CN113912709B - 新型冠状病毒单克隆抗体及其应用 - Google Patents
新型冠状病毒单克隆抗体及其应用 Download PDFInfo
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Abstract
本申请公开了一种新型冠状病毒单克隆抗体及其应用。本申请新型冠状病毒单克隆抗体具体为VacW‑89、VacW‑92、VacW‑105、VacW‑120、VacW‑138、VacW‑201、VacW‑209、VacW‑212和VacW‑215的至少一种；所有单克隆抗体都由重链和与之配对的轻链组成，9个单克隆抗体的重链和轻链可变区序列依序分别为Seq ID No.1至18所示序列。本申请使用新型冠状病毒RBD蛋白作为诱饵，从接种灭活疫苗志愿者B细胞中获得9个单克隆抗体，对新冠病毒Kappa和Delta变种以及L452R、T478K和E484Q突变都具有交叉中和、结合活性，为新冠治疗提供了一种新的抗体。
Description
技术领域
本申请涉及新型冠状病毒治疗技术领域，具体涉及一种新型冠状病毒单克隆抗体及其应 用。
背景技术
B.1.617谱系的新型冠状病毒(SARS-CoV-2)变种于2020年10月在印度首次发现，并 迅速传播到世界各地。B.1.617谱系包括三个主要亚谱系B.1.617.1(Kappa)、B.1.617.2(Delta) 和B.1.617.3。鉴于Kappa和Delta变种的高传播性，世界卫生组织分别将其指定为待观察变 种(variant of interest，VOI)和须关切变种(variant of concern，VOC)。二者在受体结合域 (receptor binding domain，RBD)中均包括L452R突变。此外，这些变异还具有独特的突变， 例如Kappa变种的E484Q突变和Delta变种的T478K突变。
SARS-CoV-2利用病毒棘突蛋白的RBD识别靶细胞上的受体血管紧张素转换酶2(angiotensin-converting enzyme 2，ACE2)。阻断RBD-ACE2的相互作用可阻止病毒感染细胞，使其成为抗病毒药物和中和抗体(neutralizing antibodynAb)的关键候选靶点。而RBD中出现的突变通常影响病毒感染和传播，甚至导致病毒逃逸自然感染或疫苗接种引诱导的抗 体的中和作用。Kappa和Delta变种RBD上的3个残基，即L452、T478和E484，参与RBD 与ACE2相互作用，其突变可能影响抗体的中和活性。
众所周知，根据是否与ACE2竞争以及识别RBD不同构象表位的能力，RBD特异性中和抗体可分为4类。Kappa和Delta变种RBD中出现的3个突变，即L452R、E484Q和T478K， 位于RBD和第1-3类中和抗体的大多数结合界面及其附近，表明这两个变异体可能不同程度 地逃避抗体的中和作用。而第4类中和抗体识别的表位远离上述3个突变位点，提示该类抗 体仍能保持有效的中和活性。
长期以来，疫苗一直是人类预防病毒感染的重要手段。如今，各种新型冠状病毒疫苗， 包括灭活疫苗、mRNA疫苗、DNA疫苗、腺病毒载体疫苗和重组蛋白疫苗等，已被开发并用于对抗病毒感染。在动物模型和临床试验中，灭活疫苗对新型冠状病毒具有良好的免疫原性 和保护作用。且有研究表明，尽管有一定程度的下降，接种过灭活疫苗的血清仍保留了对新 型冠状病毒alpha和beta变种的中和活性。然而，灭活疫苗对于新型冠状病毒Kappa和Delta 变种的保护效果知之甚少。特别是，从灭活疫苗接受者分离的单克隆中和抗体的交叉中和作 用尚未见报道。
此前，两个研究组报告了从接受mRNA或灭活疫苗的志愿者中分离的单克隆抗体的中和 活性，这表明疫苗可以有效诱导针对新型冠状病毒及几种变种的中和抗体。然而，人们对Kappa和Delta变体是否能逃避灭活疫苗诱导的单克隆抗体的中和还知之甚少。
因此，为了解决世界各地SARS-CoV-2的不断进化和重组以及中和抗体逃逸的潜在风险， 研发新的新型冠状病毒抗体或疫苗，仍然是本领域的研究重点和难点。
发明内容
本申请的目的提供一种新的新型冠状病毒单克隆抗体及其应用。
为了实现上述目的，本申请采用了一下技术方案：
本申请的第一方面公开了一种新型冠状病毒单克隆抗体，该新型冠状病毒单克隆抗体为 VacW-89、VacW-92、VacW-105、VacW-120、VacW-138、VacW-201、VacW-209、VacW-212和VacW-215中的至少一种；所有单克隆抗体都由重链序列和与之配对的轻链序列组成；VacW-89的重链序列的CDR1、CDR2和CDR3依序为“GFTFSSYA”、“ISGSGGST”和“AKAPHWNADYFDY”，轻链序列的CDR1、CDR2和CDR3依序为“QSISSW”、“DAS” 和“QQYNSYPFT”；VacW-92的重链序列的CDR1、CDR2和CDR3依序为“GYTFTSYY”、 “INPSGGNT”和“ARDSPSKLLWFGELHILYGMDV”，轻链序列的CDR1、CDR2和CDR3 依序为“TGAVTSGHY”、“DTS”和“LLSYSSAYV”；VacW-105的重链序列的CDR1、CDR2 和CDR3依序为“GGTFRSYT”、“ILPILGIA”和“ARVTGAPVESAAWFDP”，轻链序列的 CDR1、CDR2和CDR3依序为“SSNIGSNT”、“SNN”和“AAWDDSLNGYV”；VacW-120 的重链序列的CDR1、CDR2和CDR3依序为“GGTFSSYT”、“IIPILGIA”和 “ARDSPNYYDSSGLGIVAFDI”，轻链序列的CDR1、CDR2和CDR3依序为“SSNIGAGYD”、 “GNS”和“QSYDSSLSGSV”；VacW-138的重链序列的CDR1、CDR2和CDR3依序为 “GFTFSSYA”、“ISSSGGST”和“AKSLVAYPYGMDV”，轻链序列的CDR1、CDR2和CDR3 依序为“QGISSA”、“DAS”和“QQVDTYQFT”；VacW-201的重链序列的CDR1、CDR2和 CDR3依序为“GFTFSSYW”、“IKQDGSEK”和“ARMEYPYGGVDY”，轻链序列的CDR1、 CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNRNWV”；VacW-209的重链序 列的CDR1、CDR2和CDR3依序为“GFTFSSIA”、“MSFDGSIK”和 “ARGVQGYYDRSGYYNLDYNYGMDV”，轻链序列的CDR1、CDR2和CDR3依序为 “SSNIGAGYD”、“GNS”和“QSYDSSLSGWV”；VacW-212的重链序列的CDR1、CDR2 和CDR3依序为“GFTFSSYW”、“IKQDESEK”和“ARMEYPYGGIDY”，轻链序列的CDR1、 CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNRNWV”；VacW-215的重链序 列的CDR1、CDR2和CDR3依序为“GFTVSSNY”、“IYSGGST”和“ARSTWLRGGFDY”， 轻链序列的CDR1、CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNHFYV”。
需要说明的是，本申请的关键在于，从接种疫苗的志愿者的B细胞中克隆并鉴定获得了 9个单克隆中和抗体，即VacW-89、VacW-92、VacW-105、VacW-120、VacW-138、VacW-201、VacW-209、VacW-212和VacW-215，这9个单克隆抗体能够对包括新型冠状病毒Kappa和Delta变种以及几种具有单突变的假病毒在内的多个变种病毒具有中和活性。尤其是单克隆抗 体VacW-209，能够有效中和所有测试的变异毒株，包括Kappa和Delta变种以及L452R、T478K 和E484Q突变；并且，与现有报道的从灭活疫苗中分离的中和抗体相比，本申请的VacW-209 单克隆抗体的中和作用更强。其他8个单克隆抗体虽然中和作用不如VacW-209，但是，对不 同的变种仍然有较好的交叉中和及结合活性。
可以理解，本申请的9个单克隆中和抗体可以单独使用，分别对不同的变种或突变具有 相应的中和作用；当然，根据不同的使用需求，9个单克隆抗体也可以任意组合使用，在此 不作具体限定。
本申请的一种实现方式中，新型冠状病毒单克隆抗体VacW-89的重链序列可变区为Seq ID No.1所示序列，轻链序列可变区为Seq ID No.2所示序列；VacW-92的重链序列可变区为 Seq ID No.3所示序列，轻链序列可变区为Seq ID No.4所示序列；VacW-105的重链序列可变 区为Seq ID No.5所示序列，轻链序列可变区为Seq ID No.6所示序列；VacW-120的重链序列 可变区为Seq ID No.7所示序列，轻链序列可变区为Seq ID No.8所示序列；VacW-138的重链 序列可变区为Seq ID No.9所示序列，轻链序列可变区为Seq ID No.10所示序列；VacW-201 的重链序列可变区为Seq ID No.11所示序列，轻链序列可变区为Seq IDNo.12所示序列； VacW-209的重链序列可变区为Seq ID No.13所示序列，轻链序列可变区为Seq ID No.14所示 序列；VacW-212的重链序列可变区为Seq ID No.15所示序列，轻链序列可变区为Seq ID No.16 所示序列；VacW-215的重链序列可变区为Seq ID No.17所示序列，轻链序列可变区为Seq ID No.18所示序列。
