CN113603786B - 特异性结合SARS-CoV-2 S蛋白和N蛋白的双特异性抗体 - Google Patents
特异性结合SARS-CoV-2 S蛋白和N蛋白的双特异性抗体 Download PDFInfo
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Abstract
本发明涉及免疫检测技术领域,具体而言,涉及一种特异性结合SARS‑CoV‑2 S蛋白和N蛋白的双特异性抗体。通过针对N蛋白的抗体对及针对S蛋白的抗体对的可变区序列构建而获得的双特性抗体,使得其同时针对N蛋白和S蛋白的抗原表位,不仅增强试剂盒的灵敏度和特异性,还可以解决由于突变所引起的假阴性。
Description
技术领域
本发明涉及免疫检测技术领域,具体而言,涉及一种特异性结合SARS-CoV-2 S蛋白和N蛋白的双特异性抗体。
背景技术
冠状病毒(CoVs;冠状病毒科亚科,冠状病毒科,病毒目)是一组高度多样性,有包膜的,正义链,单链RNA病毒,在多种动物中引起不同严重程度的呼吸道,肠道,肝和神经系统疾病,包括人类。冠状病毒分为四个属:α冠状病毒,β冠状病毒(βCoV),γ冠状病毒和δ冠状病毒。在过去的12年中,出现了两种新型的β-冠状病毒,即严重的急性呼吸道综合症(SARS-CoV)和中东呼吸道综合症(MERS-CoV),这两种病毒会引起严重的人类疾病。
2019新型冠状病毒,被世界卫生组织命名为“2019-nCoV”,后被国际病毒分类委员会命名为“严重急性呼吸综合征冠状病毒2(SARS-CoV-2)”。SARS-CoV-2是以前从未在人体中发现的冠状病毒新毒株。其同源性与急性呼吸道综合症(SARS-CoV)达到80%以上,其中的两者的结构蛋白Nucleocapsid protein同源性为94.1%,两者的Spike protein同源性为84.1%。SARS-CoV-2 IgM抗体的检测,同时结合SARS-CoV-2 IgG抗体的检测,可以用于辅助诊断新型冠状病毒疾病(COVID-19),是新冠核酸诊断试剂的有效补充。新冠IgM和IgG检测试剂盒的开发,关键在于SARS-CoV-2有效抗原的获得。SARS-CoV-2结构蛋白有刺突蛋白(Spike protein,跨膜蛋白,同源三聚体结构,如“冠状”分布于病毒表面,是介导病毒感染细胞的核心组分)、核衣壳蛋白(Nucleoprotein,是新冠病毒结构蛋白中表达丰度最高的组分)、包膜蛋白(Envelope Protein)和膜蛋白(Membrane Protein),其中根据蛋白的丰度和空间位置,用于IgM和IgG诊断的主要是核衣壳蛋白以及刺突蛋白。但由于核衣壳蛋白的保守性较强,且由于被包裹在病毒内,机体针对其产生的抗体特别是IgM抗体比较晚。因此,新冠抗体诊断试剂特别是IgM抗体诊断,主要使用的刺突蛋白。
现有的检测新型冠状病毒的方法有两种,其一是核酸检测,主要通过咽、鼻拭子样品提取基因组后,通过特定的探针和引物,使用qPCR的方法进行分析。虽然该方法是新型冠状病毒感染诊断的金标准,但是操作过程繁琐,涉及到基因提取、处理、分析的步骤,操作要求和时间较长。对操作人员操作水平要求较高,而且容易因为样本提取质量的影响等原因而造成假阴性。其二是通过重组表达新型冠状病毒结构蛋白如N抗原或者刺突蛋白,用于检测血液样本中的IgG、IgM或者IgA抗体,以间接指示病毒的感染情况。但是检出时间相对较晚,IgM抗体一般需要在感染的7天后方可出测,IgG抗体一般需要在感染的14天后方可检出。
面对全球严峻和复杂的疫情形势,世界卫生组织、全球创新诊断基金会大力推进更快更便捷的检测手段-抗原检测,抗原检测试剂相比核酸检测试剂成本低、操作方便、用时更短;抗原检测试剂相比抗体检测试剂检测时间提前、速度快、群体性筛查方便。
现有技术常常使用可特异性识别新型冠状病毒N抗原或S抗原的单克隆抗体对,检测新型冠状病毒的抗原,来反映新冠病毒含量,尽管N抗原的含量丰富和高度保守,但是灵敏度较低,在病毒滴度较低时如感染的早期阶段,难以对阴、阳性样本进行区分了;而新冠S蛋白属于突变的高发区域,容易造成漏检。
有鉴于此,特提出本发明。
发明内容
