CN114573691B - 一株人源中和抗体或其抗原结合片段及其应用 - Google Patents
一株人源中和抗体或其抗原结合片段及其应用 Download PDFInfo
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Abstract
本发明涉及一株人源中和抗体或其抗原结合片段及其应用，其包含重链可变区和/或轻链可变区，所述重链可变区包含氨基酸序列：(Ⅰ)分别如SEQ ID NO:1、2、3所示的HCDR1、HCDR2和HCDR3；或(Ⅱ)分别如SEQ ID NO:11、12、13所示的HCDR1、HCDR2和HCDR3；或(Ⅲ)氨基酸序列分别如SEQ ID NO:21、22、23所示的HCDR1、HCDR2和HCDR3；所述轻链可变区包含氨基酸序列：(Ⅰ)分别如SEQ ID NO:4、5、6所示的LCDR1、LCDR2和LCDR3；或(Ⅱ)分别如SEQ ID NO:14、15、16所示的LCDR1、LCDR2和LCDR3；或(Ⅲ)分别如SEQ IDNO:24、35、26所示的LCDR1、LCDR2和LCDR3。本发明的中和抗体YB9‑258、YB13‑292和YB13‑208能有效抑制SARS‑CoV‑2假病毒感染，对SARS‑CoV‑2真病毒也具有较好的中和活性。
Description
技术领域
本发明涉及生物医药领域，具体涉及一株人源中和抗体或其抗原结合片段及其应用，更具体地，涉及一种与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段、多肽、多核苷酸、核酸构建体、表达载体、转化的细胞、药物组合物，以及它们在制备预防或治疗或检测或诊断新冠病毒感染的药物中的应用。
背景技术
冠状病毒病2019(COVID-19)由一种名为严重急性呼吸综合征的新型冠状病毒引起(SARS-CoV-2)，已经在全球范围内严重蔓延。目前，COVID-19已波及全球100多个国家或地区，累计感染2亿多人，并直接造成了440多万人死亡。SARS-CoV-2是一种表面蛋白氨基酸突变率较高的RNA病毒，目前已经报道了多株变异毒株，随着印度Delta变异毒株的扩增，全球多个国家出现疫情的反扑，并呈现暴增的现象，每日全球仍将近有几十万新增确诊感染。而近日出现的新冠变异毒株Omicron在其表面的刺突(S)糖蛋白上超过30个突变，其中受体结合域(receptor-binding domain,RBD)上多达15个突变，对当前疫苗与单克隆抗体药物的有效性带来严重的威胁。疫情的蔓延及持续威胁着人类的生命及健康，严重影响人类正常的社会经济活动。
SARS-CoV-2的S蛋白介导了病毒的膜融合和受体识别。其中，刺突(S)糖蛋白位于N端区域的S1亚基负责病毒的附着，其RBD直接与宿主细胞上的ACE2受体结，合S2亚基(C端)负责膜融合。目前，大多数正在开发的SARS-CoV-2疫苗以刺突(S)糖蛋白为靶点，并具有诱出高水平的以S蛋白或RBD为靶点的中和抗体(NAbs)的能力。但考虑到临床试验的长期性和疫苗在人体内有效性的不确定性，研究具有预期疗效和安全性的SARS-CoV-2中和抗体也是COVID-19治疗策略的关键。目前，已报道多种SARS-CoV-2特异性中和抗体药物获批或正在临床研究。
现有新冠病毒中和抗体大多为通过新冠病毒感染康复患者体内分离获得的传统单克隆抗体，由于自康复病人血清中分离的中和抗体，受病毒株变异等因素影响，分离所获得的中和抗体的广谱中和活性往往受到限制。例如，礼来的Bamlanivimab(LY-CoV555)(Jones et al.,2020)和君实生物的Etesevimab(JS016或LY-CoV016)(Shi et al.,2020)，为分别从美国和中国的新冠病毒感染患者的恢复期血浆中分离出来的中和抗体，于2021年2月被FDA授权紧急联合使用，但由于对巴西Gamma及南非Beta变异株疗效并不显著，于2021年6月25日宣布暂停供应。具有代表性的CR3022和S309为SARS-CoV和SARS-CoV-2交叉反应抗体。然而，S309的中和活性被发现对英国变种有损害，CR3022的效力是否也受到影响仍有待确定。抗体鸡尾酒疗法是两种克隆抗体药物casirivimab和imdevimab的组合，是否能应对新冠的变异并不明确，安全性和有效性也有待评估。
但SARS-CoV-2是一种表面蛋白氨基酸突变率较高的RNA病毒，目前已经报道了多株变异毒株，如Delta，Lambda，Kappa等，近日又出现了新的变异毒株Omicron。这些变异毒株大都具有更强传染性，复制能力更强，病毒载量更高，而且能够逃避中和抗体的中和能力。目前抗体药物对于近期出现的Omicron(B.1.1.529)变异毒株的中和抗体能力下降明显，因此筛选一种可以预防已知和未来变种感染的广谱性的中和抗体迫在眉睫。
发明内容
发明目的
本发明的目的在于提供一种人源中和抗体或其抗原结合片段及其应用，更具体地，涉及一种与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段、多肽、多核苷酸、核酸构建体、表达载体、转化的细胞、药物组合物，以及它们在制备预防或治疗或检测或诊断新冠病毒感染的药物中的应用。本发明的人源中和抗体能有效中和包括新冠病毒SARS-CoV-2原始毒株(WT)、变异毒株Beta(B.1.351)、变异毒株Delta(B.1.617.2)、变异毒株Omicron(B.1.1.529)等在内的多种新冠变异毒株，可以满足我国新冠疫情防控的药品需求，为科学应对复杂多变的新冠疫情提供重要工具。
解决方案
为实现上述目的，本发明提供了如下技术方案：
第一方面，本发明提供了一种与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段，其包含重链可变区和/或轻链可变区，
所述重链可变区包含：
(Ⅰ)氨基酸序列分别如SEQ ID NO:1(即，SNYMH)、SEQ ID NO:2(即，VLYAGGSAFYADSVKG)和SEQ ID NO:3(即，CARGLGDYLDSW)所示的HCDR1、HCDR2和HCDR3；或与SEQ ID NO:1(即，SNYMH)、SEQ ID NO:2(即，VLYAGGSAFYADSVKG)和SEQ ID NO:3(即，CARGLGDYLDSW)所示氨基酸序列分别具有1、2或3个氨基酸差异的HCDR1、HCDR2和HCDR3；或
(Ⅱ)氨基酸序列分别如SEQ ID NO:11(即，GFSFITY)、SEQ ID NO:12(即，SSNILS)和SEQ ID NO:13(即，CARTRSRSVRNCTSATCPVDAFDLW)所示的HCDR1、HCDR2和HCDR3；或与SEQID NO:11(即，GFSFITY)、SEQ ID NO:12(即，SSNILS)和SEQ ID NO:13(即，CARTRSRSVRNCTSATCPVDAFDLW)所示氨基酸序列分别具有1、2或3个氨基酸差异的HCDR1、HCDR2和HCDR3；或