需要说明的是，以上具体序列的重链序列可变区和轻链序列可变区只是本申请的一种实 现方式中具体采用的单克隆抗体序列；可以理解，对于单克隆抗体而言，影响其与抗原决定 簇形成精密互补的区域是互补性决定区(缩写CDR)，具体的，即重链序列的CDR1、CDR2 和CDR3，以及轻链序列的CDR1、CDR2和CDR3；因此，只要保障本申请的重链序列和轻链序列的CDR1、CDR2和CDR3序列不变，都能够基本实现本申请新型冠状病毒单克隆抗 体的功能和作用。也就是说，本申请的新型冠状病毒单克隆抗体，其具体序列不仅限于以上 具体序列的重链序列可变区和轻链序列可变区。
本申请的第二方面公开了一种编码本申请的新型冠状病毒单克隆抗体的核酸片段。
本申请的一种实现方式中，编码Seq ID No.1所示的重链序列可变区的核酸序列为Seq ID No.19所示序列，编码Seq ID No.2所示的轻链序列可变区的核酸序列为Seq IDNo.所示序列 20；编码Seq ID No.3所示的重链序列可变区的核酸序列为Seq ID No.21所示序列，编码Seq ID No.4所示的轻链序列可变区的核酸序列为Seq ID No.22所示序列；编码Seq ID No.5所示 的重链序列可变区的核酸序列为Seq ID No.23所示序列，编码Seq IDNo.6所示的轻链序列可 变区的核酸序列为Seq ID No.24所示序列；编码Seq ID No.7所示的重链序列可变区的核酸序 列为Seq ID No.25所示序列，编码Seq ID No.8所示的轻链序列可变区的核酸序列为Seq ID No.26所示序列；编码Seq ID No.9所示的重链序列可变区的核酸序列为Seq ID No.27所示序 列，编码Seq ID No.10所示的轻链序列可变区的核酸序列为Seq ID No.28所示序列；编码Seq ID No.11所示的重链序列可变区的核酸序列为Seq ID No.29所示序列，编码Seq ID No.12所 示的轻链序列可变区的核酸序列为Seq IDNo.30所示序列；编码Seq ID No.13所示的重链序 列可变区的核酸序列为Seq ID No.31所示序列，编码Seq ID No.14所示的轻链序列可变区的 核酸序列为Seq ID No.32所示序列；编码Seq ID No.15所示的重链序列可变区的核酸序列为 Seq ID No.33所示序列，编码SeqID No.16所示的轻链序列可变区的核酸序列为Seq ID No.34 所示序列；编码Seq IDNo.17所示的重链序列可变区的核酸序列为Seq ID No.35所示序列， 编码Seq ID No.18所示的轻链序列可变区的核酸序列为Seq ID No.36所示序列。
需要说明的是，以上具体的核酸序列只是本申请的一种实现方式中具体采用的核酸序列， 可以理解，对于一个氨基酸而言可以有多个密码子；因此，根据密码子的简并性，在保障编 码序列不变的情况下，除了以上限定的核酸序列以外，还可以有若干种编码相同重链序列或 轻链序列的核酸序列，都在本申请的保护范围内。
本申请的第三方面公开了一种含有本申请的核酸片段的重组质粒。
需要说明的是，本申请的重组质粒是为了能够有效的表达本申请的核酸片段，从而获得 相应的重链序列、轻链序列或新型冠状病毒单克隆抗体；因此，原则上只要能够将核酸片段 转染到宿主细胞中进行核酸表达的载体都可以用于本申请。
本申请的第四方面公开了一种含有本申请的核酸片段或本申请的重组质粒的重组细胞。
需要说明的是，本申请的重组细胞是指转染有本申请的核酸片段或重组质粒的宿主细胞； 一般可以通过直接培养这样的宿主细胞获得本申请的重链序列、轻链序列或新型冠状病毒单 克隆抗体。
本申请的第五方面公开了一种本申请的新型冠状病毒单克隆抗体的制备方法，包括采用 本申请的重组细胞对本申请的重组质粒进行蛋白表达，提取并纯化表达蛋白，即获得本申请 的新型冠状病毒单克隆抗体。
本申请的第六方面公开了本申请的新型冠状病毒单克隆抗体，或者本申请的核酸片段， 或者本申请的重组质粒，或者本申请的重组细胞，在制备新型冠状病毒疫苗、新型冠状病毒 防治药物或新型冠状病毒检测试剂中的应用。
需要说明的是，本申请的新型冠状病毒单克隆抗体能够对不同的变种具有较好的交叉中 和及结合活性；因此，能够用于制备相应的新型冠状病毒疫苗，或者其他具有类似功能的防 治新型冠状病毒的药物。同样的，本申请单克隆抗体对不同的变种的交叉中和及结合活性， 也可以用于检测相应的新型冠状病毒变种。至于核酸片段、重组质粒和重组细胞，这些可以 作为制备新型冠状病毒单克隆抗体的原材料，从而用于制备新型冠状病毒疫苗、新型冠状病 毒防治药物或新型冠状病毒检测试剂。
本申请的第七方面公开了一种新型冠状病毒疫苗，该新型冠状病毒疫苗中含有本申请的 新型冠状病毒单克隆抗体，或者含有能够诱导产生或体内表达本申请的新型冠状病毒单克隆 抗体的物质。
本申请的第八方面公开了一种新型冠状病毒检测试剂，该新型冠状病毒检测试剂中含有 本申请的新型冠状病毒单克隆抗体，或者含有能够特异性结合本申请的新型冠状病毒单克隆 抗体的抗原。
由于采用以上技术方案，本申请的有益效果在于：
本申请的新型冠状病毒单克隆抗体，对新型冠状病毒Kappa和Delta变种以及L452R、 T478K和E484Q突变都具有交叉中和、结合活性；并且，其中部分单克隆抗体表现出优于现 有灭活疫苗分离中和抗体的中和作用，为新型冠状病毒的防治提供了一种新的选择。
附图说明
图1为本申请实施例中流式细胞仪分选新型冠状病毒野生型病毒株RBD特异性IgG+B 细胞的结果图；
图2为本申请实施例中单克隆抗体结合新冠病毒RBD活性的酶联免疫吸附试验结果；
图3为本申请实施例中单克隆抗体对SARS-CoV-2假病毒的中和试验结果；
图4为本申请实施例中单克隆抗体的交叉中和试验结果。
具体实施方式
现有技术对Kappa和Delta变体是否能逃避灭活疫苗诱导的单克隆抗体的中和还知之甚 少。因此，本申请使用新型冠状病毒RBD蛋白作为诱饵，通过流式细胞术从用接种2剂灭活 疫苗(国药集团武汉生物制品研究所)的志愿者中分离单个B细胞，并从中克隆、鉴定获得 9个单克隆中和抗体，即VacW-89、VacW-92、VacW-105、VacW-120、VacW-138、VacW-201、 VacW-209、VacW-212和VacW-215，其针对新型冠状病毒野生型病毒株(野生型、WT)假病毒IC50范围为0.03至11.11μg/mL。这些抗体的基因来自多个家系，包括IGHV1-46、1-69、3-23、3-7等。重要的是，VacW-209和VacW-215的重链分别属于IGHV3-30和3-53家系， 在新冠肺炎患者中也有这种抗体，称为公共抗体，通常在恢复期个体中富集。新型冠状病毒 灭活疫苗具诱可导出具有不同长度CDR3和不同程度的体细胞超突变率的广泛的抗体反应。更重要的是，本申请获得了一株高效的中和抗体VacW-209，其中和新型冠状病毒野生型病毒 株假病毒的IC50为0.03μg/mL。与先前报道的从灭活疫苗中分离的中和抗体相比，VacW-209 的中和作用更强。
本申请进一步采用竞争ELISA，通过这9种中和抗体分别与4个代表性中和抗体(类别 1:P2C-1F11、类别2:BD-368-2、类别3:S309和类别4:EY6A)竞争结果预测了9个单克隆抗体的结合表位。结果显示，VacW-92和VacW-120为第2/3类，VacW-138识别第1类的表位，VacW-201、VacW-212和VacW-215属于第4类中和抗体，VacW-209与第1类(P2C-1F11) 和第4类(EY6A)抗体表现出高度竞争。虽然本申请未能预测VacW-89和VacW-105的识别 表位，但是分析认为这2个中和抗体也有可能属于上述四类以外的一些新表位。
最后，本申请测试了这9种单克隆中和抗体对新型冠状病毒Kappa和Delta变种以及几 种具有单突变的假病毒的交叉中和、结合活性。结果显示，大多数抗体仍然保持其对变种病 毒的中和活性。L452R突变在这些抗体的中和活性降低中起着关键作用。值得注意的是， VacW-209能够有效中和了所有测试的变异毒株，包括Kappa和Delta变种以及L452R、T478K 和E484Q突变。这些抗体与野生型和突变RBD蛋白(RBD-WT、L452R和E484Q、L452R 和T478K、L452R、T478K和E484Q)的亲和力与它们的中和活性表现出相同的模式，表明 结合亲和力和中和作用之间的强相关性。VacW-92和VacW-120与携带L452R的突变RBD蛋 白的结合非常弱，这揭示了新型冠状病毒变种逃逸抗体中和作用的机制。
因此，本申请从接受野生型灭活疫苗的个体中分离并鉴定了一系列单克隆中和抗体，它 们的种系基因使用、表位识别、中和效力和对SARS-CoV-2变种的交叉中和与自然病毒感染 诱导的中和抗体相似。本申请研究结果强调了灭活疫苗免疫对预防Kappa和Delta变种感染 的重要性，这对控制大流行和阻止SARS-CoV-2传播都有重要作用。此外，本申请注意到的 另一个独特趋势是，本申请证明了灭活疫苗诱导广泛单克隆中和抗体的能力，并获得了一种 有效的中和剂VacW-209，可作为候选治疗性抗体，用于被动预防各种SARS-CoV-2变异。
