CN112574298B - 一种抗西尼罗河病毒的人源中和性抗体 - Google Patents
一种抗西尼罗河病毒的人源中和性抗体 Download PDFInfo
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Abstract
本发明公开了一种抗西尼罗河病毒的人源中和性抗体，该抗体的特异性结合抗原是WNV E蛋白的第三结构域，包括轻链CDR1、轻链CDR2、轻链CDR3、重链CDR1、重链CDR2和重链CDR3。本发明的单克隆抗体具有较强的病毒中和活性，可作为临床抗WNV药物的候选。
Description
技术领域
本发明属于生物医药领域，涉及抗病毒抗体，具体涉及一种抗西尼罗河病毒的人源中和性抗体。
背景技术
西尼罗病毒(West Nile virus，WNV)属黄病毒科黄病毒属，为单股正链RNA病毒，与圣路易斯脑炎病毒(Saint-Louis encephalitis virus)和墨累河谷热病毒(MurrayValley fever virus)同属日本脑炎病毒(Japanese encephalitis virus，JEV)血清群，可引起人和动物发生西尼罗河热和西尼罗病毒脑膜脑炎，库蚊属的蚊子是其主要的传播媒介，鸟类是该病毒的中间宿主，而人和马则是终端宿主。WNV病广泛分布于非洲、中东、欧洲的部分地区。1999年夏季，WNV首次登陆美国，随后几年内在北美和中美洲迅速传播，导致美国和加拿大等国家历史上虫媒病毒感染的最大流行。虽然我国至今没有WNV疫情发生，但周边国家和地区己经爆发该疫病，随时有输入性传播的可能，而且作为一种潜在的生物战剂，存在被用于生物恐怖袭击的可能，加强相关领域的技术储备，对于我国的公共卫生及生物安全保障具有重要意义。
WNV抗原的检测可以通过细胞培养分离技术和噬斑滴定、传统的RT-PCR、实时荧光RT-PCR和免疫组织化学等方法进行。其中RT-PCR和实时荧光RT-PCR可以快速检测病毒抗原，但该方法成本昂贵，容易出现由于样品污染而呈假阳性结果；通过细胞培养技术分离病毒和检测样品中的病毒噬斑也可以检测病毒抗原，但该方法检测周期长，且需要专业的技术人员以及BSL-3生物安全试验室，因而在大范围检测中难以普及；而利用抗原捕获ELISA、间接免疫荧光、免疫组化等方法可以快速、灵敏地检测WNV抗原，适于在大规模的监测系统中应用。抗原捕获ELISA、间接免疫荧光、免疫组化等检测方法的应用依赖于针对WNV抗原特异性的单克隆抗体的研制。
西尼罗病毒粒子表面有两个膜蛋白：M蛋白和E蛋白。其中E蛋白是主要的膜蛋白，与病毒和受体细胞的识别、结合和病毒的毒力有关。晶体结构分析表明E蛋白包含三个结构域：即结构域I、II和III，其中结构域III(EDIII)被认为是诱导病毒特异性抗体和中和抗体的主要抗原表位。本申请的研究目的是开发以EDIII作为抗原表位的抗WNV的中和抗体。
发明内容
本发明的主要目的在于提供一种单克隆抗体，所述单克隆抗体是以西尼罗病毒的E蛋白第三结构域作为抗原制备而成。
为了实现上述目的，本发明采用了如下技术方案：
本发明第一方面，提供了一种单克隆抗体或其抗原结合片段，所述单克隆抗体或其抗原结合片段包括轻链CDR1、轻链CDR2、轻链CDR3、重链CDR1、重链CDR2和重链CDR3；
重链CDR1具有SEQ ID NO:1所示的氨基酸序列；
重链CDR2具有SEQ ID NO:2所示的氨基酸序列；
重链CDR3具有SEQ ID NO:3所示的氨基酸序列；
轻链CDR1具有SEQ ID NO:5所示的氨基酸序列；
轻链CDR2具有SEQ ID NO:6所示的氨基酸序列；
轻链CDR3具有SEQ ID NO:7所示的氨基酸序列。
在一优选例中，所述单克隆抗体的重链可变区具有SEQ ID NO:4所示的氨基酸序列；所述单克隆抗体的轻链可变区具有SEQ IDNO:8所示的氨基酸序列。
本发明的单克隆抗体，其重链类型可以为IgG1、IgG2、IgG3或Ig4。
本发明单克隆抗体，其轻链类型为κ或λ。
本发明的单克隆抗体不仅包括可变区，还包括恒定区，恒定区可以为人IgG1、IgG2、IgG3或IgG4中的任意一种。