(Ⅲ)氨基酸序列分别如SEQ ID NO:21(即，TSGVSVG)、SEQ ID NO:22(即，LIYWDDDKRYSPSLTS)和SEQ ID NO:23(即，PRYYGDSSGYYWI)所示的HCDR1、HCDR2和HCDR3；或与SEQ ID NO:21(即，TSGVSVG)、SEQ ID NO:22(即，LIYWDDDKRYSPSLTS)和SEQ ID NO:23(即，PRYYGDSSGYYWI)所示氨基酸序列分别具有1、2或3个氨基酸差异的HCDR1、HCDR2和HCDR3；
所述轻链可变区包含：
(Ⅰ)氨基酸序列分别如SEQ ID NO:4(即，RASQGIGSWLA)、SEQ ID NO:5(即，AASTLQS)和SEQ ID NO:6(即，QQANSVLALT)所示的LCDR1、LCDR2和LCDR3；或与SEQ ID NO:4(即，RASQGIGSWLA)、SEQ ID NO:5(即，AASTLQS)和SEQ ID NO:6(即，QQANSVLALT)所示氨基酸序列分别具有1、2或3个氨基酸差异的LCDR1、LCDR2和LCDR3；或
(Ⅱ)氨基酸序列分别如SEQ ID NO:14(即，RSSQSLLRSNGYNYLD)、SEQ ID NO:15(即，LGSNRAS)和SEQ ID NO:16(即，MQALQTPYT)所示的LCDR1、LCDR2和LCDR3；或与SEQ IDNO:14(即，RSSQSLLRSNGYNYLD)、SEQ ID NO:15(即，LGSNRAS)和SEQ ID NO:16(即，MQALQTPYT)所示氨基酸序列分别具有1、2或3个氨基酸差异的LCDR1、LCDR2和LCDR3；或
(Ⅲ)氨基酸序列分别如SEQ ID NO:24(即，SGDALPKQYAY)、SEQ ID NO:25(即，KTSERPS)和SEQ ID NO:26(即，QSADSSGFYV)所示的HCDR1、HCDR2和HCDR3；或与SEQ ID NO:24(即，SGDALPKQYAY)、SEQ ID NO:25(即，KTSERPS)和SEQ ID NO:26(即，QSADSSGFYV)所示氨基酸序列分别具有1、2或3个氨基酸差异的HCDR1、HCDR2和HCDR3。
本发明的冠状病毒主要是指新冠病毒SARS-CoV-2，对其它的冠状病毒可能也具有中和活性。本发明中的S蛋白主要是指新冠病毒SARS-CoV-2的S1抗原。
在一些实施方式中，所述人源中和抗体或其抗原结合片段，其中，所述抗体或其抗原结合片段包含重链可变区和/或轻链可变区，
所述重链可变区包含：
(Ⅰ)氨基酸序列分别如SEQ ID NO:1(即，SNYMH)、SEQ ID NO:2(即，VLYAGGSAFYADSVKG)和SEQ ID NO:3(即，CARGLGDYLDSW)所示的HCDR1、HCDR2和HCDR3；或
(Ⅱ)氨基酸序列分别如SEQ ID NO:11(即，GFSFITY)、SEQ ID NO:12(即，SSNILS)和SEQ ID NO:13(即，CARTRSRSVRNCTSATCPVDAFDLW)所示的HCDR1、HCDR2和HCDR3；或
(Ⅲ)氨基酸序列分别如SEQ ID NO:21(即，TSGVSVG)、SEQ ID NO:22(即，LIYWDDDKRYSPSLTS)和SEQ ID NO:23(即，PRYYGDSSGYYWI)所示的HCDR1、HCDR2和HCDR3；
所述轻链可变区包含：
(Ⅰ)氨基酸序列分别如SEQ ID NO:4(即，RASQGIGSWLA)、SEQ ID NO:5(即，AASTLQS)和SEQ ID NO:6(即，QQANSVLALT)所示的LCDR1、LCDR2和LCDR3；或
(Ⅱ)氨基酸序列分别如SEQ ID NO:14(即，RSSQSLLRSNGYNYLD)、SEQ ID NO:15(即，LGSNRAS)和SEQ ID NO:16(即，MQALQTPYT)所示的LCDR1、LCDR2和LCDR3；或
(Ⅲ)氨基酸序列分别如SEQ ID NO:24(即，SGDALPKQYAY)、SEQ ID NO:25(即，KTSERPS)和SEQ ID NO:26(即，QSADSSGFYV)所示的HCDR1、HCDR2和HCDR3。
在一些实施方式中，所述人源中和抗体或其抗原结合片段，其包含：
(Ⅰ)重链可变区，其氨基酸序列具有分别如SEQ ID NO:1(即，SNYMH)、SEQ ID NO:2(即，VLYAGGSAFYADSVKG)和SEQ ID NO:3(即，CARGLGDYLDSW)所示的HCDR1、HCDR2和HCDR3；和轻链可变区，其氨基酸序列具有分别如SEQ ID NO:4(即，RASQGIGSWLA)、SEQ ID NO:5(即，AASTLQS)和SEQ ID NO:6(即，QQANSVLALT)所示的LCDR1、LCDR2和LCDR3；或
(Ⅱ)重链可变区，其氨基酸序列具有分别如SEQ ID NO:11(即，GFSFITY)、SEQ IDNO:12(即，SSNILS)和SEQ ID NO:13(即，CARTRSRSVRNCTSATCPVDAFDLW)所示的HCDR1、HCDR2和HCDR3；和轻链可变区，其氨基酸序列具有分别如SEQ ID NO:14(即，RSSQSLLRSNGYNYLD)、SEQ ID NO:15(即，LGSNRAS)和SEQ ID NO:16(即，MQALQTPYT)所示的LCDR1、LCDR2和LCDR3；或
(Ⅲ)重链可变区，其氨基酸序列具有分别如SEQ ID NO:21(即，TSGVSVG)、SEQ IDNO:22(即，LIYWDDDKRYSPSLTS)和SEQ ID NO:23(即，PRYYGDSSGYYWI)所示的HCDR1、HCDR2和HCDR3；和轻链可变区，其氨基酸序列具有分别如SEQ ID NO:24(即，SGDALPKQYAY)、SEQ IDNO:25(即，KTSERPS)和SEQ ID NO:26(即，QSADSSGFYV)所示的LCDR1、LCDR2和LCDR3。
在一些实施方式中，所述人源中和抗体或其抗原结合片段包含重链可变区和/或轻链可变区，
(Ⅰ)所述重链可变区包含如SEQ ID NO:7所示的氨基酸序列，或与SEQ ID NO:7所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列；和所述轻链可变区包含如SEQ ID NO:8所示的氨基酸序列，或与SEQ ID NO:8所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列；或