本发明涉及双特异性抗体,其包括靶向SARS-CoV-2 N蛋白的第一功能域和靶向SARS-CoV-2 S蛋白的第二功能域;
其中所述第一功能域具有a或b所述的互补决定区,所述第二功能域具有c或d所述的互补决定区;
本发明还涉及核酸,其编码如上所述的双特异性抗体。
本发明还涉及载体,其包含如上所述的核酸。
本发明还涉及宿主细胞,其包含如上所述的核酸或被如上所述的载体所转化。
本发明还涉及生产如上所述的双特异性抗体的方法,包括:
在合适的培养条件下培养如上所述的宿主细胞;以及
从培养基中或从所培养的宿主细胞中回收如此产生的双特异性抗体。
本发明还涉及试剂或者试剂盒,其包含如上所述的双特异性抗体。
本发明还涉及如上所述的双特异性抗体在制备SARS-CoV-2诊断试剂或者试剂盒中的应用。
本发明的有益效果为:
通过针对N蛋白的抗体对及针对S蛋白的抗体对的可变区序列构建而获得的双特性抗体,使得其同时针对N蛋白和S蛋白的抗原表位,不仅增强试剂盒的灵敏度和特异性,还可以解决由于突变所引起的假阴性。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明一个实施例中N-Ab-01抗体亲和力检测结果;
图2为本发明一个实施例中N-Ab-02抗体亲和力检测结果;
图3为本发明一个实施例中S-Ab-01抗体亲和力检测结果;
图4为本发明一个实施例中S-Ab-02抗体亲和力检测结果;
图5为本发明一个实施例中pFUSE-CHIg-mG1的载体图谱;
图6为本发明一个实施例中pFUSE2-CLIg-mk的载体图谱;
图7为本发明一个实施例中双特异性抗体构建的示意图;
图8为本发明一个实施例中制备的双特异性抗体SDS-PAGE电泳图;
图9为本发明一个实施例中制备的NS-Ab-01抗体亲和力检测结果;
图10为本发明一个实施例中制备的NS-Ab-02抗体亲和力检测结果。
具体实施方式
现将详细地提供本发明实施方式的参考,其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上,对本领域技术人员而言,显而易见的是,可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如,作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中,来产生更进一步的实施方式。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本发明涉及一种双特异性抗体,其包括靶向SARS-CoV-2 N蛋白的第一功能域和靶向SARS-CoV-2 S蛋白的第二功能域;
其中所述第一功能域具有a或b所述的互补决定区,所述第二功能域具有c或d所述的互补决定区;
在一些实施方式中,所述双特异性抗体具有a和c所述的互补决定区。
在一些实施方式中,所述双特异性抗体具有a和d所述的互补决定区。
在一些实施方式中,所述双特异性抗体具有b和c所述的互补决定区。
在一些实施方式中,所述双特异性抗体具有b和d所述的互补决定区。
术语“互补性决定区”或“CDR”是指免疫球蛋白的重链和轻链的高度可变区,如Kabat等人所定义(Kabat等人,Sequences of proteins of immunological interest,5thEd"US Department of Health and Human Services,NIH,1991,和后来的版本)。有三种重链CDR和三种轻链CDR。此处,取决于情况,术语“CDR”和“CDRs”用于指包含一种或多种或者甚至全部的对抗体与其识别的抗原或表位的结合亲和力起作用的主要氨基酸残基的区域。在另一具体实施方式中,CDR区或CDR是指IMGT定义的免疫球蛋白的重链和轻链的高度可变区。
术语“重链”在本文中理解为包括全长重链,该重链包含具有决定抗原特异性的氨基酸序列的可变区(VH)和具有三个恒定结构域(CH1、CH2和CH3)或四个恒定结构域(CH1、CH2、CH3和CH4)的恒定区,以及它们的片段。同样,术语“轻链”在本文中包括全长轻链,该轻链包含具有决定抗原特异性的氨基酸序列的可变区(VL),还包含恒定区(CL),以及它们的片段。此外,在本发明中,若非特别强调,可变区从由如下顺序串联得到FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
