受试者样本的N蛋白，以降低测定的复杂性和成本。可使用本发明所述的能够检测样本冠状病毒N蛋白的任何形式的样本测定。通常，所述测定将定量样本中抗体至一定的程度，例如它们的浓度或量是高于还是低于预定阈值。此类试剂盒包括胶体金免疫试剂盒、化学发光试剂盒、放射免疫试剂盒、酶联免疫试剂盒(ELISA)、荧光免疫试剂盒或微流体芯片。需要指明的是本发明所述的检测方法和试剂盒不仅应用于对患者(人、动物)的样品进行检测，也包括对环境中的环境样品包括但不限于水样品、食物样品、空气样品、微生物样品、动物细胞样品、地表物质、土壤样品、晶体样品和工业样品等多种样品的非诊断目的的检测。
在本发明中，术语“样本”以其最广泛的意义使用。在某种情况下，样本包括细胞(例如细菌、酵母和真菌)、有机体、从任何来源获得的试样或培养物，以及生物和环境样品。其中，生物样品可从动物(包括人)获得并且指在其中发现的生物材料或组合物，包括但不限于骨髓、组织间液、尿液、脑脊液、核酸、 DNA、血液、血清、血小板、血浆、组织以及其纯化或过滤形式；环境样品包括但不限于水样品、食物样品、空气样品、微生物样品、动物细胞样品、地表物质、土壤样品、晶体样品和工业样品。
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HEK293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OP2，序列如表2所示。
表2单克隆抗体OP2的序列
实施例2单克隆抗体OP2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536mg/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OP2凝胶电泳纯度测定所用仪器设备
| 名称 | 生产厂家 | 型号 |
| 化学发光成像仪 | Tanon | Tanon-5200 |
| 电泳仪 | BIO-RAD | poweerpac basic |
| 电泳槽 | BIO-RAD | DYC-Mini4 |
2)主要试剂
表4单克隆抗体OP2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OP2 HPLC纯度测定所用仪器设备
2)主要试剂
表6单克隆抗体OP2 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OP2 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OP2结合活性测定所用仪器设备
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OP2可以与抗原N蛋白特异性结合， EC50为0.01134μg/ml。且可以与冠状病毒SARS-COV2变异株B1617特异性结合，EC50为0.01664μg/ml。
综上，本发明中的抗体OP2与冠状N蛋白抗原或冠状病毒变异株具有较好的结合活性，可用于临床检测冠状病毒SARS-COV2，提高冠状病毒原蛋白或其变异株的检测准确率。
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> 一种抗冠状病毒N蛋白的抗体及其应用
<141> 2022-06-22
<160> 18
<170> SIPOSequenceListing 1.0
<210> 20
<211> 419
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
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Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg
20 25 30
Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn
35 40 45
Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu
50 55 60
Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro
65 70 75 80
Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly
85 90 95
Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr
100 105 110
Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp
115 120 125
Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp
130 135 140
His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
145 150 155 160
Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
165 170 175
Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn
180 185 190
Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala
195 200 205
Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu
210 215 220
Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln
225 230 235 240
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 Asp 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
<210> 2
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gly Ser Thr Phe Ser Asn Phe Gly Met
1 5
<210> 3
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ser Ser Ala Ser Ser Ile Ile
1 5
<210> 4
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Ala Arg Ser Ala Met Asp Tyr
1 5
<210> 5
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser
20 25
<210> 6
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala Tyr
1 5 10 15
Ile
<210> 7
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Tyr Tyr Ala Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
1 5 10 15
Pro Lys Asn Thr Leu Phe Leu Gln Met Thr Ser Leu Arg Ser Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 8
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 9
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Asn Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ala Ser Ser Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 10
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Tyr Ser Gly Asp Ser Tyr
1 5
<210> 11