位于E484和L452的突变并非首次从SARS-CoV-2活病毒中鉴定出来。相反，E484K以前也在2种新型冠状病毒须关切变种(Beta和Gamma)和2种待观察变种(Eta和Iota)中 发现。另外两个主要的变异(Epsilon和Lambda)在区域范围内迅速传播，也分别携带L452R 和L452Q突变。考虑到世界各地SARS-CoV-2的不断进化和重组以及中和抗体逃逸的潜在风险，必须持续监测新出现的突变和变异的流行病学，并评估它们对自然感染和各种形式疫苗 诱导的抗体的敏感性，更新疫苗以确保可保护变种病毒的感染。
基于以上认识和研究，本申请创造性的一种新型冠状病毒单克隆抗体，该新型冠状病毒 单克隆抗体为VacW-89、VacW-92、VacW-105、VacW-120、VacW-138、VacW-201、VacW-209、 VacW-212和VacW-215中的至少一种；所有单克隆抗体都由重链序列和与之配对的轻链序列 组成；VacW-89的重链序列的CDR1、CDR2和CDR3依序为“GFTFSSYA”、“ISGSGGST” 和“AKAPHWNADYFDY”，轻链序列的CDR1、CDR2和CDR3依序为“QSISSW”、“DAS” 和“QQYNSYPFT”；VacW-92的重链序列的CDR1、CDR2和CDR3依序为“GYTFTSYY”、 “INPSGGNT”和“ARDSPSKLLWFGELHILYGMDV”，轻链序列的CDR1、CDR2和CDR3 依序为“TGAVTSGHY”、“DTS”和“LLSYSSAYV”；VacW-105的重链序列的CDR1、CDR2 和CDR3依序为“GGTFRSYT”、“ILPILGIA”和“ARVTGAPVESAAWFDP”，轻链序列的 CDR1、CDR2和CDR3依序为“SSNIGSNT”、“SNN”和“AAWDDSLNGYV”；VacW-120 的重链序列的CDR1、CDR2和CDR3依序为“GGTFSSYT”、“IIPILGIA”和 “ARDSPNYYDSSGLGIVAFDI”，轻链序列的CDR1、CDR2和CDR3依序为“SSNIGAGYD”、 “GNS”和“QSYDSSLSGSV”；VacW-138的重链序列的CDR1、CDR2和CDR3依序为 “GFTFSSYA”、“ISSSGGST”和“AKSLVAYPYGMDV”，轻链序列的CDR1、CDR2和CDR3 依序为“QGISSA”、“DAS”和“QQVDTYQFT”；VacW-201的重链序列的CDR1、CDR2和 CDR3依序为“GFTFSSYW”、“IKQDGSEK”和“ARMEYPYGGVDY”，轻链序列的CDR1、 CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNRNWV”；VacW-209的重链序 列的CDR1、CDR2和CDR3依序为“GFTFSSIA”、“MSFDGSIK”和 “ARGVQGYYDRSGYYNLDYNYGMDV”，轻链序列的CDR1、CDR2和CDR3依序为 “SSNIGAGYD”、“GNS”和“QSYDSSLSGWV”；VacW-212的重链序列的CDR1、CDR2 和CDR3依序为“GFTFSSYW”、“IKQDESEK”和“ARMEYPYGGIDY”，轻链序列的CDR1、 CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNRNWV”；VacW-215的重链序 列的CDR1、CDR2和CDR3依序为“GFTVSSNY”、“IYSGGST”和“ARSTWLRGGFDY”， 轻链序列的CDR1、CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNHFYV”。
本申请的新型冠状病毒单克隆抗体，对新型冠状病毒Kappa和Delta变种以及L452R、 T478K和E484Q突变都具有交叉中和、结合活性；尤其是其中一株高效的中和抗体VacW-209， 与先前报道的从灭活疫苗中分离的中和抗体相比，其中和作用更强，可用于被动预防各种 SARS-CoV-2变异，为新型冠状病毒防治提供了一种新的候选治疗性抗体。
下面通过具体实施方式结合附图对本发明作进一步详细说明。以下实施例仅对本申请进 行进一步说明，不应理解为对本申请的限制。除非特别说明，以下实施例中采用的仪器、材 料都是实验室常规使用的器材。
实施例
一、材料和方法
1.研究批准和生物样品
本研究由深圳市第三人民医院伦理委员会批准(批准号：2020-030)。所有参与者都提供 了书面知情同意书，用于样本采集和后续分析。从深圳市第三人民医院第2次接种SARS-CoV-2灭活疫苗(武汉生物制品研究所有限公司WIBP-CorV)约2周后采集血清和外 周血单个核细胞(PBMC)样本。所有血清样本在使用前于-80℃下储存，并在56℃下热灭活 1小时。PBMC保存在液氮中。
本例具体采集了2个样本，样本采集方法如下：
血清样本收集：用干燥真空管采静脉血10mL，室温放置1小时，4000rpm离心10分钟， 吸取上层血清，分装保存于-80℃。
外周血单个核细胞分离：用抗凝管采静脉血10mL，转入50mL离心管中，加入10mL的PBS溶液稀释，混匀；取两支15mL离心管，各加5mL的Ficoll分离液。然后将稀释的血液 各10mL加到ficoll分离液上层；2000rpm离心20分钟；吸取白细胞层至干净15mL离心管； 加入PBS至10mL，1500rpm离心10分钟后去掉上清，用3mL细胞冻存液重悬，各取1mL 细胞至3个冻存管中，放入冻存盒后置于-80℃冰箱过夜，次日将细胞转入液氮中长期保存。
2.从灭活疫苗接种者体内分离单克隆抗体
复苏冻存的外周血单个核细胞，用10mL的PBS洗涤2次。在100μL染色缓冲液(PBS+2％ 胎牛血清)中加入CD19-PE-Cy7,CD3-Pacific Blue,CD8-Pacific Blue,CD14-PacificBlue, IgG-FITC(均来自BD Biosciences)和带有His标签的新型冠状病毒野生型病毒株RBD(Sino Biological)探针混合物，重悬外周血单个核细胞，于4℃染色30分钟。PBS洗涤2次后，在 100μL染色缓冲液(PBS+2％胎牛血清)中加入APC和PE标记的抗His标签二抗(Abcam)， 于4℃对细胞染色30分钟。PBS洗涤2次后，通过BD FACS Aria II分选型流式细胞仪分选 新型冠状病毒野生型病毒株RBD特异性IgG+B细胞。
将单个B细胞分选到含有裂解缓冲液的96孔PCR板中，然后按照文献(Liao HX,Levesque MC,Nagel A,Dixon A,Zhang R,Walter E,et al.High-throughput isolationof immunoglobulin genes from single human B cells and expression asmonoclonal antibodies.Journal of virological methods.2009；158:171-9.)的方法进行RT-PCR和巢式PCR，分别扩增重链和轻 链可变区域。将PCR扩增产物送至生工生物工程(上海)股份有限公司进行测序。
将测序获得的抗体可变区序列送金斯瑞生物科技有限公司合成，并由该公司将抗体重链 和轻链的可变区域分别克隆到全长IgG1重链和轻链表达载体pcDNA3.4(金斯瑞生物科技有 限公司)中，并大量制备抗体重链和轻链的质粒。获得金斯瑞公司制备的质粒后，通过将成 对的重链和轻链质粒共转染293F细胞表达、使用proteinA吸附柱从培养上清中纯化单克隆抗 体，具体实验步骤如下：
将293F细胞浓度调整为1.2×106个/mL，继续培养2小时；配制A液：向25mL的opti-MEM加入500μg抗体重链DNA和500μg抗体轻链DNA；配制B液：向25mL的opti-MEM 加入5mL的PEI转染试剂，静置5分钟；将A液和B液混合，静置20分钟，获得AB混合 液；将50mL的AB混合液逐滴加入到1L的293F细胞中，边滴加边摇匀；将细胞置于8％CO2， 37℃培养箱中，摇动培养5天；离心293F细胞，12000rpm，离心20分钟，收集上清，使用 0.22μm滤膜过滤；打开Protein A重力柱中盖子，利用重力让柱子中20％的乙醇溶液完全流 出，用5倍柱体积的10mM的PBS溶液平衡Protein A重力柱；向Protein A重力柱内加入过 滤后的细胞上清液，依靠重力作用流出；用3倍体积的10mM的PBS溶液清洗Protein A重 力柱，再用5倍体积的0.1M的甘氨酸-盐酸溶液(PH＝3.0)洗脱；将洗脱液置于30KD的超 滤浓缩管中，用10mM的PBS补满，4℃下，3500rpm离心40分钟，弃去收集管中废液，加 入20mL的10mM的PBS溶液，4℃下，3500rpm离心40分钟，吸取浓缩置换后的抗体溶液， 测定抗体蛋白浓度。
3.酶联免疫吸附试验(ELISA)和竞争ELISA
通过ELISA实验检测所获得的单克隆抗体与新型冠状病毒RBD特异性结合能力，通过 假病毒中和试验筛选具中和能力的单克隆抗体。ELISA和中和试验详细如下。