(Ⅱ)所述重链可变区包含如SEQ ID NO:17所示的氨基酸序列，或与SEQ ID NO:17所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列；和所述轻链可变区包含如SEQ ID NO:18所示的氨基酸序列，或与SEQ ID NO:18所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列；或
(Ⅲ)所述重链可变区包含如SEQ ID NO:27所示的氨基酸序列，或与SEQ ID NO:27所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列；和所述轻链可变区包含如SEQ ID NO:28所示的氨基酸序列，或与SEQ ID NO:28所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列。
在一些实施方式中，所述人源中和抗体或其抗原结合片段包含重链可变区和/或轻链可变区，
(Ⅰ)所述重链可变区包含如SEQ ID NO:7所示的氨基酸序列，和所述轻链可变区包含如SEQ ID NO:8所示的氨基酸序列，具有分别如SEQ ID NO:7、SEQ ID NO:8所示的氨基酸序列的抗体命名为YB9-258；或
(Ⅱ)所述重链可变区包含如SEQ ID NO:17所示的氨基酸序列，和所述轻链可变区包含如SEQ ID NO:18所示的氨基酸序列，具有分别如SEQ ID NO:17、SEQ ID NO:18所示的氨基酸序列的抗体命名为YB13-292；或
(Ⅲ)所述重链可变区包含如SEQ ID NO:27所示的氨基酸序列；和所述轻链可变区包含如SEQ ID NO:28所示的氨基酸序列，具有分别如SEQ ID NO:27、SEQ ID NO:28所示的氨基酸序列的抗体命名为YB13-208。
上述实施例中，中和抗体YB9-258的重链可变区SEQ ID NO:7所示的氨基酸序列如下所示：
上述实施例中，中和抗体YB9-258的轻链可变区SEQ ID NO:8所示的氨基酸序列如下所示：
上述实施例中，中和抗体YB13-292的重链可变区SEQ ID NO:17所示的氨基酸序列如下所示：
上述实施例中，中和抗体YB13-292的轻链可变区SEQ ID NO:18所示的氨基酸序列如下所示：
上述实施例中，中和抗体YB13-208的重链可变区SEQ ID NO:27所示的氨基酸序列如下所示：
上述实施例中，中和抗体YB13-208的轻链可变区SEQ ID NO:28所示的氨基酸序列如下所示：
在一些实施方式中，所述的人源中和抗体或其抗原结合片段，其中所述抗原结合片段选自Fab、Fab'、Fab'-SH、Fv、scFv、F(ab')2、双抗体。
第二方面，本发明提供一种多肽，其含有选自SEQ ID NO:7、SEQ ID NO:8、SEQ IDNO:17、SEQ ID NO:18、SEQ ID NO:27和/或SEQ ID NO:28所示的序列；可选地，第二方面所述的多肽具有SEQ ID NO:7和/或SEQ ID NO:8所示的序列；可选地，第二方面所述的多肽具有SEQ ID NO:17和/或SEQ ID NO:18所示的序列；可选地，第二方面所述的多肽具有SEQ IDNO:27和/或SEQ ID NO:28所示的序列。
第三方面，提供一种多核苷酸，其编码所述的与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段。
进一步地，所述多核苷酸为DNA或mRNA。
进一步地，所述多核苷酸具有如SEQ ID NO:9和/或SEQ ID NO:10的核苷酸序列；或所述多核苷酸具有如SEQ ID NO:19和/或SEQ ID NO:20的核苷酸序列；或所述多核苷酸具有如SEQ ID NO:29和/或SEQ ID NO:30的核苷酸序列。
在一些实施例中，所述多核苷酸具有如SEQ ID NO:9和SEQ ID NO:10的核苷酸序列；或所述多核苷酸具有如SEQ ID NO:19和SEQ ID NO:20的核苷酸序列；或所述多核苷酸具有如SEQ ID NO:29和SEQ ID NO:30的核苷酸序列。
SEQ ID NO:9所示的核苷酸序列对应编码SEQ ID NO:7的氨基酸序列，SEQ ID NO:9所示的核苷酸序列如下：
SEQ ID NO:10所示的核苷酸序列对应编码SEQ ID NO:8的氨基酸序列，SEQ IDNO:10所示的核苷酸序列如下：
SEQ ID NO:19所示的核苷酸序列对应编码SEQ ID NO:17的氨基酸序列，SEQ IDNO:19所示的核苷酸序列如下：
SEQ ID NO:20所示的核苷酸序列对应编码SEQ ID NO:18的氨基酸序列，SEQ IDNO:20所示的核苷酸序列如下：
SEQ ID NO:29所示的核苷酸序列对应编码SEQ ID NO:27的氨基酸序列，SEQ IDNO:19所示的核苷酸序列如下：
SEQ ID NO:30所示的核苷酸序列对应编码SEQ ID NO:28的氨基酸序列，SEQ IDNO:20所示的核苷酸序列如下：
第四方面，本发明提供一种核酸构建体，其包含所述的多核苷酸。
进一步优选地，所述多核苷酸还包含与所述多核苷酸可操作地连接的至少一个表达调控元件。例如组氨酸标签、终止密码子等。
第五方面，本发明提供一种表达载体，其包含所述的核酸构建体。
第六方面，本发明提供了一种转化的细胞，其包括如上述第二方面所述的多肽、如上述第三方面所述的多核苷酸、如上述第四方面所述的核酸构建体或如上述第五方面所述的表达载体。可选地，为真核表达载体。
第其方面，本发明提供了一种药物组合物，其包含如上述第一方面所述的与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段、如上述第二方面所述的多肽、如上述第三方面所述的多核苷酸、如上述第四方面所述的核酸构建体、如上述第五方面所述的表达载体或如上述第六方面所述的转化的细胞，以及药学上可接受的载体和/或赋形剂。
进一步优选地，所述药物组合物为鼻喷剂、口服制剂、栓剂或胃肠外制剂的形式。
进一步优选地，所述鼻喷剂选自气雾剂、喷雾剂和粉雾剂。
进一步优选地，所述口服制剂选自片剂、粉末剂、丸剂、散剂、颗粒剂、细粒剂、软/硬胶囊剂、薄膜包衣剂、小丸剂、舌下片和膏剂。
进一步优选地，所述胃肠外制剂为经皮剂、软膏剂、硬膏剂、外用液剂、可注射或可推注制剂。
第八方面，本发明提供了一种如上述第一方面所述的与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段、如上述第二方面所述的多肽、如上述第三方面所述的多核苷酸、如上述第四方面所述的核酸构建体、如上述第五方面所述的表达载体或如上述第六方面所述的转化的细胞或如上述第七方面所述的药物组合物在制备预防或治疗或检测或诊断新冠病毒感染的药物中的应用。