进一步，所述单克隆抗体的抗原结合片段包括但不限于Fab、F(ab’)、F(ab’)2、Fv、dAb、Fd、互补决定区(CDR)片段、单链抗体(scFv)、二价单链抗体、单链噬菌体抗体、双特异双链抗体、三链抗体、四链抗体以及至少含有足以赋予与PD-1结合免疫球蛋白的片段的(多)肽或其片段。
包括优选抗体氨基酸序列的保守序列变体的抗体也包括在本发明的范围之内。保守氨基酸序列变体包括不显著改变本发明的单克隆抗体结合性质的氨基酸序列的修饰，如源于本领域熟知的相似氨基酸替代的变体，氨基酸的缺失、增加导致的变体。
相似氨基酸替代包括其中氨基酸残基由具有相似结构或者化学性质的另一氨基酸残基置换的取代。具有相似侧链的氨基酸残基的家族己经在本领域中限定。这些家族包括具有碱性侧链的氨基酸(例如赖氨酸、精氨酸、组氨酸)、酸性侧链氨基酸(例如天冬氨酸、谷氨酸)、无电荷极性侧链氨基酸(例如天冬酞胺、谷氨酞胺、丝氨酸、苏氨酸、酪氨酸、半肤氨酸、色氨酸)、非极性侧链氨基酸(例如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、分支侧链氨基酸(例如苏氨酸、缬氨酸、异亮氨酸)以及芳香侧链氨基酸(例如酪氨酸、苯丙氨酸、色氨酸)。本领域技术人员明白也可以使用除了上述家族之外的其它氨基酸残基家族分类方式。另外，变体可具有非保守的氨基酸取代，例如氨基酸由具有不同结构或者化学性质的另一氨基酸残基置换。相似的小变异也可包括氨基酸缺失或者插入，或者这二者。使用本领域熟知的计算机程序可以发现确定哪些氨基酸残基可以被取代、插入或者缺失而不消除免疫学活性的指导。
本发明的单克隆抗体可以在重链和轻链可变区包含一个或多个糖基化位点，如本领域内熟知的，在可变区中存在的一个或多个糖基化位点可以导致增强的抗体免疫原性，或者由于改变了抗原结合而改变抗体的药物动力学。
本发明的单克隆抗体可以被设计为在Fc区域内包含修改，通常是改变抗体的1个或多个功能特性，如血清半衰期、补体结合、Fc受体结合、和/或抗原依赖的细胞毒性。此外，本发明的抗体可以被化学修饰(如，可以将一个或多个化学基团连接于抗体)，或被修饰以改变其糖基化，从而再改变抗体的一个或多个功能特性。
本发明的单克隆抗体可以被设计的另一个修饰是聚乙二醇化。抗体可被聚乙二醇化，从而，例如，增加抗体的生物(如血清)半衰期。为了使抗体聚乙二醇化，该抗体或其片段通常在适合于一个或多个聚乙二醇(PEG)基团连接到该抗体或抗体片段的条件下，与PEG反应，如聚乙二醇的活性酯或醛衍生物。优选地，该聚乙二醇化是通过与活性的PEG分子(或类似的活性水溶性聚合物)进行酰化反应或烷基化反应而实现。
本发明第二方面，提供了一种编码本发明第一方面的单克隆抗体或其抗原结合片段的多核苷酸。
所述多核苷酸序列如SEQ ID NO:9-SEQ ID NO:16所示。
其中，重链CDR1对应的多核苷酸序列如SEQ IDNO:9所示，重链CDR2对应的多核苷酸序列如SEQ IDNO:10所示，重链CDR3对应的多核苷酸序列如SEQ IDNO:11所示，重链可变区对应的多核苷酸序列如SEQ IDNO:12所示，轻链CDR1对应的多核苷酸序列如SEQ IDNO:13所示，轻链CDR2对应的多核苷酸序列如SEQ IDNO:14所示，轻链CDR3对应的多核苷酸序列如SEQ IDNO:15所示，轻链可变区对应的多核苷酸序列如SEQ IDNO:16所示。
本发明第三方面，提供了一种含有本发明第二方面的多核苷酸的重组载体。
本发明第四方面，提供了一种宿主细胞，所述宿主细胞含有本发明第三方面的重组载体或细胞的基因组中整合了外源性的本发明第二方面的多核苷酸。
在另一优选例中，所述宿主细胞是哺乳动物细胞，较佳地，CHO细胞。
本发明第五方面，提供了一种生产本发明第一方面的单克隆抗体的方法，所述方法包括培养本发明第四方面所述的宿主细胞，和收集表达的抗体。
可以使用本领域常用的方法从宿主细胞中收集抗体。例如，离心分离培养基和宿主细胞，高压匀浆破碎细胞、离心过滤去除细胞碎片，亲和层析纯化抗体。对于分离纯化所得的产物，可以使用本领域常用的方法进行纯度鉴定。例如，考马斯亮蓝法、凯氏定氮法、双缩脲法、lowry法、紫外吸收法、亲和层析、抗原抗体法、电泳分析(例如十二烷基磺酸钠聚丙烯酰胺凝胶电泳)、沉降分析、扩散分析、恒溶度法、蛋白质谱等。
本发明第六方面，提供了一种药物组合物，其含有本发明的单克隆抗体或其抗原结合部分。