96孔酶标板中将SARS-CoV-2RBD蛋白在4℃下包被过夜。用PBST缓冲液洗涤酶标板， 加入封闭液(PBS溶解5％脱脂奶粉和2％牛血清白蛋白)于室温封闭1小时。PBST洗涤后， 加入梯度稀释的单克隆抗体，于37℃下孵育1小时。PBST洗涤后，加入HRP标记的羊抗人IgG二抗(ZSGB-BIO)，于37℃下孵育1小时。PBST洗涤后，加入TMB底物(BD Biosciences) 于室温孵育20分钟，加入2M H2SO4终止反应。酶标仪中检测450nm波长吸光度值。
对于竞争ELISA，将将单克隆抗体于U型底96孔板内20ug/ml起始3倍倍比稀释，具体 的，120μL体系，7个稀释度，第8个孔不加抗体作为对照。之后分别加入等体积的4种HRP标记的代表性中和抗体，即P2C-1F11、BD-368-2、S309和EY6A，混匀后转移至预包被的酶 标板中，100μL/孔，然后在37℃下孵育1小时。PBST洗涤后，加入HRP标记的羊抗人IgG 二抗(ZSGB-BIO)，于37℃下孵育1小时。PBST洗涤后，加入TMB底物(BD Biosciences) 于室温孵育20分钟，加入2M的H2SO4终止反应。
4.表面等离子体共振(SPR)
使用Biacore 8K系统(GE Healthcare)进行野生型和突变型SARS-CoV-2RBD蛋白(Sino Biological)与单克隆抗体的结合试验。具体而言，用10mM醋酸钠缓冲液(pH 5.0)溶解野 生型或突变型RBD(Sino Biological)，共价包被CM5传感芯片的一个流动池，获得250左右 的最终响应单元(RU)，而另一个流动池则保持未包被状态，封闭后作为对照。在HBS-EP 缓冲液(10mM的HEPES pH 7.4、150mM的NaCl、3mM的EDTA和0.05％吐温-20)中以 30μL/min的流速进行所有分析。分别注射连续稀释的抗体60秒，所得数据用Biacore评估软 件(GE Healthcare)在1:1结合模型中拟合。每次测量进行两次，并使用单个值产生平均亲 和常数。
5.SARS-CoV-2假病毒的中和试验
HEK-293T细胞和HEK-293T-hACE2细胞用含10％胎牛血清和1％青链霉素的DMEM培养基、于37℃5％CO2培养箱中培养。新型冠状病毒假病毒是通过将10μg新型冠状病毒刺 突蛋白表达质粒和20μg env缺陷型HIV-1骨架载体质粒(pNL4-3.Luc.R-E-)与共转染 HEK-293T细胞产生的。其中新型冠状病毒刺突蛋白表达质粒由金斯瑞生物科技有限公司合 成制备，野生型病毒株刺突蛋白序列参考Genbank数据库(MN988668.1)，Delta变种是野生 型病毒株的基础上包含以下突变：T19R,G142D,ΔF157/ΔR158,L452R,T478K,D614G,P681R,D950N。
假病毒制备的具体实验步骤如下：待T75细胞培养瓶中HEK-293T细胞汇合度达到80％ 左右时，吸弃培养基，用胰酶消化后，加入培养基重悬细胞，1000rpm离心5min，弃上清， 加10mL培养基重悬细胞，计数后取6×106细胞至新的T75细胞培养瓶中培养过夜；取2个 1.5mL离心管，各加无血清培养基400μL，分别加入PEI转染试剂120μL和20μg pNL4-3.Luc.R-E-加10μg SARS-CoV-2刺突蛋白表达质粒，混匀后于室温静置5分钟后将两者 混合，室温静置20分钟；将转染试剂加入到HEK-293T T75细胞瓶中，混匀后于培养箱中培 养约7小时，吸弃培养基，加入新鲜培养基，继续培养48小时；吸取含假病毒的细胞培养基， 转移至50mL离心管中，3000rpm离心10分钟，取上清用0.45μm滤器过滤，分装冻存于负 80℃低温冰箱备用。
为了确定抗体中和活性，在96孔板中，单克隆抗体以100μg/mL起始3倍的倍比稀释9 次，加入等体积稀释的假病毒，在37℃下孵育1小时。随后每孔加入HEK-293T-hACE2细胞100μL，即含2.5万个细胞。于37℃5％CO2培养箱中培养48小时后，移除细胞培养基并向 细胞孔中添加100μL Bright Lite荧光素酶试剂(Vazyme Biotech)。室温孵育2分钟后，将90μL 细胞裂解物转移到96孔白板中，使用多功能酶标仪检测化学发光信号。使用GraphPadPrism 8.0软件，通过对数(抑制剂)与标准化反应-可变斜率(四参数)模型计算50％抑制性浓度 (IC50)。
二、结果及分析
1.单克隆抗体分离
通过流式细胞术从2名志愿者外周血中分离新型冠状病毒(SARS-CoV-2)特异性IgG+B 细胞。结果如图1所示，外周血淋巴细胞比例约占40％，通过CD3、CD8、CD14等分子排除T淋巴细胞、单核细胞，通过CD19分子选出B细胞，进一步选出IgG阳性的B细胞，最 后通过SARS-CoV-2RBD探针选出新型冠状病毒特异性B细胞。2名志愿者外周血中新型冠 状病毒特异性B细胞占IgG阳性B细胞的比例分别为0.39％和0.19％。
本例分离获得了9个单克隆中和抗体，即VacW-89、VacW-92、VacW-105、VacW-120、VacW-138、VacW-201、VacW-209、VacW-212和VacW-215，其重链可变区域和轻链可变区域 序列，以及测序结果如表1和表2所示。其中，表1为分离获得的9个单克隆抗体及其序列； 表2为单克隆抗体重链可变区域和轻链可变区域PCR扩增后的测序结果。
表1单克隆抗体序列及其核酸序列
表2单克隆抗体核酸测序结果
分析结果显示，VacW-89的重链序列的CDR1、CDR2和CDR3依序为“GFTFSSYA”、“ISGSGGST”和“AKAPHWNADYFDY”，轻链序列的CDR1、CDR2和CDR3依序为 “QSISSW”、“DAS”和“QQYNSYPFT”；VacW-92的重链序列的CDR1、CDR2和CDR3 依序为“GYTFTSYY”、“INPSGGNT”和“ARDSPSKLLWFGELHILYGMDV”，轻链序列的 CDR1、CDR2和CDR3依序为“TGAVTSGHY”、“DTS”和“LLSYSSAYV”；VacW-105的 重链序列的CDR1、CDR2和CDR3依序为“GGTFRSYT”、“ILPILGIA”和“ARVTGAPVESAAWFDP”，轻链序列的CDR1、CDR2和CDR3依序为“SSNIGSNT”、“SNN” 和“AAWDDSLNGYV”；VacW-120的重链序列的CDR1、CDR2和CDR3依序为“GGTFSSYT”、 “IIPILGIA”和“ARDSPNYYDSSGLGIVAFDI”，轻链序列的CDR1、CDR2和CDR3依序为 “SSNIGAGYD”、“GNS”和“QSYDSSLSGSV”；VacW-138的重链序列的CDR1、CDR2和 CDR3依序为“GFTFSSYA”、“ISSSGGST”和“AKSLVAYPYGMDV”，轻链序列的CDR1、 CDR2和CDR3依序为“QGISSA”、“DAS”和“QQVDTYQFT”；VacW-201的重链序列的 CDR1、CDR2和CDR3依序为“GFTFSSYW”、“IKQDGSEK”和“ARMEYPYGGVDY”， 轻链序列的CDR1、CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNRNWV”； VacW-209的重链序列的CDR1、CDR2和CDR3依序为“GFTFSSIA”、“MSFDGSIK”和 “ARGVQGYYDRSGYYNLDYNYGMDV”，轻链序列的CDR1、CDR2和CDR3依序为 “SSNIGAGYD”、“GNS”和“QSYDSSLSGWV”；VacW-212的重链序列的CDR1、CDR2 和CDR3依序为“GFTFSSYW”、“IKQDESEK”和“ARMEYPYGGIDY”，轻链序列的CDR1、 CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNRNWV”；VacW-215的重链序 列的CDR1、CDR2和CDR3依序为“GFTVSSNY”、“IYSGGST”和“ARSTWLRGGFDY”， 轻链序列的CDR1、CDR2和CDR3依序为“SGSIASNY”、“EDN”和“QSYDSSNHFYV”。
2.酶联免疫吸附试验(ELISA)
通过ELISA实验分析从志愿者外周血中分离的9个单克隆抗体，即表1所示单克隆抗体， 对新型冠状病毒RBD蛋白的结合活性。结果如图2所示，与对照抗体P2C-1F11类似，尽管 强度不同，9个单克隆抗体均可特异性结合新型冠状病毒RBD蛋白，且吸光度值具有明显的 浓度依赖性。该结果表明，9个单克隆抗体均具有新型冠状病毒特异性。
3.SARS-CoV-2假病毒的中和试验结果
通过假病毒中和实验进一步分析9个新型冠状病毒RBD蛋白特异性单克隆抗体的中和活 性。结果如图3所示，与对照抗体P2C-1F11类似，尽管中和活性不同，9个单克隆抗体均可 阻断新型冠状病毒假病毒对靶细胞的感染，且且中和活性具有明显的浓度依赖性。其中 VacW-209具有较强的中和活性，IC50为0.03μg/mL。该结果表明，9个单克隆抗体均为新型冠状病毒中和抗体。
4.交叉中和及结合活性试验结果