优选地，所述新冠病毒为SARS-CoV-2原始毒株和/或SARS-CoV-2变异毒株。
进一步优选地，所述SARS-CoV-2变异毒株包括Alpha(B.1.1.7)、Beta(B.1.351)、Gamma(P.1)、Lambda(C.37)、Kappa(B.1.617.1)、Delta(B.1.617.2)和/或Omicron(B.1.1.529)毒株。
其中，中和抗体YB9-258和YB13-292对新冠病毒SARS-CoV-2的原始毒株(WT)及变异毒株Alpha(B.1.1.7)、Beta(B.1.351)、Gamma(P.1)、Lambda(C.37)、Kappa(B.1.617.1)、Delta(B.1.617.2)和/或Omicron(B.1.1.529)毒株均具有较好的中和活性。
中和抗体YB13-208对新冠病毒SARS-CoV-2的原始毒株(WT)及变异毒株Alpha(B.1.1.7)、Beta(B.1.351)、Gamma(P.1)、Lambda(C.37)、Kappa(B.1.617.1)和/或Delta(B.1.617.2)毒株均具有较好的中和活性。
第九方面，本发明提供了一种预防或治疗新冠病毒的方法，其包括：向有需要的受试者施用预防或治疗有效量的如上述第一方面所述的与冠状病毒S蛋白结合的人源中和抗体或其抗原结合片段、如上述第二方面所述的多肽、如上述第三方面所述的多核苷酸、如上述第四方面所述的核酸构建体、如上述第五方面所述的表达载体或如上述第六方面所述的转化的细胞或如上述第七方面所述的药物组合物。
优选地，所述新冠病毒为SARS-CoV-2原始毒株和/或SARS-CoV-2变异毒株。
进一步优选地，所述SARS-CoV-2变异毒株为Alpha(B.1.1.7)、Beta(B.1.351)、Gamma(P.1)、Lambda(C.37)、Kappa(B.1.617.1)、Delta(B.1.617.2)和/或Omicron(B.1.1.529)毒株。
本发明的药物组合物的有效成分的给药量，根据给药对象、对象脏器、症状、给药方法等不同而存在差异，可以考虑剂型的种类、给药方法、患者的年龄和体重、患者的症状等，根据医生的判断来确定。
有益效果
(1)本发明的中和抗体YB9-258和YB13-292对新冠病毒SARS-CoV-2原始毒株(WT)、变异毒株Alpha(B.1.1.7)、变异毒株Beta(B.1.351)、变异毒株Delta(B.1.617.2)、变异毒株Gamma(P.1)、变异毒株Lambda(C.37)、变异毒株Omicron(B.1.1.529)等均具有较好的中和活性，本发明的中和抗体YB9-258和YB13-292对危害性大的SARS-CoV-2变异毒株Delta(B.1.617.2)、变异毒株Omicron(B.1.1.529)的真病毒、假病毒的中和活性高，IC50≤0.04ug/ml；本发明的中和抗体YB13-208对SARS-CoV-2原始毒株(WT)、变异毒株Alpha(B.1.1.7)、变异毒株Beta(B.1.351)、变异毒株Delta(B.1.617.2)、变异毒株Gamma(P.1)、变异毒株Kappa(B.1.617.1)、变异毒株Delta(B.1.617.2)、变异毒株Lambda(C.37)均具有较好的中和活性，对SARS-CoV-2变异毒株Omicron(B.1.1.529)无中和活性。本发明的中和抗体YB9-258、YB13-292和YB13-208能有效抑制SARS-CoV-2假病毒感染，对真病毒也具有较好的中和活性。本发明的中和抗体有着临床治疗和预防SARS-CoV-2感染的应用价值。
(2)本发明筛选获得的中和抗体具有广谱中和活性，可以有效中和SARS-CoV-2及几种传染性强、危害性大的SARS-CoV-2新冠病毒变异株，例如英国的新冠病毒SARS-CoV-2变异毒株Alpha(B.1.1.7)，南非的新冠病毒SARS-CoV-2变异毒株Beta(B.1.351)，爆发各国的印度新冠病毒SARS-CoV-2变异毒株Delta(B.1.617.2)以及新冠病毒SARS-CoV-2变异毒株Omicron(B.1.1.529)。
(2)本发明利用不同新冠变异毒株感染后康复的患者血浆，可以获得具有较高广谱性候选抗体；采用流式分选和单细胞高通量测试技术，相比传统方法，从高通量scVDJ测序(scVDJ-seq)获得的大规模数据使我们能够在体外抗体表达之前检测B细胞克隆型的富集，快速高效且通量高。本发明所用的稳定高效表达抗体的真核表达系统，使获得的抗体是全人源化的，不需要进一步的人源化处理。
(3)本发明采集了不同新冠变异毒株感染后康复的患者血浆，首先通过磁珠富集出B细胞，通过流式分选技术分选出新冠S1特异性单B细胞，采用10×Genomics技术进行了单细胞建库、BCR免疫组库和转录组的高通量测序。通过数据分析，我们对抗体序列按照不同参数如抗体序列的丰度、频率、使用的胚系基因、突变率等进行排序和打分，从中挑选出有潜在亲和里的抗体序列进行批量合成和真核表达纯化。接着我们采用ELISA、SPR等方法对候选抗体于不同新冠变异毒株S1蛋白的结合能力和亲和能力进行测试，并对不同新冠变异毒株的假病毒和真病毒的中和能力等进行探究，确保筛选出中和抗体是有效且广谱的。
(4)本发明为新型冠状病毒的临床预防、治疗和检测提供了潜在的抗体新药。
附图说明
一个或多个实施例通过与之对应的附图中的图片进行示例性说明，这些示例性说明并不构成对实施例的限定。在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
图1是本发明实施例3的采用ELISA法分析中和抗体对不同新冠病毒原始毒株及变异毒株S1抗原的结合活性；
图2是本发明实施例4的不同中和抗体与不同SARS-CoV-2病毒株S1抗原的亲和力常数结果示意图；
图3是本发明实施例7的中和抗体中和不同SARS-CoV-2假病毒株的中和效果示意图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。
另外，为了更好的说明本发明，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。在一些实施例中，对于本领域技术人员熟知的原料、元件、方法、手段等未作详细描述，以便于凸显本发明的主旨。
以下，对本发明进行详述。
定义
当提及配体/受体、抗体/抗原或其它结合对时，“特异性”结合是指在蛋白和/或其它生物试剂的异质群体中确定是否存在所述蛋白例如本发明的中和抗体与SARS-CoV-2S1蛋白的结合反应。因此，在所指定的条件下，特定的配体/抗原与特定的受体/抗体结合，并且并不以显著量与样品中存在的其它蛋白结合。
本发明以下实施例中所使用的试剂、酶、培养基、抗生素和牛奶等化学材料均为市售产品，例如，(Chromium Single Cell V(D)J Reagent Kits,10X Genomics)试剂盒购自10XGenomics公司。
