CN116903732A - 一种人源SARS-CoV-2单克隆抗体的制备及其应用 - Google Patents
一种人源SARS-CoV-2单克隆抗体的制备及其应用 Download PDFInfo
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Abstract
本发明公开了一种人源SARS‑CoV‑2单克隆抗体的制备及其应用，对灭活病毒疫苗免疫志愿者得到的全血分离得到外周血淋巴细胞，用荧光标记抗体对记忆B淋巴细胞表面分子CD3‑CD19+CD27+IgG+进行区分，通过流式细胞术分选得到新冠病毒刺突蛋白特异性的记忆B细胞。利用单细胞逆转录试剂盒和特异性引物从记忆B细胞中扩增得到一对匹配的抗体可变区基因序列，将其构建到抗体表达载体。在HEK293T细胞中表达纯化出抗体并初步检测其功能和效价。本发明还公开了单克隆抗体用于新冠治疗药物中的应用，可应用于SARS‑CoV‑2的检测试剂盒，对SARS‑CoV‑2病毒的诊断、治疗具有重大应用价值。
Description
技术领域
本发明涉及医疗技术领域，尤其涉及一种人源SARS-CoV-2单克隆抗体的制备及其应用。
背景技术
新型冠状病毒感染患者发病后轻则发烧无力、嗅觉味觉障碍，重则呼吸困难，最后发展为多器官功能衰竭。新型冠状病毒，属冠状病毒科冠状病毒属β亚属，具有包膜，刺突蛋白位于包膜上。病毒利用刺突蛋白结合于细胞表面的血管紧张素转化酶 2（angiotensinconverting enzyme 2，ACE2）进入细胞。因此刺突蛋白是新型冠状病毒肺炎疫苗或单克隆抗体制备的重要靶点。单克隆抗体由于其特异性好，在科研、诊断有着广泛的应用。近年来，单细胞PCR 技术制备单克隆抗体技术兴起，可以大批量筛选特异性单克隆抗体。本研究基于单细胞 PCR 技术制备新型冠状病毒刺突蛋白单克隆抗体。
冠状病毒属于套式病毒目(Nidovirales)、冠状病毒科(Coronaviridae)、冠状病毒属(Coronavirus)，是目前人类已知的RNA病毒中基因组最大的病毒，其长度为27至32kb。冠状病毒有至少4个主要结构蛋白，包括刺突蛋白(S)，膜蛋白(M)，包膜蛋白(E)和核衣壳(N)蛋白，这些蛋白对于病毒与细胞受体结合至关重要，都是构成病毒完成结构所必需的。其中核衣壳蛋白(N)是一种碱性磷蛋白，其中央区与病毒基因组RNA结合，形成卷曲的核衣壳螺旋，是包裏病毒遗传物质的核心结构，在感染细胞中是表达量最高的病毒蛋白之一。
最初的单克隆抗体的制备技术是杂交瘤技术。该方法将小鼠B淋巴细胞与骨髓瘤细胞融合，形成杂交细胞系就是杂交瘤，杂交瘤可以持续大量分泌特异性单克隆抗体。但是随着对这种抗体的认识不断加深，人们在临床发现，由于物种不相容性，这些抗体在人体内会产生针对鼠抗体的中和抗体，从而降低甚至抵消其治疗效果，更不用说过敏反应导致的风险。因此，核心问题是产生人源化抗体。随着分子生物学和免疫学方法技术的进步，人源化抗体的制备可以通过人源化抗体改造、表达人类抗体基因的转基因小鼠或通过噬菌体展示来完成。利用噬菌体展示技术是一种比较新的产生人源化抗体的方法，从淋巴细胞中获得完整的人的可变区基因，然后克隆抗体可变区至噬菌体外壳蛋白结构基因组上并随着噬菌体的重新组装在噬菌体表面表达。通过与特定的抗原的结合筛选噬菌体，并通过多轮突变改进结合的抗体。这一整个过程模拟了具有一系列特异性结合表位的 B 淋巴细胞群自然免疫选择的过程。
单细胞PCR技术是一个细胞内的DNA或RNA作为模板进行PCR。近年来，随着单细胞PCR技术的广泛地运用，人们开始将单细胞PCR技术用作抗体制备的技术。B淋巴细胞含有表达抗体的成熟转录本。单细胞PCR技术与其他技术相比，不仅使用样本量很少，而且可以获得自然条件下重轻链配对的抗体可变区基因。同时由于体内抗体已经经历过了亲和力成熟，不用再像噬菌体展示技术通过多轮突变改进结合的抗体，更加高效。使用单细胞 PCR技术制备单克隆抗体可以低样本量、高通量、自动快速、高特异性的得到全人源的单克隆抗体，从而将得到的来自每个单个细胞的重链和轻链可变区序列克隆到表达载体上，瞬转细胞表达并纯化抗体。
发明内容
本发明目的就是为了弥补已有技术的缺陷，提供一种人源SARS-CoV-2单克隆抗体的制备及其应用，本发明获得天然配对的人源抗SARS-CoV-2单克隆抗体的体外诊断以及治疗效果检测。
本发明是通过以下技术方案实现的：
一种人源抗SARS-CoV-2单克隆抗体，以新冠疫苗志愿者的外周血记忆B细胞进行单细胞PCR得到抗体可变区序列，然后再体外表达纯化获得；本发明提供的人源SARS-CoV-2单克隆抗体，是一种IgG，其轻链由轻链可变区和轻链恒定区组成，其重链由重链可变区、铰链区和重链恒定区组成；所述抗体可变区序列分为抗体轻链可变区和抗体重链可变区，抗体轻链可变区如下（a）或（b）：（a）序列表的序列1自5’末端第1-312位核苷酸所示的DNA分子和序列2自5’末端第1-369位核苷酸所示的DNA分子；（b）序列表的序列1和2所对应的蛋白质即序列5自N端第1-104位氨基酸所示的蛋白质分子和序列6自N端第1-123位氨基酸所示的蛋白质分子；所述的抗体重链可变区为如下（c）或（d）：（c）序列表的序列3自5’末端第1-420位核苷酸所示的DNA分子和序列4自5’末端第1-417位核苷酸所示的DNA分子；（d）序列表的3和4所对应的蛋白质即序列7自N端第1-140位氨基酸所示的蛋白质分子和序列8自N端第1-139位氨基酸所示的蛋白质分子。