为检测新型冠状病毒变种(特别是Kappa和Delta变种)对9个中和抗体中和活性的影 响。本例制备了Kappa和Delta变种的假病毒，同时制备了L452R，T478K，E484Q等3个 突变体假病毒，通过对比野生型(野生型病毒株，WT)病毒的中和活性，分析单克隆抗体对 突变株的中和作用。结果如图4所示，9个中和抗体中的6个，即VacW-105、VacW-138、 VacW-201、VacW-209、VacW-212、VacW-215，对Kappa和Delta变种的中和活性并没有或 只有轻度的减弱，其中强中和抗体VacW-209还具有良好的广谱性，对Kappa和Delta变种的 中和活性并没有发生显著改变。此外，VacW-89、VacW-92和VacW-120对Kappa和Delta突 变种失去中和作用，其中L452R突变导致VacW-92和VacW-120失去中和活性，表明该突变 是Kappa和Delta变种逃逸中和作用的关键。
5.表面等离子体共振(SPR)结果
通过表面等离子体共振技术检测9个中和抗体与新型冠状病毒及其Kappa和Delta变种 以及L452R，T478K,E484Q等3个突变体RBD蛋白的亲和力，结果如表3所示。
表3单克隆抗体的表面等离子体共振结果
| KD(nM) | RBD-WT | Kappa | Delta | L452R | T478K | E484Q |
| VacW-89 | 3.10 | 6.41 | 6.51 | 5.62 | 3.39 | 5.02 |
| VacW-92 | 0.00998 | 985 | 507 | 472 | 0.0232 | 0.0364 |
| VacW-105 | 1.64 | 4.13 | 5.10 | 3.69 | 3.37 | 5.22 |
| VacW-120 | 0.0503 | 81.1 | 158 | 126 | 0.0731 | 0.107 |
| VacW-138 | 1.10 | 3.17 | 3.11 | 1.96 | 1.75 | 3.12 |
| VacW-201 | 0.880 | 1.71 | 2.14 | 1.57 | 1.64 | 2.25 |
| VacW-209 | 0.0113 | 0.0234 | 0.0467 | 0.0237 | 0.0230 | 0.0330 |
| VacW-212 | 0.653 | 1.32 | 1.83 | 1.20 | 1.22 | 1.74 |
| VacW-215 | 0.405 | 0.676 | 1.02 | 0.714 | 0.683 | 0.967 |
表3的结果显示，大部分中和抗体对野生型(WT)和Kappa和Delta变种及单点突变RBD的亲和力并没有明显改变。但VacW-92和VacW-120对Kappa和Delta突变种以及L452R 突变体RBD蛋白的亲和力显著下降，与该抗体对Kappa和Delta变种病毒失去中和活性相关，提示亲和力显著下降是抗体中和活性下降的关键因素。
以上内容是结合具体的实施方式对本申请所作的进一步详细说明，不能认定本申请的具 体实施只局限于这些说明。对于本申请所属技术领域的普通技术人员来说，在不脱离本申请 构思的前提下，还可以做出若干简单推演或替换。
SEQUENCE LISTING
<110> 深圳国家感染性疾病临床医学研究中心
深圳市第三人民医院
<120> 新型冠状病毒单克隆抗体及其应用
<130> 21I32527
<160> 36
<170> PatentIn version 3.3
<210> 1
<211> 120
<212> PRT
<213> VacW-89重链可变区
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Ala Pro His Trp Asn Ala Asp Tyr Phe Asp Tyr Trp Gly Gln
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Gly Thr Leu Val Thr Val Ser Ser
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<210> 2
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<213> VacW-89轻链可变区
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Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
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Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Phe
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Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
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<213> VacW-92重链可变区
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
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Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Val Ile Asn Pro Ser Gly Gly Asn Thr Arg Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
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Met Glu Leu Ser Ser Leu Arg Phe Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Ser Pro Ser Lys Leu Leu Trp Phe Gly Glu Leu His Ile
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Leu Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
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Ser
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<211> 109
<212> PRT
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Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
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Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
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His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Thr
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Leu Ile Tyr Asp Thr Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe
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Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
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Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Tyr Ser Ser
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Ala Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
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<210> 5
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<213> VacW-105重链可变区
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ser Tyr
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Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Leu Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Val Thr Gly Ala Pro Val Glu Ser Ala Ala Trp Phe Asp Pro
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Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