本发明的药物组合物还可以包括药学上可接受的载体。“药学上可接受的载体”是指生产药品和调配处方时，使用的赋形剂和附加剂，是指除活性成分外，在安全性方面已进行了合理的评估，并且包含在药物制剂中的物质。同一药用载体可用于不同给药途径的药物制剂，且有不同的作用和用途。在本发明提供的药物中添加的药学上可接受的载体，能够起到赋型、或提高稳定性的作用，此外，还具有增溶、助溶或缓控释等重要功能。
典型但非限制性的药学上可接受的载体包括：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、湿润剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂或释放阻滞剂中的一种或多种。填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等；崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素纳等；润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等；助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等；粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等；矫味剂包括：甜味剂及各种香精；防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等；基质包括：PEG6000、PEG4000、虫蜡等。
本发明涉及的药物组合物的剂量水平取决于成分活性、给药途径、待治疗疾病的严重程度以及待治疗患者的情况和前病史。
本发明涉及的药物组合物剂型可以是药学上可接受的任意一种剂型，包括但不限于粉剂、注射剂、胶囊、片剂、缓释剂、口服液。
本发明涉及的药物组合物的给药途径可以是一种或多种任何可能的途径，根据患者状况和其他重要参数，这些途径包括口服、注射、呼吸道、皮肤、直肠和经粘膜。
本发明第七方面，提供了一种缀合物，所述缀合物可以是以化学方法或者通过基因工程将本发明的单克隆抗体或其抗原结合部分与其他因子缀合而成。这些因子提供将抗体靶向所需功能位点的作用或者为抗体提高或提供其他性能；
或
可以是以化学方法或者通过基因工程标记，以提供可检测的抗体；可检测的部分包括但不限于酶、辅基、荧光材料、发光材料，生物发光材料、放射性材料、正电子发射金属以及非放射性顺磁性金属离子。
根据以上提示，本发明还提供了一种检测试剂盒，所述检测试剂盒包括本发明的单克隆抗体或其抗原结合部分。
本发明第八方面，提供了一种非诊断目的的检测WNV的方法，所述方法包括如下步骤：
(1)提取含有WNV的样品；
(2)将步骤(1)获取的样品与本发明的单克隆抗体或其抗原结合部分接触；
(3)检测样品与单克隆抗体或其抗原结合部分的免疫反应。
本发明第九方面，提供了一种非诊断目的的检测WNV的E蛋白的方法，所述方法包括如下步骤：
(1)提取含有WNV的E蛋白的样品；
(2)将步骤(1)获取的样品与本发明的单克隆抗体或其抗原结合部分接触；
(3)检测样品与单克隆抗体或其抗原结合部分的免疫反应。
本发明第十方面，提供了一种抗WNV感染的方法，包括步骤：向需要的对象施用有效量的本发明的单克隆抗体或其抗原结合部分。
本发明涉及的药物施用对象包括哺乳动物或所述哺乳动物感染WNV的细胞。所述哺乳动物优选为啮齿目动物、偶蹄目动物、奇蹄目动物、兔形目动物、灵长目动物等。所述灵长目动物优选为猴、猿或智人。
在一实施方式中，前面所述的方法包括与一种或多种抗WNV药物同时、分别或序贯性地联合施用有效量的本发明的单克隆抗体或其抗原结合部分。
本发明第十一方面，提供了一种本发明的单克隆抗体或其抗原结合部分的用途，所述用途包括以下任一项所述的用途：
(1)制备用于检测WNV或其E蛋白的产品中的用途；
(2)制备抗WNV感染的药物中的用途；
(3)制备预防或治疗WNV感染导致的疾病的药物中的用途。
术语解释
本文术语“单克隆抗体”指从一类基本均一的群体获得的抗体，除少数可能存在的天然发生的突变外，该群体中包含的单个抗体是相同的。修饰语“单克隆”仅表示抗体的特性，是从基本均一的抗体群中获得的，这不能解释成需要用任何特殊方法来生产抗体。