一种编码人源抗SARS-CoV-2单克隆抗体的基因的方法，包括有编码轻链的基因和编码重链的基因，具体如下：
编码轻链的基因为如下（1）或（2）：
（1）序列表的序列1所示的DNA分子；
（2）序列表的序列2所示的DNA分子；
编码重链的基因为如下（3）或（4）：
（3）序列表的序列3所示的DNA分子；
（4）序列表的序列4所示的DNA分子。
一种人源抗SARS-CoV-2单克隆抗体的制备方法，从新冠疫苗志愿者外周血中分离得到记忆B淋巴细胞，利用单细胞PCR方法获得抗体序列，并克隆进抗体表达载体中，在体外进行表达纯化。具体如下：
1.分离疫苗免疫志愿者外周血单核细胞；
2.流式分选抗原特异性记忆B细胞；
3.单细胞 PCR 扩增抗体可变区基因；
4.将天然配对的抗体重轻链构建到体外表达抗体的载体上；
5.体外表达并纯化人源抗SARS-CoV-2单克隆抗体。
人源抗SARS-CoV-2单克隆抗体对抗原识别的检测
所述的人源抗SARS-CoV-2单克隆抗体在制备用于检测诊断SARS-CoV-2中的应用。
所述的人源抗SARS-CoV-2单克隆抗体在制备用于检测诊断SARS-CoV-2中的应用，所述诊断可检测SARS-CoV-2刺突蛋白。
一种用于治疗SARS-CoV-2的药物，其活性成分为所述的人源抗SARS-CoV-2单克隆抗体。
可以竞争性与SARS-CoV-2刺突蛋白竞争性结合到细胞膜表面ACE2受体上。
所述的人源抗SARS-CoV-2单克隆抗体在制备用于SARS-CoV-2的检测中的应用以及在SARS-CoV-2治疗药物中的应用。
本发明的优点是：本发明对灭活病毒疫苗免疫志愿者得到的全血分离得到外周血淋巴细胞，用荧光标记抗体对记忆 B 淋巴细胞表面分子 CD3-CD19+CD27+IgG+进行区分，通过流式细胞术分选得到新冠病毒刺突蛋白特异性的记忆 B 细胞，利用单细胞逆转录试剂盒和特异性引物从记忆 B 细胞中扩增得到一对匹配的抗体可变区基因序列，将其构建到抗体表达载体。然后在HEK293T细胞中表达纯化出抗体并初步检测其功能和效价。本发明单克隆抗体的制备用于新冠治疗药物中，可应用于SARS-CoV-2的检测试剂盒，对SARS-CoV-2病毒的诊断、治疗具有重大应用价值。
附图说明
图1为实施方法2中流式分选抗原特异性单个记忆B细胞。
图2为实施方法3单细胞 PCR 扩增抗体可变区基因电泳结果。
图3为实施方法5中Protein A纯化抗体。
图4为实施方法5中SDS-PAGE检测抗体组装完整性。
图5为实施方法5中亲和层析纯化后的抗体过分子筛图。
图6为实施方法6中人源抗SARS-CoV-2单克隆抗体对抗原识别的检测。
图7为实施方法7中人源抗SARS-CoV-2单克隆抗体阻断ACE2与SARS-CoV-2-RBD 蛋白结合。
具体实施方式
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明， 均为自常规生化试剂商店购买得到的。以下实施例中的定量试验，均设置三次重复实 验，结果取平均值。
AbVec_IGKC载体：Addegene公司，目录号#183702，用于表达抗体轻链κ链。AbVec_IGHC：Addgene公司，目录号#183701，用于表达抗体重链。Hela-ACE2细胞、NIH3T3-ACE2细胞：本实验室构建。人外周血淋巴细胞分离液：SolarbioP8610。Alexa Fluor 700 anti-human CD3 Antibody （BioLegend 317339）、PE/Cy7 anti-human CD19 Antibody（BioLegend 302215）、APC anti-human CD19 Antibody （BioLegend 302809）、PE anti-human IgG Fc Antibody （BioLegend 409303）均购自于BioLegend 。RNA酶抑制剂：SolarbioR8061。SARS-CoV-2 Spike RBD-mFc Recombinant Protein ：Sino Biological40592-V05H。scriptⅡOne Step RT-PCR Kit：SPARK AG0402。哺乳动物贴壁无血清培养基：BI 05-060-1。PEI MAX 40K：YEASEN公司，目录号40816ES03。
实施方法1：全血样本的外周血单核细胞的分离
拿到新鲜抽取的灭活新冠病毒疫苗免疫后的全血样本后，立即使用人外周血淋巴细胞分离液来分离外周血淋巴细胞 。该产品是一种用于分离人外周血淋巴细胞的密度梯度分离液。其分离原理是根据血细胞的密度差异经过密度梯度离心使细胞按相应密度梯度分布， 从而将淋巴细胞从人外周血中分离出来。 使用人外周血淋巴细胞分离液 我们分离得到了大量的人外周血单个核细胞。