术语“特异性结合”、“选择性结合”、“选择性地结合”和“特异性地结合”是指抗体对预先确定的抗原上的表位的结合。通常,抗体以大约小于10-4M、10-5M、10-6M、10-7M、10-8M、10-9M或10-10M或更小的亲和力(KD)结合。靶向通常是特异性结合。
抗体的变体也在本发明范围内,例如各自与本发明所述的各个CDR或FR、或可变区VL和/或VH、或抗体全长的氨基酸或核苷酸序列具有至少70%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或高于99%同一性的序列。在一些情况下,抗体的变体至少包括上述6个CDR;在一些情况下,抗体的变体至少包括一个重链和一个轻链,而在其他情况下,变体形式含有两个相同的轻链和两个相同的重链(或其子部分)。在一些情况下,抗体的变体是在本发明所提供的抗体序列上发生保守修饰或保守置换或取代所得到的。“保守修饰”或“保守置换或取代”是指具有类似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚性等)的其它氨基酸置换蛋白中的氨基酸,使得可频繁进行改变而不改变蛋白的生物学活性。本领域技术人员知晓,一般而言,多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性(参见例如Watson等(1987)Molecular Biology of theGene,The Benjamin/Cummings Pub.Co.,第224页,(第4版))。另外,结构或功能类似的氨基酸的置换不大可能破环生物学活性。所属领域技术人员将能够使用熟知的技术确定如本文所阐明的抗原结合分子的合适变体。对于核苷酸和氨基酸序列,术语“同一性”表明当具有适当的插入或缺失的情况下最佳比对和比较时两个核酸或两个氨基酸序列之间的同一性程度。
在一些实施方式中,所述第一功能域均位于所述双特异性抗体靠近N端的位置,所述第二功能域均位于所述双特异性抗体靠近C端的位置。
在一些实施方式中,所述第一功能域均位于所述双特异性抗体靠近C端的位置,所述第二功能域均位于所述双特异性抗体靠近N端的位置。
在一些实施方式中,所述双特异性抗体是小鼠来源抗体、人-小鼠嵌合抗体或人源化抗体。
术语“嵌合抗体(chimeric antibody)”,是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体,可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体,要先建立分泌鼠源性特异性单抗的杂交瘤,然后从鼠杂交瘤细胞中克隆可变区基因,再根据需要克隆人抗体的恒定区基因,将鼠可变区基因与人恒定区基因连接成嵌合基因后插入表达载体中,最后在真核系统或原核系统中表达嵌合抗体分子。
术语“人源化抗体(humanized antibody)”,也称为CDR移植抗体(CDR-graftedantibody),是指将鼠的CDR序列移植到人的抗体可变区框架,即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量鼠蛋白成分,从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(www.mrccpe.com.ac.uk/vbase)获得,以及在Kabat,E.A.等人,1991,Sequences ofProteins of Immunological Interest,第5版中找到。为避免免疫原性下降的同时,引起的活性下降,可对所述的人抗体可变区框架序列进行最少反向突变或回复突变,以保持活性。为避免免疫原性下降的同时,引起的活性下降,可对所述的人抗体可变区可进行最少反向突变,以保持活性。
在一些实施方式中,所述的双特异性抗体还包括与a~d所述的互补决定区依次对应的骨架区,它们与所述互补决定区所组成的重链和轻链可变区片段如a'~d'所示:
在一些实施方式中,所述双特异性抗体具有双特异轻链可变区和双特异重链可变区;