文中术语“Fab”是指含有一条轻链的可变区和恒定区和一条重链的可变区和恒定区经二硫键结合起来的抗体分子的一部分。
文中术语“Fab’”是指包含了部分铰链区的Fab片段。
文中术语“F(ab’)2”指的是Fab’的二聚体。
文中术语“Fv”指的是含有抗体重链可变区、轻链可变区并具有全部抗原结合位点的最小抗体片段。
文中术语“单链抗体”指的是由轻链可变区与重链可变区直接相连或通过一个肽链连接而成的工程抗体。
本文术语“有效量”是指无毒性但足够量的提供所需的作用的药物或药剂。“有效量”会因受试对象的不同而不同，依据年龄和个体的一般情况，特定的活性药物等等。因此，不可能总是一定精确的“有效量”，然而，任何个体病例中合适的“有效量”可以由本领域的普通技术人员应用常规的实验方法来测定。
本文术语“抗WNV感染”指的是预防或治疗WNV感染。
本文术语“治疗”指的是减缓、干扰、停止、减轻、阻碍、减少或逆转现有症状、障碍、病症或疾病的进展或严重程度。
如本文所用，术语“载体”是指表达载体和非表达载体，并包括病毒和非病毒载体，其包括染色体外载体(如，多拷贝质粒)和整合载体(其设计为可并入宿主染色体)。
本发明中的多肽序列均是按照从N端到C端的顺序列出。
附图说明
图1显示本发明的单克隆抗体的SDS-PAGE电泳图，其中A：非还原，B：还原；
图2显示利用ELISA检测本发明的单克隆抗体的抗原结合特异性的结果图；
图3显示利用假病毒中和实验检测本发明的单克隆抗体中和活性的结果图。
具体实施方式
下面结合具体实施例对本发明作更进一步的说明，但本发明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发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1 WN-XH1单克隆抗体制备
1、实验材料
PRT/KIgG1载体(参见专利文献：一种特异性结合PD-1的单克隆抗体，申请号：201810273628.7)
2、步骤
(1)利用基因合成的方法合成抗体重链可变区序列(序列如SEQ ID NO：4所示)、轻链可变区序列(序列如SEQ ID NO:8所示)，并将其利用分子克隆的方法将片段克隆入PRT/KIgGl中。
(2)将步骤1构建的抗体表达重组载体转染对数生长期的293T细胞，转染后6-8小时换新鲜培养基，并在37℃8％CO2培养箱中培养96小时。收集转染上清，4000rpm离心1小时，利用蛋白(Protein)A亲和层析法进行纯化。利用SDS-PAGE和Western Blot实验检验抗体的表达及纯化情况。
3、结果
结果见图1A-B，证实得到较纯蛋白，并可清察到解链后的抗体轻、重链。
实施例2 WN-XH1单克隆抗体结合活性和中和活性测定
1、单克隆抗体结合活性测定
包被液稀释WNV的EDIII抗原至1μg/mL，100μL每孔加入酶联板中，置于湿盒中4℃过夜。洗板机清洗酶联板3次，1.5％酪蛋白封闭，每孔200μL，湿盒37℃封闭1h。用1xPBS稀释抗体到不同浓度，并以100μL每孔加入酶联板中，湿盒中37℃反应1h，清洗酶联板3次，加入羊抗人(Fab')2-HRP二抗室温反应45min，清洗酶联板5次并加入100μL TMB底物显色，反应3min并用100μL2N H2SO4终止反应，酶联免疫检测仪450nm读数。并以抗体浓度为横坐标，OD值为纵坐标绘制抗体-抗原结合曲线。
结果如图2所示，本发明制备的单克隆抗体够特异性识别固相载体上的WNV的EDIII抗原分子，且随着抗体浓度的增加抗原一抗体之间结合具有良好的剂量依赖性。图中的3-14为无关抗体(抗甲型流感病毒H2N2单克隆抗体)作为对照。
2、单克隆抗体中和活性测定
用假病毒在感染BHK21细胞的过程中分别加入WN-XH1抗体进行中和实验，用无关抗体3-14作为对照。具体步骤如下：
1、假病毒包装：
接种293T细胞于6孔板。80％融片后，按照Lipo3000转染试剂说明书，将prWNV-Rluc以及pcDNA3.1-CME以1：1的比例共转染进293T细胞。72hr后收取培养上清。3000rmp，4℃离心10min后，上清经0.45μm的滤膜过滤，添加20％的血清，置-80℃保存。
2、假病毒感染