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<210> 6
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<213> VacW-105轻链可变区
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Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Pro Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
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Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
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Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
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Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
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Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
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Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
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<210> 7
<211> 127
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<213> VacW-120重链可变区
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Ser Pro Asn Tyr Tyr Asp Ser Ser Gly Leu Gly Ile Val
100 105 110
Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 8
<211> 111
<212> PRT
<213> VacW-120轻链可变区
<400> 8
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Phe
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Val
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 9
<211> 120
<212> PRT
<213> VacW-138重链可变区
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ser Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Ser Leu Val Ala Tyr Pro Tyr Gly Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 10
<211> 107
<212> PRT
<213> VacW-138轻链可变区
<400> 10
Ala Ile Gln Leu Thr Gln Ser Pro Phe Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
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Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Val Asp Thr Tyr Gln Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 11
<211> 119
<212> PRT
<213> VacW-201重链可变区
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Met Glu Tyr Pro Tyr Gly Gly Val Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 12
<211> 112
<212> PRT
<213> VacW-201轻链可变区
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Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
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Thr Val Thr Ile Ser Cys Thr Gly Ser Ser Gly Ser Ile Ala Ser Asn
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Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
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Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
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Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
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Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
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Ser Asn Arg Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 13
<211> 131
<212> PRT
<213> VacW-209重链可变区
<400> 13
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Asp Tyr Asn Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
115 120 125
Val Ser Ser
130
<210> 14
<211> 111
<212> PRT
<213> VacW-209轻链可变区
<400> 14
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
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Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
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Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
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Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
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Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 15
<211> 119
<212> PRT
<213> VacW-212重链可变区
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Glu Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Glu Tyr Pro Tyr Gly Gly Ile Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 16
<211> 112
<212> PRT
<213> VacW-212轻链可变区
<400> 16