在一些实施方式中,从N端到C端,b'和d'中的轻链可变区通过第一连接肽融合得到所述双特异轻链可变区;b'和d'中的重链可变区通过第二连接肽融合得到所述双特异重链可变区。
在一些实施方式中,从N端到C端,b'和d'中的轻链可变区通过第一连接肽融合得到所述双特异轻链可变区;b'和d'中的重链可变区通过第二连接肽融合得到所述双特异重链可变区。
在一些实施方式中,所述第一连接肽融和所述第二连接肽均为柔性连接肽。
连接肽是柔性的,可以减少融合蛋白与目的蛋白之间的空间位阻,从而更有利于蛋白正确折叠。
在一些实施方式中,所述柔性连接肽的氨基酸是不具有除连接以外的额外功能(例如蛋白定位、酶切位点等)的无意义多肽。
在一些实施方式中,所述柔性连接肽的氨基酸序列选自Gly、Ser、Pro、Ala以及Glu中的一种或多种。
在一些实施方式中,所述第一连接肽融和所述第二连接肽的氨基酸序列独立的选自(GGS)n、(GGGS)n或(GGGGS)n,其中n为正整数。
在一些实施方式中,n选自1,2,3,4,5或6。
所第一连接肽及所述第二连接肽的氨基酸序列均如SEQ ID NO:33所示。
在一些实施方式中,所述的双特异性抗体还具有恒定区。
在一些实施方式中,重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任意一种的恒定区。
在一些实施方式中,轻链恒定区为κ或λ链。
在一些实施方式中,所述恒定区的种属来源为牛、马、猪、羊、大鼠、小鼠、狗、猫、兔、骆驼、驴、鹿、貂、鸡、鸭、鹅或人。
在一些实施方式中,所述双特异性抗体还可以包括分泌信号序列。
分泌信号序列是指,通过连接至编码序列位于细胞膜外侧或细胞外侧的N端而诱导所表达的蛋白或肽的分泌的序列,所述信号序列可以是由约18~30个氨基酸组成的肽序列。所有能转运到细胞膜外侧的蛋白有不同的信号序列,所述信号序列被细胞膜上的信号肽酶切割。通常,对于并非宿主细胞天然表达的外来蛋白而言,可以采用能将该蛋白分泌到细胞周质或培养基中的分泌信号序列,或采用修饰的序列。
在一些实施方式中,所述双特异性抗体具有可检测的标记。
在一些实施方式中,所述可检测的标记包括荧光物质、量子点、地高辛标记探针、生物素、放射性同位素、放射性造影剂、顺磁离子荧光微球、电子致密物质、化学发光标记物、超声造影剂、光敏剂、胶体金或酶中的任一种。
本发明还涉及分离的核酸,其编码如上所述的双特异性抗体。
核酸通常是RNA或DNA,核酸分子可以是单链或双链的,但优选是双链DNA。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。当其连入载体时优选采用DNA核酸。此外,核酸分子可根据不同的宿主细胞进行密码子优化。
本发明还涉及载体,其包含如上所述的的核酸。
术语“载体(vector)”是指,可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。在一些实施方式中,本发明所述载体中包含基因工程中常用的调控元件,例如增强子、启动子、内部核糖体进入位点(IRES)和其他表达控制元件(例如转录终止信号,或者多腺苷酸化信号和多聚U序列等)。
本发明还提供宿主细胞,其包含如上所述的核酸或被如上所述的载体所转化。
适用于表达本发明的抗原结合蛋白的宿主细胞或细胞系包括:哺乳动物细胞诸如NS0、Sp2/0、CHO、COS、HEK、成纤维细胞和骨髓瘤细胞。可以使用人细胞,因而允许分子用人糖基化模式来修饰。或者,可以采用其他真核细胞系。合适的哺乳动物宿主细胞的选择,以及用于转化、培养、扩增、筛选和产物产生和纯化的方法,是本领域已知的。
可以证明,细菌细胞可用作宿主细胞。用于表达的各种大肠杆菌菌株,是生物技术领域中众所周知的宿主细胞。枯草芽孢杆菌、链霉菌属、其他芽孢杆菌属等的各种菌株,也可以用于该方法中。
如果需要,本领域技术人员已知的酵母细胞菌株以及昆虫细胞,例如果蝇和鳞翅目昆虫和病毒表达系统,也可用作宿主细胞。
根据本发明的再一方面,还涉及生产如上所述的双特异性抗体的方法,包括:
在合适的培养条件下培养如上所述的宿主细胞;以及
从培养基中或从所培养的宿主细胞中回收如此产生的双特异性抗体。