实施方法2：:流式分选抗原特异性单个B淋巴细胞
使用BECKMAN COULTER MoFlo Astrios EQ超速流式细胞分选仪。通过淋巴细胞的细胞表面分子来区分B细胞与T细胞，目前对于人类的淋巴细胞的表面分子的研究已经比较全面、成熟。简单来说，B细胞系表面特征是CD19和CD20，T细胞系表面特征是CD7和CD3。在对之前相关的研究总结中，我们发现常用的B细胞分选特征为CD3-CD19+CD27+CD38+。在淋巴细胞群中，通过T细胞与B细胞表面特异性的CD3和CD19将B细胞与T细胞分离开来。研究人员对于记忆B细胞的特异表面分子是CD27这一结论达成了共识，这可以让我们精确区分出记忆B细胞。B细胞表面有抗原受体（BCR）复合物，BCR复合物包括可以特异性识别和结合抗原的mIg，而浆细胞表面不表达 mIg。据此，我们可以将抗原特异性的记忆B细胞与其他细胞分离开来。如图1所示，不同坐标轴代表不同荧光标记抗体，荧光强度越大越靠近两边。如图A，首先通过FSC和SSC将淋巴细胞分离开来。淋巴细胞位于左下角，右下方细胞团为单核细胞，右上方细胞团为中性粒细胞。在选中的门控里，如图B，然后通过CD3和CD19荧光强度框选出左上方CD3-CD19+细胞群，即为B细胞。在图C中，继续在选定的门控中，根据CD27和IgG荧光强度，用IgG+和CD27+分区分出右上方细胞群，即为记忆B细胞。最后在图D中，通过荧光标记的刺突蛋白分选出Spike+的细胞群，即为SARS-CoV-2 Spike RBD蛋白特异性的记忆B淋巴细胞。
最后我们将分选得到的阳性目的细胞，按照每孔一个细胞加入到提前添加入了RNA酶抑制剂的96孔板中，分选得到了共计288个的抗原特异性记忆B淋巴细胞。立即置于冰上，保存于-80 ℃冰箱。
实施方法3：单细胞 PCR 扩增抗体可变区基因
以先前分选得到的抗原特异性的人单个记忆B淋巴细胞为材料，使用特异性引物通过一轮逆转录 PCR 得到特定的含有抗体基因序列的cDNA。接下来，将得到的从 DNA 模板分为三份，分别使用抗体重链 H，轻链 κ、λ可变区对应的特异性引物集进行 PCR 反应。对 PCR 反应产物使用特异性引物测序，最终得到抗体可变区基因的序列信息。逆转录 PCR是使用混合引物进行巢式PCR完成的，目的是尽可能的覆盖所有的抗体可变区基因家族。再进行PCR时，使用抗体重轻链对应的特异性引物，一方面可以进一步特异性获得抗体重链、轻链可变区序列，同时也是为了获得足够多的抗体重链和轻链可变区序列。使用文献报道中的扩增抗体可变区特异性引物集，对分选的单个 B 细胞进行单细胞 PCR 来筛选抗体可变区基因。PCR 电泳结果如图2所示，框中选中区域为从同一 B 细胞 C6 同时扩增得到的抗体重轻链可变区。我们对分选得到的单个 B 细胞中的 288个细胞进行了单细胞 PCR，H链扩增得到 61个阳性结果，阳性率为 21%；κ 链扩增得到 34个阳性结果，阳性率为12%；λ链扩增得到 8个阳性结果，阳性率为 3%。H 链扩增阳性率最高，κ 链次之，κ 型抗体更多，这也符合人体抗体类型 κ：λ 约为 2：1 的结果。最终得到两对匹配的抗体重轻链可变区，见序列1、2、3、4、5、6、7、8。
实施方法:4：人源抗SARS-CoV-2单克隆抗体表达载体的构建
将两对天然配对的抗体重轻链可变区构建到抗体表达载体上，将序列表的序列3、4所示的DNA分子分别插入AbVec_IGHC载体，得到重组质粒AbVec_IGHC-1和AbVec_IGHC-2，将序列表的序列1、2所示的DNA分子分别插入AbVec_IGKC载体，得到重组质粒 AbVec_IGKC-1和AbVec_IGKC-2。AbVec_IGHC-1编码的重链可变区序列见序列7，AbVec_IGHC-2编码的重链可变区序列见序列8，AbVec_IGKC-1编码的轻链可变区序列见序列5，AbVec_IGKC-2编码的轻链可变区序列见序列6。
实施方法5：制备人源抗SARS-CoV-2单克隆抗体
提取完整抗体表达载体的无内毒素的质粒，准备转染细胞。转染前将 HEK293T 细胞接种到 150 mm 细胞培养皿内，确保第二天细胞汇合度达到 70%-80%。转染当天提前将细胞培养基换为新鲜的 DMEM。对于要转染的每个细胞培养皿，将2.4 mL DMEM 加入到锥形管中。每个培养皿加入 9 μg 重链质粒和 9 μg 轻链质粒，添加到 DMEM 中，轻轻混匀。另将 100 μL Polyethylenimine (PEI)溶液加入到孵育好的质粒混合物中。轻轻混匀后，在室温下孵育 15 分钟。将 2.5 mL PEI 和质粒混合物轻轻添加到每个细胞培养皿中，充分摇动以确保PEI 和质粒混合物均匀分布。 加入转染试剂后的细胞在 37 °C 的培养箱中培养 8 小时。然后更换培养基为无血清细胞培养基。5天后从细胞培养皿中收集上清，然后用0.45 μm滤膜过滤，收集滤液。采用rProteinA Sepharose4B亲和层析柱进行纯化。rProteinA Sepharose4B亲和层析柱（法玛西亚公司，XK16柱子）：柱体积为 40毫升，内径为16毫米。