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Gly Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Asn Arg Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 17
<211> 118
<212> PRT
<213> VacW-215重链可变区
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Thr Trp Leu Arg Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 18
<211> 112
<212> PRT
<213> VacW-215轻链可变区
<400> 18
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Gly Ser Ser Gly Ser Ile Ala Ser Asn
20 25 30
Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val
35 40 45
Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
85 90 95
Ser Asn His Phe Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 19
<211> 360
<212> DNA
<213> VacW-89重链可变区
<400> 19
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagctccg 300
cactggaacg cagactactt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360
<210> 20
<211> 321
<212> DNA
<213> VacW-89轻链可变区
<400> 20
gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaacag tataatagtt acccattcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 21
<211> 387
<212> DNA
<213> VacW-92重链可变区
<400> 21
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg catctggata caccttcacc agctactata tgtactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagta atcaacccta gtggtggtaa cacaaggtac 180
gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atttgaggac acggccgtgt attactgtgc gagagatagt 300
ccgagtaaat tactatggtt cggggagtta catatcctct acggtatgga cgtctggggc 360
caagggacca cggtcaccgt ctcctca 387
<210> 22
<211> 327
<212> DNA
<213> VacW-92轻链可变区
<400> 22
caggctgtgg tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60
acctgtggct ccagcactgg agctgtcacc agtggtcatt atccctactg gttccagcag 120
aagcctggcc aagcccccag gacactgatt tatgatacaa gcaacaaaca ctcctggacc 180
cctgcccggt tctcaggctc cctccttggg ggcaaagctg ccctgaccct ttcgggtgcg 240
cagcctgagg atgaggctga gtattactgc ttgctctcct atagtagtgc ttatgtcttc 300
ggaactggga ccaaggtcac cgtccta 327
<210> 23
<211> 369
<212> DNA
<213> VacW-105重链可变区
<400> 23
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgtaagg cttctggagg caccttcaga agttatacta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcctcccta tccttggtat agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagttaca 300
ggggccccgg tggagtcggc cgcctggttc gacccctggg gccagggaac cctggtcacc 360
gtctcctca 369
<210> 24
<211> 330
<212> DNA
<213> VacW-105轻链可变区
<400> 24
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtccccatc 60
tcttgttctg gaagcagctc caacatcggg agtaatactg taaactggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccctc aggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tctgaggatg aggctgatta ttactgtgca gcatgggatg acagcctgaa tggttatgtc 300
ttcggaactg ggaccaaggt caccgtccta 330
<210> 25
<211> 381
<212> DNA
<213> VacW-120重链可变区
<400> 25
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattcc 300
cccaattact atgatagtag tggtttgggg atcgttgctt ttgatatctg gggccaaggg 360
acaatggtca ccgtctcttc a 381
<210> 26
<211> 333
<212> DNA
<213> VacW-120轻链可变区
<400> 26
cagtctgtgc tgacgcagcc gccctcagtg tctggggccc caggacagag ggtcaccatc 60
tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtaccagcag 120
cttccaggaa cagcccccaa attcctcatc tatgggaaca gcaatcggcc ctcaggggtc 180
cctgaccgag tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtggttcg 300
gtgttcggcg gagggaccaa gctgaccgtc cta 333
<210> 27
<211> 360
<212> DNA
<213> VacW-138重链可变区
<400> 27
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtagta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaagtttg 300
gtcgcttacc cctacggtat ggacgtctgg ggccaaggga ccacggtcac cgtctcctca 360
<210> 28
<211> 321
<212> DNA
<213> VacW-138轻链可变区
<400> 28
gccatccagt tgacccagtc tccattctcc ttgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttattt ctgtcaacag gttgatactt accaattcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 29
<211> 357
<212> DNA
<213> VacW-201重链可变区
<400> 29
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agctattgga tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaagcagg atggaagtga gaaatactat 180
gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaatggaa 300