接种BHK21细胞于96孔细胞培养板，细胞密度为1X105/ml，放置细胞培养箱过夜。将含有WNV病毒样颗粒的上清预先与相应浓度的抗体孵育，室温1hr。之后将病毒样颗粒上清+抗体混合液感染BHK21细胞，同时设置未加抗体的病毒上清和加入无关抗体的病毒上清做为对照。48h后，裂解细胞测荧光素酶活性(RLU)。
结果如图3所示，本发明的单克隆抗体具有中和病毒的中和活性。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。
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<110> 中国人民解放军军事科学院军事医学研究院
<120> 一种抗西尼罗河病毒的人源中和性抗体
<141> 2020-10-09
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65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Ser Tyr Gly Asp Tyr Ala Asp Tyr Trp Gly His Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 5
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 6
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Trp Ala Ser Thr Arg His Thr
1 5
<210> 7
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Gln His Tyr Asn Thr Pro Leu Thr
1 5
<210> 8
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Ser Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Asn Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 9
<211> 15
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
gattattgga ttgaa 15
<210> 10
<211> 51
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
gatattctct atggcaacgg ccgcacccgc tataacgaaa aactgaaagg c 51
<210> 11
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
agcgcgagct atggcgatta tgcggattat 30
<210> 12
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
caggtgcagc tgcagcagag cggcagcgaa ctggtgaaac cgggcgcgag cgtgcatatt 60
agctgcaaag cgaatggcta tacctacagc gattattgga ttgaatgggt gaaacagcgc 120
ccgggccacg gcctggaatg gattggcgat attctctatg gcaacggccg cacccgctat 180
aacgaaaaac tgaaaggcaa ggcgaccttt accgcggata ccagcagcaa caccgcgttt 240
atgcagctga gcagcctgac cagcgaagat agcgcggtgt attattgcgc gcgcagcgcg 300
agctatggcg attatgcgga ttattggggc catggcacca ccctgaccgt gagcagc 357
<210> 13
<211> 33
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
aaagcgagcc aggatgtaag caccgcggtg gcg 33
<210> 14