结合缓冲液（pH7.0）：含0.15 M NaCl的20 mM磷酸盐缓冲液。
洗脱缓冲液（pH3.0）：0.1 M柠檬酸缓冲液。
流速：1-3 mL/min。
过程：（1）用400 mL结合缓冲液平衡柱子；（2）上样；（3）用400 mL结合缓冲液洗涤柱子；（4）用100 mL洗脱缓冲液洗脱目的蛋白，洗脱曲线见图3，收集保留体积为30-64 mL的过柱后溶液。
得到的过柱后溶液，用Tris水溶液（pH9.0）调pH至7.0，然后使用截留分子量为30kd的超滤管（Millipore公司）进行浓缩，得到的溶液即为含人源抗SARS-CoV-2单克隆抗体的溶液， 10% SDS-PAGE图谱见图4，将亲和层析纯化后的抗体过分子筛，图谱见图5。
实施方法6：人源抗SARS-CoV-2单克隆抗体对抗原识别的检测
以SARS-CoV-2 Spike RBD 蛋白作为样品，牛血清白蛋白BSA作为对照，检测所纯化的人源抗SARS-CoV-2单克隆抗体对抗原的识别能力，如图6所示，两个泳道的样品分别为蛋白 SARS-CoV-2 Spike RBD 和对照蛋白 BSA。孵育抗体后，条带为蛋白SARS-CoV-2Spike RBD（理论值约为 51.5 kDa）。表明该抗体能够识别SARS-CoV-2 Spike RBD，可用于SARS-CoV-2的检测。
实施方法7：:人源抗SARS-CoV-2单克隆抗体功能的初步鉴定
通过配置梯度浓度的蛋白 SARS-CoV-2 RBD-mFc，分别与相同数量的细胞孵育后，使用荧光蛋白进行标记，通过流式细胞仪检测细胞与蛋白 SARS-CoV-2 RBD-mFc 的结合能力。从图7可知，随着孵育的抗体的浓度提高，Hela-ACE2 细胞的荧光强度没有发生明显的偏移，只有在 50 μg/mL 和 100 μg/mL 浓度的抗体组，即峰值发生了明显的偏移，说明细胞表面荧光发生了明显降低，表面结合的 RBD蛋白数量下降。表明制备的单克隆抗体对于阻断 RBD 结合到 Hela-ACE2 细胞表面的能力有限，需要在高浓度条件下才可发挥对细胞明显的保护作用。
综上所述，该人源抗SARS-CoV-2单克隆抗体能够体外检测到SARS-CoV-2刺突蛋白，可作为体外检测抗体，同时具有良好的阻碍病毒S蛋白与细胞膜表面ACE2受体结合的能力，有望成为一种用于临床治疗的抗体药物。
序列1
κ1轻链序列：
ATGACCCAGACTCCACTCTCCCTGTCTGCATCTGTAGGAGACAGAGTCAACATTGCCTGCCGGGCAAGTCAGAGCATTGGCACTAACATCCACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAGACTCCTGATCAAATATGCCTCCGAAAGCATCAGTGGGGTCCCATCAAGATTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAATCTATTACTGTCAGCAAAATAACAATTGGCCTACTACGTTCGGCGGAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
序列2
κ2轻链序列：
ATGCCTCCGAAAGCATCAGTGGGGTCCCATCAAGATTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAATCTATTACTGTCAGCAAAATAACAATTGGCCTACTACGTTCGGCGGAGGGACCAAGGTGGAAATCAAACGAACTGTGGCGGCGCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGGAAATCTGGTACCGCTAGCGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGGGACAGCACACCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
序列3
H1重链序列：
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCCGAGGTGCAGCTGGTGCAGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATTCAGCCTGACTAACTACGGCGTCCACTGGGTGCGACAGGCCCCTGGACAAAGACTTGAGTGGATGGGAGTGATCTGGAGTGGTGGTAACACTGACTACAACACCCCCTTCACTAGCAGAGTCACCATCACCAGGGACACGTCCGCTACTACAGCCTACATGGGCCTGTCTAGCCTGAGACCCGAGGACACGGCCGTATATTACTGTGCGAGAGCCCTGACTTATTACGACTACGAGTTCGCCTACTGGGGCCAGGGGACCCTGGTCACCGTCTCCTCAGCGTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCTGTGACGGTCTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA
序列4
H2重链序列为
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCCGAGGTGCAGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATTCAGCCTGACTAACTACGGCGTCCACTGGGTGCGACAGGCCCCTGGACAAAGACTTGAGTGGATGGGAGTGATCTGGAGTGGTGGTAACACTGACTACAACACCCCCTTCACTAGCAGAGTCACCATCACCAGGGACACGTCCGCTACTACAGCCTACATGGGCCTGTCTAGCCTGAGACCCGAGGACACGGCCGTATATTACTGTGCGAGAGCCCTGACTTATTACGACTACGAGTTCGCCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCGTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCTGTGACGGTCTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA
序列5
κ1轻链可变区编码序列
Met Thr Gln Thr Pro Leu Ser Leu Ser Ala Ser Val Gly Asp Arg Val AsnIle Ala Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln LysPro Gly Lys Ala Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly ValPro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser SerLeu Gln Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro ThrThr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser ValPhe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val CysLeu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn AlaLeu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser ThrTyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys ValTyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe AsnArg Gly Glu Cys *
序列6
κ2轻链可变区编码序列
Met Pro Pro Lys Ala Ser Val Gly Ser His Gln Asp Ser Ala Ala Val AspLeu Ala Gln Ile Ser Leu Ser Pro Ser Ala Ala Cys Ser Leu Lys Ile Leu Gln SerIle Thr Val Ser Lys Ile Thr Ile Gly Leu Leu Arg Ser Ala Glu Gly Pro Arg TrpLys Ser Asn Glu Leu Trp Arg Arg His Leu Ser Ser Ser Ser Arg His Leu Met SerArg Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg GluAla Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu SerVal Thr Glu Gln Asp Ser Lys Gly Thr Ala His Arg Thr Val Ala Ala Pro Ser ValPhe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val CysLeu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn AlaLeu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser ThrTyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys ValTyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe AsnArg Gly Glu Cys *
序列7