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Ala Ala Ser
1
<210> 12
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gln Gln Ser Glu Glu Gln Pro Tyr Thr
1 5
<210> 13
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asn
20 25 30
<210> 14
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
1 5 10 15
Tyr
<210> 15
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
1 5 10 15
Thr Asp Phe Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala
20 25 30
Thr Tyr Tyr Cys
35
<210> 16
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 17
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asn Tyr Ser
20 25 30
Gly Asp Ser Tyr Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Glu
85 90 95
Glu Gln Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 18
<211> 419
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
1 5 10 15
Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg
20 25 30
Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn
35 40 45
Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu
50 55 60
Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro
65 70 75 80
Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly
85 90 95
Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr
100 105 110
Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp
115 120 125
Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp
130 135 140
His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
145 150 155 160
Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
165 170 175
Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn
180 185 190
Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Met Gly Thr Ser Pro Ala
195 200 205
Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu
210 215 220
Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln
225 230 235 240
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)
1.一种抗体或其抗原结合片段，其特征在于，所述抗体或其抗原结合片段包括重链可变区的互补决定区CDR1、CDR2、CDR3和/或轻链可变区的互补性决定区域CDR1、CDR2、CDR3；重链可变区CDR1、CDR2、CDR3的氨基酸序列分别如SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4所示；轻链可变区CDR1、CDR2、CDR3的氨基酸序列分别如SEQ ID NO:10、SEQ ID NO:11、SEQID NO:12所示；
优选地，所述抗体或其抗原结合片段为抗冠状病毒N蛋白的抗体或其抗原结合片段；
优选地，冠状病毒选自SARS-CoV-2、MERS-CoV、SARS-CoV；
优选地，所述冠状病毒为SARS-CoV-2。
2.根据权利要求1所述的抗体或其抗原结合片段，其特征在于，所述抗体的重链可变区的氨基酸序列包括如SEQ ID NO:9所示的序列或与其具有至少90％的同一性的序列；轻链可变区的氨基酸序列包括如SEQ ID NO:17所示的序列或与其具有至少90％的同一性的序列。
3.根据权利要求1或2所述的抗体或其抗原结合片段，其特征在于，所述抗体的抗原结合片段包括Fab、Fab′、F(ab′)2、Fv或单链抗体。
4.一种分离的核酸分子，其特征在于，所述核酸分子编码权利要求1-3中任一项所述的抗体或其抗原结合片段；
优选地，所述载体还包含与本发明第一方面所述的抗体或其抗原结合片段可操作性地连接的信号肽。
5.一种表达载体，其特征在于，所述表达载体包括权利要求4所述的核酸分子。
6.一种宿主细胞，其特征在于，所述宿主细胞包括权利要求4所述的核酸分子或权利要求5所述的表达载体；
优选地，所述宿主细胞选自原核生物或真核生物；
优选地，所述宿主细胞选自真核生物；
优选地，所述宿主细胞选自哺乳动物细胞；
优选地，所述宿主细胞选自HEK293细胞。
7.一种药物组合物，其特征在于，所述该药物组合物包含权利要求1-3中任一项所述的抗体或其抗原结合片段、权利要求4所述的核酸分子、权利要求5所述的表达载体、权利要求6所述的宿主细胞和/或药学上可接受的载体。
8.一种检测产品，其特征在于，所述检测产品包括权利要求1-3中任一项所述的抗体或其抗原结合片段、权利要求4所述的核酸分子、权利要求5所述的表达载体和/或权利要求6所述的宿主细胞；
优选地，所述产品包括试剂盒；
优选地，所述试剂盒包括胶体金免疫试剂盒、化学发光试剂盒、放射免疫试剂盒、酶联免疫试剂盒(ELISA)、荧光免疫试剂盒或微流体芯片。
9.一种方法，其特征在于，所述方法包括以下任一种：
1)一种产生权利要求1-3中任一项所述的抗体或其抗原结合片段的方法，所述方法包括培养权利要求6所述的宿主细胞，并且回收得到所述的抗体或其抗原结合片段；
2)一种检测冠状病毒感染的方法，所述方法包括将待测样本与权利要求1-3中任一项所述的抗体或其抗原结合片段接触，观察待测样本与抗体或其抗原结合片段的免疫反应，以确定样本中N蛋白的表达水平或冠状病毒感染情况；
优选地，所述方法是非诊断目的检测方法。
10.一种应用，其特征在于，所述应用包括以下任一种：
1)权利要求1-3中任一项所述的抗体或其抗原结合片段、权利要求4所述的核酸分子、权利要求5所述的表达载体、权利要求6所述的宿主细胞、权利要求8所述的检测产品在检测冠状病毒感染中的应用；
2)权利要求1-3中任一项所述的抗体或其抗原结合片段、权利要求4所述的核酸分子、权利要求5所述的表达载体、权利要求6所述的宿主细胞、权利要求7所述的药物组合物在抑制冠状病毒感染中的应用；
3)权利要求1-3中任一项所述的抗体或其抗原结合片段、权利要求4所述的核酸分子、权利要求5所述的表达载体、权利要求6所述的宿主细胞、权利要求8所述的检测产品在制备诊断冠状病毒感染相关疾病的产品中的应用；
4)权利要求1-3中任一项所述的抗体或其抗原结合片段、权利要求4所述的核酸分子、权利要求5所述的表达载体、权利要求6所述的宿主细胞、权利要求7所述的药物组合物在制备预防/治疗与冠状病毒感染相关疾病的药物中的应用；
优选地，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；
优选地，所述冠状病毒选自SARS-CoV-2病毒。
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