本发明还涉及试剂或者试剂盒,其包含如上所述的双特异性抗体。
本发明还涉及如上所述的双特异性抗体在制备SARS-CoV-2诊断试剂或者试剂盒中的应用。
上述用途的受试者可以指患者或怀疑携带有SARS-CoV-2的动物,特别是哺乳动物,例如蝙蝠、果子狸;优选为灵长类动物,更优选为人。
使用本发明的重组抗原,制备新型冠状病毒抗体检测试剂盒或试纸条,可有效提高试剂的灵敏度和检出率。
本发明还涉及一种检测SARS-CoV-2病毒的方法,包括:
使用如上所述的多肽、试剂盒或试纸条检测SARS-CoV-2抗原。
在一些实施方式中,所述检测的受试样品选自生物组织或其灌洗液、细胞、体液,进一步选自血液、血清、血浆、抗凝血、细胞培养上清、唾液、精液、羊水、绒毛、组织或组织裂解液、咽拭子、鼻拭子、眼结膜拭子、粪便标本、粪便、尿液、支气管灌洗液、肺泡灌洗液、痰液。
下面将结合实施例对本发明的实施方案进行详细描述。
实施例1免疫原制备
合成新型冠状病毒核衣壳(N蛋白)全长序列,构建至pET28a表达载体中,并通过BL21(DE3)重组表达后,利用亲和层析和离子交换层析法制备,获得免疫原。然后合成新型冠状病毒刺突蛋白(S蛋白)全长序列,构建至pcDNA3.1(+)表达载体中,并通过293F重组表达后,利用亲和层析和离子交换层析法制备,获得免疫原。
(1)新型冠状病毒N抗原的氨基酸序列组成如下:
MSDNGPQNQR NAPRITFGGP SDSTGSNQNG ERSGARSKQR RPQGLPNNTA SWFTALTQHGKEDLKFPRGQ GVPINTNSSP DDQIGYYRRA TRRIRGGDGK MKDLSPRWYF YYLGTGPEAG LPYGANKDGIIWVATEGALN TPKDHIGTRN PANNAAIVLQ LPQGTTLPKG FYAEGSRGGS QASSRSSSRS RNSSRNSTPGSSRGTSPARM AGNGGDAALA LLLLDRLNQL ESKMSGKGQQ QQGQTVTKKS AAEASKKPRQ KRTATKAYNVTQAFGRRGPE QTQGNFGDQE LIRQGTDYKH WPQIAQFAPS ASAFFGMSRI GMEVTPSGTW LTYTGAIKLDDKDPNFKDQV ILLNKHIDAY KTFPPTEPKK DKKKKADETQ ALPQRQKKQQ TVTLLPAADL DDFSKQLQQSMSSADSTQA
(2)新型冠状病毒S抗原的氨基酸序列组成如下:
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
实施例2小鼠免疫、杂交瘤细胞筛选及抗体对筛选
使用制备的新型冠状病毒N抗原免疫8~12周Balb/c小鼠,包被N免疫原通过ELISA检测小鼠尾血,直至效价达到105时停止免疫,取出小鼠脾脏。处理后与小鼠骨髓瘤细胞Sp2/0进行融合,并通过有限稀释法筛选阳性杂交瘤细胞株。将阳性杂交瘤打入小鼠腹部制备腹水,纯化后获得的抗体利用双抗夹心的方法筛到针对N抗原的抗体对N-Ab-01和N-Ab-02。
使用制备的新型冠状病毒S抗原分别免疫8~12周Balb/c小鼠,包被S免疫原通过ELISA检测小鼠尾血,直至效价达到105时停止免疫,取出小鼠脾脏,处理后与小鼠骨髓瘤细胞Sp2/0进行融合,并进而通过有限稀释法筛选阳性杂交瘤细胞株。将阳性杂交瘤打入小鼠腹部制备腹水,纯化后获得的抗体利用双抗夹心的方法筛到针对S抗原的抗体对S-Ab-01和S-Ab-02。
实施例3亲和力检测
使用Biacore T200检测单克隆抗体的亲和力,CM5芯片上固定新型冠状病毒全长N蛋白,使用不同浓度的待测单克隆抗体,按照合适的时间与固相化的N蛋白进行反应,反应所得的动力学曲线通过软件进行拟合,亲和力检测结果如图1和图2所示。获得N-Ab-01抗体亲和力KD为4.98×10-10,其中kd为2.671×10-4,ka为5.363×105;获得N-Ab-02抗体亲和力为1.529×10-9,其中kd为2.992×10-4,ka为1.957×105。