本发明以下实施例中的抗原、假病毒均为市售产品，例如，RBD抗原或S1抗原均购自北京义翘神州科技股份有限公司，其中，
原始毒株(WT)S1抗原的货号为：40591-V08H，北京义翘神州科技股份有限公司。
原始毒株(WT)RBD抗原的货号为：40592-V08H，北京义翘神州科技股份有限公司。
变异毒株Delta S1抗原的货号为：40591-V08H23，北京义翘神州科技股份有限公司。
变异毒株Delta RBD抗原的货号为：40592-V08H90，北京义翘神州科技股份有限公司。
变异毒株Beta RBD抗原的货号为：40592-V08H85，北京义翘神州科技股份有限公司。
变异毒株Beta S1抗原的货号为：40591-V08H10，北京义翘神州科技股份有限公司。
变异毒株Omicron RBD抗原的货号为：40592-V08H121，北京义翘神州科技股份有限公司。
变异毒株Omicron S1抗原的货号为：40591-V08H41，北京义翘神州科技股份有限公司。
假病毒变异毒株Omicron购自南京诺唯赞生物科技股份有限公司，货号：DD1768-03。
假病毒变异毒株Delta购自苏州博奥龙科技有限公司，货号：BDAA0115。
假病毒原始毒株WT购自南京诺唯赞生物科技股份有限公司，货号：DD1402-03。
一些常用的生物材料，如感受态细胞、载体、辅助噬菌体、待转化的细胞等也为市售产品。
下述实施例中的抗体编号分别对应的是：
抗体YB9-258具有如SEQ ID NO:7所示的重链可变区的氨基酸序列和SEQ ID NO:8所示的轻链可变区的氨基酸序列。
抗体YB13-292具有如SEQ ID NO:17所示的重链可变区的氨基酸序列和SEQ IDNO:18所示的轻链可变区的氨基酸序列。
抗体YB13-208具有如SEQ ID NO:27所示的重链可变区的氨基酸序列和SEQ IDNO:28所示的轻链可变区的氨基酸序列。
实施例1：高通量单细胞测序获得抗体序列信息
从Delta(B.1.617.2)新冠病毒变异毒株感染后康复的患者采集血液，新鲜血液中用Ficoll进行梯度离心分离外周血单个核细胞(PBMCs)。并通过磁珠法从PBMC中分离出B细胞，抗原结合B细胞富集。然后进行文库构建，文库构建是根据试剂盒说明书(ChromiumSingle Cell V(D)J Reagent Kits,10X Genomics)在P2实验室进行的。测序在华大测序平台上进行，运行MGISEQ-2000RS Sequencing Flow cell试剂盒(华大智造)。测序下机后对数据进行分析，并进行抗体组装。
实施例2抗体蛋白表达及纯化
委托金斯瑞公司进行抗体蛋白表达及纯化。
实施例3 ELISA法分析中和抗体与SARS-CoV-2原始毒株及突变毒株抗原的结合能力
取50ng的新冠病毒RBD抗原或新冠病毒S1抗原包被ELISA板，4℃，过夜。PBST(0.05％)洗涤3次。每孔中加入5％脱脂奶粉100ul，室温封闭2h。PBST洗涤3次。中和抗体用脱脂奶粉进行梯度稀释，起始浓度为1.5μg/ml(10nM)，并依次5倍梯度稀释，共8个浓度梯度，加入孔中，每个浓度梯度重复3个孔，加入50ul用脱脂奶粉配制成2ug/ml的一抗，室温孵育1h。PBST洗涤3次。加入50ul 8000倍稀释的Anti human-FC的二抗，室温孵育45min，PBST洗涤3次。加入100μl TMB显色液(abcam)，显色10min，加入等体积TMB stop buffer(abcam)终止显色，OD450读值。分析中和抗体与SARS-CoV-2不同病毒株的抗原结合能力。
采用不同SARS-CoV-2新冠病毒株的S1抗原的ELISA检测结果如图1显示。结果表明：
中和抗体YB9-258和YB13-292能与新冠病毒SARS-CoV-2原始毒株(WT)的S1抗原、变异毒株Alpha(B.1.1.7)的S1抗原、变异毒株Beta(B.1.351)的S1抗原、变异毒株Delta(B.1.617.2)的S1抗原、变异毒株Gamma(P.1)的S1抗原、变异毒株Lambda(C.37)的S1抗原、变异毒株Omicron(B.1.1.529)的S1抗原等均具有较好的结合活性，显示出良好的广谱性。
中和抗体YB13-208除了对新冠病毒SARS-CoV-2变异毒株Omicron(B.1.1.529)的S1蛋白结合活性较低外，对其它新冠病毒SARS-CoV-2病毒株的S1抗原均具有较好的结合活性，也具有较好的广谱性。
实施例4 SPR法测定中和抗体同原始毒株及突变型抗原的亲和力常数
分别将新冠病毒SARS-CoV-2原始毒株(WT)S1抗原，Delta(B.1.617.2)S1抗原及Omicron(B.1.1.529)S1抗原耦联至CM5芯片，抗体蛋白用HBS-P缓冲液稀释，本例中，以19.2μg/ml(128nM)作为抗体起始浓度，依次2倍梯度稀释，稀释6个浓度梯度，以缓冲液作为对照。每次进样120s，解离240s，流速30ul/min，再用10mM PH2.0 Glycine再生，重复循环直至所有浓度梯度进样完成。程序运行结束后，使用Biacore T200(GE)仪器自带分析程序进行拟合分析，得出中和抗体亲和力常数结果，结果如表1和图2。结果显示，中和抗体YB9-258、YB13-292、YB13-208均对与新冠病毒的原始毒株(WT)，变异毒株Delta(B.1.617.2)及变异毒株Omicron(B.1.1.529)的SARS-CoV-2S1抗原具有较高的亲和力。
表中1和各抗中体和亲抗和体力亲和的力结的合结解合离解离常常数数KDKD(M(M))
| 抗体信息 | WT | Delta | Omicron |
| YB9-258 | 7.17E-11 | 8.33E-10 | 4.17E-12 |
| YB13-292 | 1.80E-10 | 3.91E-12 | 6.06E-09 |
| YB13-208 | 8.20E-11 | 6.39E-10 | 3.11E-09 |
实施例5利用SPR法预测中和抗体结合竞争表位
取CM5芯片，包被SARS-CoV-2新冠病毒Delta(B.1.617.2)S1抗原至响应值为150RU。中和抗体用HBS-P缓冲液配制成200nM，上样速度10ul/min，饱和时间200s，再生时间60s。每一个抗体都先单独饱和，记录饱和时的响应值。再进行竞争实验时，先上其中一个抗体饱和，再接着上另一个抗体，看响应值以及实时曲线的趋势，来判断两个抗体之间的表位关系。若两个抗体为不同表位，那么上完样时，两抗体的RU值分别与单独饱和时的响应值一样，若存在表位竞争，当上第二个抗体时，数值会有所下降，根据下降的多少来看两者的竞争情况。结果显示，这些中和抗体分为2类不同表位，中和抗体YB9-258与抗体YB13-208表位相同，中和抗体YB13-292与YB9-258、YB13-208表位不同，说明中和抗体YB13-292可以与中和抗体YB9-258或YB13-208联合使用。