tacccctacg gtggtgttga ctactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 30
<211> 336
<212> DNA
<213> VacW-201轻链可变区
<400> 30
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccg gcagcagtgg cagcattgcc agcaactatg tgcagtggta ccagcagcgc 120
ccgggcagtg cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcag caatcgaaat 300
tgggtgttcg gcggagggac caagctgacc gtccta 336
<210> 31
<211> 393
<212> DNA
<213> VacW-209重链可变区
<400> 31
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agtattgcta tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atgtcatttg atggaagtat taaatactat 180
ggagactccg tgaagggccg attcaccatc tccagagaca attccaagag cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaggggtc 300
cagggttact atgatagaag tggttattac aacctcgatt acaactacgg tatggacgtc 360
tggggccaag ggaccacggt caccgtctcc tca 393
<210> 32
<211> 333
<212> DNA
<213> VacW-209轻链可变区
<400> 32
cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtaccagcag 120
cttccaggaa cagcccccaa actcctcatc tatggtaaca gcaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtggttgg 300
gtgttcggcg gagggaccaa gctgaccgtc cta 333
<210> 33
<211> 357
<212> DNA
<213> VacW-212重链可变区
<400> 33
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agctattgga tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaagcaag atgaaagtga gaaatactat 180
gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgttt 240
ctgcaaatga acagcctgag agtcgaggac acggctgtgt attactgtgc gagaatggag 300
tacccctacg gtggtattga ctactggggc cagggaaccc tggtcaccgt ctccgca 357
<210> 34
<211> 336
<212> DNA
<213> VacW-212轻链可变区
<400> 34
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccg gcagcagtgg cagcattgcc agcaactatg tgcagtggta ccagcagcgc 120
ccgggcagtg cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcag caatcgaaat 300
tgggtgttcg gcggagggac caagctgacc gtccta 336
<210> 35
<211> 354
<212> DNA
<213> VacW-215重链可变区
<400> 35
gaggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag atccacttgg 300
ctacgggggg gatttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 36
<211> 336
<212> DNA
<213> VacW-215轻链可变区
<400> 36
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccg gcagcagtgg cagcattgcc agcaactatg tgcagtggta ccagcagcgc 120
ccgggcagtg cccccaccac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagcag caatcatttt 300
tatgtcttcg gaactgggac caaggtcacc gtccta 336
Claims (10)
1.一种新型冠状病毒单克隆抗体，其特征在于：所述新型冠状病毒单克隆抗体为VacW-209，该单克隆抗体由重链和与之配对的轻链组成；
VacW-209的重链的CDR1、CDR2和CDR3的序列依序为“GFTFSSIA”、“MSFDGSIK”和“ARGVQGYYDRSGYYNLDYNYGMDV”，轻链的CDR1、CDR2和CDR3的序列依序为“SSNIGAGYD”、“GNS”和“QSYDSSLSGWV”。
2.根据权利要求1所述的新型冠状病毒单克隆抗体，其特征在于：VacW-209的重链可变区序列为Seq ID No.13所示，轻链可变区序列为Seq ID No.14所示。
3.一种编码权利要求1或2所述的新型冠状病毒单克隆抗体的核酸片段，其编码所述重链和所述轻链。
4.根据权利要求3所述的核酸片段，其特征在于：包含编码Seq ID No.13所示的重链可变区的核酸片段，其序列为Seq ID No.31所示，编码Seq ID No.14所示的轻链可变区的核酸片段，其序列为Seq ID No.32所示。
5.一种含有权利要求3或4所述的核酸片段的重组质粒。
6.一种含有权利要求3或4所述的核酸片段或权利要求5所述的重组质粒的重组细胞。
7.根据权利要求1或2所述的新型冠状病毒单克隆抗体的制备方法，其特征在于：包括采用权利要求6所述的重组细胞对权利要求5所述的重组质粒进行蛋白表达，提取并纯化表达蛋白，即获得所述新型冠状病毒单克隆抗体。
8.根据权利要求1或2所述的新型冠状病毒单克隆抗体，或者权利要求3或4所述的核酸片段，或者权利要求5所述的重组质粒，或者权利要求6所述的重组细胞，在制备新型冠状病毒疫苗、新型冠状病毒防治药物或新型冠状病毒检测试剂中的应用。
9.一种新型冠状病毒疫苗，其特征在于：所述新型冠状病毒疫苗中含有权利要求1或2所述的新型冠状病毒单克隆抗体。
10.一种新型冠状病毒检测试剂，其特征在于：所述新型冠状病毒检测试剂中含有权利要求1或2所述的新型冠状病毒单克隆抗体。
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| CN111592594A (zh) * | 2020-03-13 | 2020-08-28 | 北京大学 | 一种抗新型冠状病毒的单克隆抗体及其应用 |
| WO2020243642A2 (en) * | 2019-05-31 | 2020-12-03 | The Trustees Of Columbia University In The City Of New York | Multiply auxotrophic cell line for the production of recombinant proteins and methods thereof |
| CN112940110A (zh) * | 2021-04-14 | 2021-06-11 | 中山大学 | 抗新型冠状病毒n蛋白单克隆抗体及其应用 |
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| WO2020243642A2 (en) * | 2019-05-31 | 2020-12-03 | The Trustees Of Columbia University In The City Of New York | Multiply auxotrophic cell line for the production of recombinant proteins and methods thereof |
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| CN111592594A (zh) * | 2020-03-13 | 2020-08-28 | 北京大学 | 一种抗新型冠状病毒的单克隆抗体及其应用 |
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