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
tgggcgagca cccgccatac c 21
<210> 15
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
cagcagcatt ataatacccc gctgacc 27
<210> 16
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
gatattgtga tgacccagag ccataaattt atgagcacca gcgtgggcga tcgcgtgagc 60
attacctgca aagcgagcca ggatgtaagc accgcggtgg cgtggtatca gcagaaaccg 120
ggccagagcc cgaaactgct gattagctgg gcgagcaccc gccataccgg cgtgccggat 180
cgctttaccg gcagcggcag cggcaccgat tataccctga ccattagcag cgtgcaggcg 240
gaagatctgg cgctgtatta ttgccagcag cattataata ccccgctgac ctttggcgcg 300
ggcaccaaac tggaactgaa a 321
Claims (10)
1.一种抗西尼罗河病毒的单克隆抗体或其抗原结合片段，其特征在于，所述单克隆抗体或其抗原结合片段包括轻链CDR1、轻链CDR2、轻链CDR3、重链CDR1、重链CDR2和重链CDR3；
重链CDR1具有SEQ ID NO:1所示的氨基酸序列；
重链CDR2具有SEQ ID NO:2所示的氨基酸序列；
重链CDR3具有SEQ ID NO:3所示的氨基酸序列；
轻链CDR1具有SEQ ID NO:5所示的氨基酸序列；
轻链CDR2具有SEQ ID NO:6所示的氨基酸序列；
轻链CDR3具有SEQ ID NO:7所示的氨基酸序列。
2.根据权利要求1所述的单克隆抗体或其抗原结合片段，其特征在于，所述单克隆抗体的重链可变区具有SEQ ID NO:4所示的氨基酸序列；所述单克隆抗体的轻链可变区具有SEQID NO:8所示的氨基酸序列。
3.一种编码权利要求1或2所述的单克隆抗体或其抗原结合片段的多核苷酸。
4.根据权利要求3所述的多核苷酸，其特征在于，所述多核苷酸序列如SEQ ID NO:9-16所示；其中，重链CDR1对应的多核苷酸序列如SEQ ID NO:9所示，重链CDR2对应的多核苷酸序列如SEQ ID NO:10所示，重链CDR3对应的多核苷酸序列如SEQ ID NO:11所示，重链可变区对应的多核苷酸序列如SEQ ID NO:12所示，轻链CDR1对应的多核苷酸序列如SEQ ID NO:13所示，轻链CDR2对应的多核苷酸序列如SEQ ID NO:14所示，轻链CDR3对应的多核苷酸序列如SEQ ID NO:15所示，轻链可变区对应的多核苷酸序列如SEQ ID NO:16所示。
5.一种含有权利要求4所述的多核苷酸的重组载体。
6.一种宿主细胞，其特征在于，所述宿主细胞含有权利要求5所述的重组载体或细胞基因组中整合了外源性的权利要求3或4所述的多核苷酸。
7.一种生产权利要求1或2所述的单克隆抗体的方法，所述方法包括培养权利要求6所述的宿主细胞。
8.一种药物组合物、缀合物、或检测试剂盒，其特征在于，所述药物组合物、缀合物、或检测试剂盒包括权利要求1或2所述的单克隆抗体或其抗原结合片段。
9.一种非诊断目的的检测WNV或其E蛋白的方法，所述方法包括如下步骤：
(1)提取含有WNV或其E蛋白的样品；
(2)将步骤(1)获取的样品与权利要求1或2所述的单克隆抗体或其抗原结合部分接触；
(3)检测样品与权利要求1或2所述的单克隆抗体或其抗原结合部分的免疫反应。
10.权利要求1或2所述的单克隆抗体或其抗原结合部分的用途，其特征在于，所述用途包括以下任一项所述的用途：
(1)制备用于检测WNV或其E蛋白的产品中的用途；
(2)制备抗WNV感染的药物中的用途；
(3)制备预防或治疗WNV感染导致的疾病的药物中的用途。
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