实施例6利用新冠假病毒实验检测抗体的中和作用
将待检测的血清于56℃水浴灭活30min，6000g离心3min，将上清转移至2.5ml离心管中待用。于B11-D11(细胞对照CC，见表2)加入DMEM无血清培养基120μl/孔；E11-G11(病毒对照VC，见表2)中加入DMEM无血清培养基60μl/孔；于G2-G10加入DMEM无血清培养基84uL/孔；B2-F10加入DMEM无血清培养基60uL/孔；血清从30倍开始稀释，于G2、G3和G4孔加入血清样品1(6μl)……以此类推，于G8、G9和G10孔加入血清样品4(6μl)。将每个血清样品进行3倍稀释。将多道移液器调至30μl，对G2～G4孔中液体轻柔的反复吹吸6～8次充分混匀，然后转移30μl液体至对应的F2～F4孔，轻柔的反复吹吸6～8次后转移至E2～E4孔，以此类推，最后从B2～B4中吸弃30μl液体，加样顺序参照表，板上其他样品依旧照此法进行。用DMEM无血清培养基将假病毒稀释至1.3×104(1×104～2×104)TCID50/ml，于第2～10列，以及E11-G11(病毒对照VC，见表2)孔加60μl，使每孔含假病毒的量为650(500-1000)/孔。将上述96孔板置于细胞培养箱中(37℃，5％CO2)孵育1小时。当孵育时间至半小时，取出培养箱中事先准备好的293T-hACE2细胞(汇合率达80％～90％)，以T75培养瓶为例，吸弃瓶中的培养基，加入5ml PBS缓冲液清洗细胞，倾去PBS后，加入3ml 0.25％胰酶-EDTA，使其浸没细胞消化1分钟，倾去胰酶，置于细胞培养箱中消化5分钟，轻轻拍打培养瓶侧壁使细胞脱落，加入10ml培养基中和胰酶，吹打几次后转移至离心管中，210g离心5分钟，倾去上清，用10ml DMEM完全培养基重悬细胞，细胞计数，用DMEM完全培养基将细胞稀释至2×105个/ml。孵育至1小时，用多通道移液器将之前于透明板孵育的样品假病毒混合物转移100ul于TC处理过的白板上。再向96孔白板中每孔加100μl细胞，使每孔细胞为2×104个。将96孔板前后左右轻轻晃动，使细胞在孔中分散均匀，将96孔板放入细胞培养箱中，37℃，5％CO2培养72小时。72小时后从细胞培养箱中取出96孔板，用多道移液器从每个上样孔中吸弃100μl上清，然后加入100μl荧光素酶检测试剂，室温避光反应2min。计算中和抑制率：抑制率＝[1－(样品组的发光强度均值－空白对照CC均值)/(阴性组的发光强度VC均值－空白对照值CC均值)]×100％。根据中和抑制率结果，利用Reed-Muench法计算IC50。
采用SARS-CoV-2原始毒株(WT)假病毒、变异毒株Delta假病毒和变异毒株Omicron假病毒的实验结果如图3所示，中和抗体YB9-258和YB13-292对原始毒株(WT)、变异毒株Delta和变异毒株Omicron假病毒均具有中和活性，而中和抗体YB13-208对SARS-CoV-2变异毒株Omicron假病毒无中和活性或中和活性较低，中和抗体YB9-258和YB13-292对SARS-CoV-2变异毒株Omicron假病毒的中和活性较高，IC50小于0.04ug/ml，表明它们具有更高的抑制Omicron(B.1.1.529)变异毒株感染靶细胞的能力。
实施例7检测抗体对不同真病毒株的中和作用
委托广东省疾病预防控制中心进行中和抗体的中和活性检测，包括原始毒株(WT)，变异毒株Delta(B.1.617.2)和变异毒株Omicron(B.1.1.529)的真病毒，结果如表2。
表2表明，中和抗体YB9-258和YB13-292对SARS-CoV-2原始毒株(WT)，变异毒株Delta(B.1.617.2)及变异毒株Omicron(B.1.1.529)的真病毒表现出较强的中和能力，中和抗体YB13-208对SARS-CoV-2原始毒株(WT)和Delta(B.1.617.2)变异毒株均表现较强的中和能力，对SARS-CoV-2变异毒株Omicron(B.1.1.529)真病毒无中和能力。表2的结果还说明中和抗体与假病毒的中和活性及与真病毒的中和活性呈现较好的相关性。
表2各中和抗体对不同真病毒的中和作用
综上，中和抗体YB9-258、YB13-292、YB13-208抗体能够作为高中和活性的新型冠状病毒(SARS-CoV-2)的中和抗体，其中，中和抗体YB9-258、YB13-292具有优异的广谱性，中和抗体YB13-208也具有较好的广谱性。
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
SEQUENCE LISTING
<110> 广州医科大学附属市八医院
深圳华大生命科学研究院
<120> 一株人源中和抗体或其抗原结合片段及其应用
<130> 1198-220055F
<160> 30
<170> PatentIn version 3.3
<210> 1
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的HCDR1的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(5)
<400> 1
Ser Asn Tyr Met His
1 5
<210> 2
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的HCDR2的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(16)
<400> 2
Val Leu Tyr Ala Gly Gly Ser Ala Phe Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 3
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的HCDR3的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(12)
<400> 3
Cys Ala Arg Gly Leu Gly Asp Tyr Leu Asp Ser Trp
1 5 10
<210> 4
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的LCDR1的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(11)
<400> 4
Arg Ala Ser Gln Gly Ile Gly Ser Trp Leu Ala