H1重链可变区编码序列：
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly ValHis Ser Glu Val Gln Leu Val Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly AlaSer Val Lys Val Ser Cys Lys Ala Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val HisTrp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly Val Ile Trp Ser GlyGly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Val Thr Ile Thr Arg Asp ThrSer Ala Thr Thr Ala Tyr Met Gly Leu Ser Ser Leu Arg Pro Glu Asp Thr Ala ValTyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly GlnGly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro LeuAla Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val LysAsp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser GlyVal His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser ValVal Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn HisLys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys ThrHis Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe LeuPhe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr CysVal Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val AspGly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser ThrTyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys GluTyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile SerLys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg AspGlu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro SerAsp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr ThrPro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val AspLys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala LeuHis Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys *
序列8
H2重链可变区编码序列：
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly ValHis Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala SerVal Lys Val Ser Cys Lys Ala Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His TrpVal Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly Val Ile Trp Ser Gly GlyAsn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Val Thr Ile Thr Arg Asp Thr SerAla Thr Thr Ala Tyr Met Gly Leu Ser Ser Leu Arg Pro Glu Asp Thr Ala Val TyrTyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln GlyThr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu AlaPro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys AspTyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly ValHis Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val ValThr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His LysPro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr HisThr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu PhePro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys ValVal Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp GlyVal Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr TyrArg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu TyrLys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser LysAla Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp GluLeu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser AspIle Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr ProPro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp LysSer Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu HisAsn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys *。
Claims (8)
1.一种人源抗SARS-CoV-2单克隆抗体，其特征在于：以新冠疫苗志愿者的外周血记忆B细胞进行单细胞PCR得到抗体可变区序列，然后再体外表达纯化获得；所述抗体可变区序列分为抗体轻链可变区和抗体重链可变区，抗体轻链可变区如下（a）或（b）：（a）序列表的序列1自5’末端第1-312位核苷酸所示的DNA分子和序列2自5’末端第1-369位核苷酸所示的DNA分子；（b）序列表的序列1和2所对应的蛋白质即序列5自N端第1-104位氨基酸所示的蛋白质分子和序列6自N端第1-123位氨基酸所示的蛋白质分子；所述的抗体重链可变区为如下（c）或（d）：（c）序列表的序列3自5’末端第1-420位核苷酸所示的DNA分子和序列4自5’末端第1-417位核苷酸所示的DNA分子；（d）序列表的3和4所对应的蛋白质即序列7自N端第1-140位氨基酸所示的蛋白质分子和序列8自N端第1-139位氨基酸所示的蛋白质分子。
2.一种编码人源抗SARS-CoV-2单克隆抗体的基因的方法，其特征在于：包括有编码轻链的基因和编码重链的基因，具体如下：
编码轻链的基因为如下（1）或（2）：
（1）序列表的序列1所示的DNA分子；
（2）序列表的序列2所示的DNA分子；
编码重链的基因为如下（3）或（4）：
（3）序列表的序列3所示的DNA分子；
（4）序列表的序列4所示的DNA分子。
3.一种人源抗SARS-CoV-2单克隆抗体的制备方法，其特征在于：从新冠疫苗志愿者外周血中分离得到记忆B淋巴细胞，利用单细胞PCR方法获得抗体序列，并克隆进抗体表达载体中，在体外进行表达纯化。
4.如权利要求1所述的人源抗SARS-CoV-2单克隆抗体在制备用于检测诊断SARS-CoV-2中的应用。
5.根据权利要求4所述的人源抗SARS-CoV-2单克隆抗体在制备用于检测诊断SARS-CoV-2中的应用，所述诊断可检测SARS-CoV-2刺突蛋白。
6.一种用于治疗SARS-CoV-2的药物，其特征在于：其活性成分为权利要求1中所述的人源抗SARS-CoV-2单克隆抗体。
7.根据权利要求6所述的一种用于治疗SARS-CoV-2的药物，其特征在于：可以竞争性与SARS-CoV-2刺突蛋白竞争性结合到细胞膜表面ACE2受体上。
8.如权利要求1所述的人源抗SARS-CoV-2单克隆抗体在制备用于SARS-CoV-2的检测中的应用以及在SARS-CoV-2治疗药物中的应用。
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