使用Biacore T200检测单克隆抗体的亲和力,CM5芯片上固定新型冠状病毒全长S蛋白,使用不同浓度的待测单克隆抗体,按照合适的时间与固相化的S蛋白进行反应,反应所得的动力学曲线通过软件进行拟合,亲和力检测结果如图3和图4所示。获得S-Ab-01抗体亲和力KD为2.096×10-10,其中kd为1.453×10-4,ka为6.930×105;获得S-Ab-02抗体亲和力KD为2.414×10-9,其中kd为4.008×10-4,ka为1.660×105。
实施例4双特性抗体制备
培养分泌单克隆抗体的细胞株,即N-01、N-02、S-01及S-02杂交瘤细胞。首先提取4株杂交瘤细胞的mRNA,利用RT-PCR的方法及合适的引物扩增其可变区的基因序列。序列命名为:VH1(N-01重链可变区),VL1(N-01轻链链可变区);VH2(S-01重链可变区),VL2(S-01轻链链可变区);VH3(N-02重链可变区),VL3(N-02轻链链可变区);VH4(S-02重链可变区),VL4(S-02轻链链可变区)。Sanger法测序确认后,将VH1和VH2同时构建至重链表达载体pFUSE-CHIg-mG1中(载体图谱如图5所示),将VL1和VL2同时构建至轻链表达载体pFUSE2-CLIg-mk中(载体图谱如图6所示)。其中,双特异性抗体构建的示意如图7所示。利用去内毒素的质粒提取试剂盒获得含有轻、重链的质粒,然后按照适当的比例瞬时转染293F细胞,约48h后收集细胞培养上清,浓缩后经Protein A亲和层析和离子交换层析纯化,获得双特异性抗体NS-Ab-01。制备的双特异性抗体SDS-PAGE电泳图如图8所示。同理将VH3和VH4同时构建至重链表达载体pFUSE-CHIg-mG1中,将VL3和VL4同时构建至轻链表达载体pFUSE2-CLIg-mk,获得双特异性抗体NS-Ab-02。
双特性抗体对氨基酸序列如下(Liner前的氨基酸序列对应的靶点为N蛋白,Liner后的氨基酸序列对应的靶点为S蛋白)
(1)NS-Ab-01重链可变区的氨基酸序列
MGWSCIIFFLVATATGVHSQVQLQQSGPELVRPGVSVKISCKGSGYTFTDYAMHWVKQSHAKSLEWIGVISTYSGNTNYNQKFKGKATMTVDKSSSTAYMELARLTSEDSAIYYCAGGGNYGFAYWGQGTLVTVSAGGGSGGGSGGGSGGGSMGWSWIFLFLLSGTAGVLSEVQLQQSGPELVKPGASVKISCKTSGYTFTEYTMHWVKQSHGKSLEWIGGINPNNGGTSYNQKFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCARDYGYGWGQGTTLTVSS
(2)NS-Ab-01轻链可变区的氨基酸序列
METHSQVFVYMLLWLSGVEGDIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPLTFGAGTKLELKGGGSGGGSGGGSGGGSMSVLTQVLALLLLWLTGARCDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKIKSLQPEDFGSYYCQHFWSIPPTFGGGTKLEIK
(3)NS-Ab-02重链可变区的氨基酸序列
MAWVWTLLFLMAAAQSIQAQIQLVQSGPELKKPGETVKISCKASGYTFTDYSMHWVKQAPGKGLKWMGWINTETGEPTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARGSDYYAMDYWGQGTSVTVSSGGGSGGGSGGGSGGGSMDWLWNLLFLMAAAQSKSAEVQLVEYHWHLVQPGGSLRLAVNPSGFTVSSAMYNWVRQAPGKGLEWVSSKGVGGFTVYIDRLVDRFTISRDNSMNTLFLQMNSLRAEDTAVYYCARVLPMYTDYVDYWGQGTLVTVSS
(4)NS-Ab-02轻链可变区的氨基酸序列
MDSQAQVLMLLLLWVSGTCGDIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPPTFGGGTKLEIKGGGSGGGSGGGSGGGSMDSQAQVLMLLLLWVSDTCGDIVPYLSARPLSASVGDRVHTGRRAQLNYSISNYWYQQKPGKAPKLLIYAQSLSSNGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQPETYQQSYSPFGQGTKLEIK
使用Biacore T200检测单克隆抗体的亲和力,CM5芯片上固定新型冠状病毒全长等摩尔量的N蛋白和S蛋白的混合物,使用不同浓度的待测单克隆抗体,按照合适的时间与固相化的N和S蛋白进行反应,反应所得的动力学曲线通过软件进行拟合,亲和力检测结果如图9和图10所示。获得NS-Ab-01抗体亲和力KD为3.97×10-11,其中kd为8.09×10-5,ka为2.04×106;获得NS-Ab-02抗体亲和力为1.55×10-11,其中kd为9.28×10-5,ka为5.97×106。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
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<110> 深圳市亚辉龙生物科技股份有限公司
<120> 特异性结合SARS-CoV-2 S蛋白和N蛋白的双特异性抗体
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Claims (12)
3.根据权利要求2所述的双特异性抗体,其具有双特异轻链可变区和双特异重链可变区;
从N端到C端,a'和c'中的轻链可变区通过第一连接肽融合得到所述双特异轻链可变区;a'和c'中的重链可变区通过第二连接肽融合得到所述双特异重链可变区;
或
从N端到C端,b'和d'中的轻链可变区通过第一连接肽融合得到所述双特异轻链可变区;b'和d'中的重链可变区通过第二连接肽融合得到所述双特异重链可变区。
4.根据权利要求3所述的双特异性抗体,所第一连接肽及所述第二连接肽的氨基酸序列均如SEQ ID NO:33所示。
5.根据权利要求3所述的双特异性抗体,其还具有恒定区,重链恒定区选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任意一种的恒定区;轻链恒定区为κ或λ链。
6.根据权利要求5所述的双特异性抗体,所述恒定区的种属来源为牛、马、猪、羊、大鼠、小鼠、狗、猫、兔、骆驼、驴、鹿、貂、鸡、鸭、鹅或人。
7.核酸,其编码权利要求1~6任一项所述的双特异性抗体。
8.载体,其包含权利要求7所述的核酸。
9.宿主细胞,其包含根据权利要求7所述的核酸或被权利要求8所述的载体所转化。
10.生产权利要求1~6任一项所述的双特异性抗体的方法,包括:
在合适的培养条件下培养权利要求9所述的宿主细胞;以及
从培养基中或从所培养的宿主细胞中回收如此产生的双特异性抗体。
11.试剂或者试剂盒,其包含权利要求1~6任一项所述的双特异性抗体。
12.权利要求1~6任一项所述的双特异性抗体在制备SARS-CoV-2诊断试剂或者试剂盒中的应用。
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CN115698057A (zh) * | 2020-02-03 | 2023-02-03 | 维尔生物科技有限公司 | 抗sars-cov-2的抗体和其使用方法 |
CN111961133B (zh) * | 2020-05-15 | 2021-03-23 | 潍坊医学院 | 一种针对新冠病毒SARS-CoV-2棘突蛋白非RBD区的单克隆抗体及其应用 |
CN112625136B (zh) * | 2020-11-18 | 2022-02-11 | 三优生物医药(上海)有限公司 | 针对冠状病毒具有中和活性的双特异性抗体及其用途 |
CN113264998B (zh) * | 2021-01-28 | 2023-02-28 | 四川大学华西医院 | 抗新冠病毒SARS-CoV-2表面S1蛋白的单链抗体及其应用 |
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