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的LCDR2的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(7)
<400> 5
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 6
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的LCDR3的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(10)
<400> 6
Gln Gln Ala Asn Ser Val Leu Ala Leu Thr
1 5 10
<210> 7
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的重链可变区的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(116)
<400> 7
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 Leu Thr Val Ser Ser Asn
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Leu Tyr Ala Gly Gly Ser Ala Phe Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asn Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Gly Leu Gly Asp Tyr Leu Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 8
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的轻链可变区的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(108)
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Val Leu Ala
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 9
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的重链可变区的编码核苷酸序列
<220>
<221> misc_feature
<222> (1)..(348)
<400> 9
gaagtgcaac tagtggaaag tggtggtggt ctgatccagc ccggaggctc tctgcggctg 60
tcttgtgctg cttctggact caccgtgtcc tccaactaca tgcactgggt gcggcaagct 120
cctggcaagg gcctggaatg ggtctccgtg ctgtatgctg gcggctccgc cttctacgcc 180
gattctgtga aaggcagatt caccatctcc cgcaacaact ccaagaacac cctgtacctg 240
cagatgaata gcctgagagc cgaggacacc gccatctact actgcgccag aggcctgggc 300
gactacctgg actcctgggg ccagggcaca ctggtgaccg tgtctagc 348
<210> 10
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> 中和抗体YB9-258的轻链可变区的编码核苷酸序列
<220>
<221> misc_feature
<222> (1)..(324)
<400> 10
gatatccaaa tgactcaaag tccaagtagt gtcagcgcct ctgtgggcga cagagtgacc 60
atcacctgta gagccagcca gggcatcggc tcctggctgg cctggtacca gcagaaaccc 120
ggcaaggccc ctcagctgct gatctacgct gcttctacac tgcaatccgg cgtgcctcca 180
cggttctccg gatctggctc tggcaccgac ttcaccctga caatcacctc cctgcagcct 240
gaggattttg cttcctacta ctgccagcag gccaactccg tgctggctct caccttcggc 300
ggcggaacca aggtggaaat caag 324
<210> 11
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的HCDR1的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(7)
<400> 11
Gly Phe Ser Phe Ile Thr Tyr
1 5
<210> 12
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的HCDR2的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(6)
<400> 12
Ser Ser Asn Ile Leu Ser
1 5
<210> 13
<211> 25
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的HCDR3的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(25)
<400> 13
Cys Ala Arg Thr Arg Ser Arg Ser Val Arg Asn Cys Thr Ser Ala Thr
1 5 10 15
Cys Pro Val Asp Ala Phe Asp Leu Trp
20 25
<210> 14
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的LCDR1的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(16)
<400> 14
Arg Ser Ser Gln Ser Leu Leu Arg Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的LCDR2的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(7)
<400> 15
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 16
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的LCDR3的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(9)
<400> 16
Met Gln Ala Leu Gln Thr Pro Tyr Thr
1 5
<210> 17
<211> 134
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的重链可变区的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(134)
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ile Thr Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Asn Ile Leu Ser Ser Thr Ser Tyr Ile Tyr Tyr
50 55 60
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Ala
65 70 75 80
Asn Ser Leu Phe Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala
85 90 95
Gln Tyr Tyr Cys Ala Arg Thr Arg Ser Arg Ser Val Arg Asn Cys Thr
100 105 110
Ser Ala Thr Cys Pro Val Asp Ala Phe Asp Leu Trp Gly Gln Gly Thr
115 120 125
Met Val Ile Val Ser Ser
130
<210> 18
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的轻链可变区的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(112)
<400> 18
Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Arg Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro His Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105 110
<210> 19
<211> 402
<212> DNA
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的重链可变区的编码核苷酸序列
<220>
<221> misc_feature
<222> (1)..(402)
<400> 19
gaagtgcaac tagtggaaag tggtggtggt ctcgtgaagc ccggcggctc tctgcggctg 60
tcctgcgctg cttctggatt ttccttcatc acctacaaca tgaactgggt gcgccaagct 120
cctggcaagg gcctggagtg ggtcagctcc atctcctcca acatcctgtc ttctacatcc 180
tacatctact atgccgactc cgtgaaaggc agattcacca tctctcggga cgatgccgcc 240
aactccctgt tcctgcagat gaatagcctg agagtggaag atacagctca gtactactgc 300
gccagaacca gatccagatc tgtgcggaac tgcacctctg ccacctgtcc tgtggacgcc 360
ttcgacctgt ggggccaggg caccatggtg atcgtgtcca gc 402
<210> 20
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-292的轻链可变区的编码核苷酸序列
<220>
<221> misc_feature
<222> (1)..(336)
<400> 20
gatatcgtgc taactcaaag tccactaagt ctgcctgtga ccccaggcga gcctgcttcc 60
atcagctgta gatcctctca gtctctgctg cggtccaacg gctacaacta cctggactgg 120
tatctccaga aacctggcca atctcctcac ctgctgatct acctgggctc caatcgggct 180
tctggagtcc ccgatagatt ctccggctct ggcagcggaa cagacttcac cctgaagatc 240
tccagagtgg aagccgagga cgtgggcgtg tactactgca tgcaggccct gcagacccct 300
tacacctttg gccagggcac caacctggag atcaag 336
<210> 21
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的HCDR1的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(7)
<400> 21
Thr Ser Gly Val Ser Val Gly
1 5
<210> 22
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的HCDR2的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(16)
<400> 22
Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Ser Pro Ser Leu Thr Ser
1 5 10 15
<210> 23
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的HCDR3的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(13)
<400> 23
Pro Arg Tyr Tyr Gly Asp Ser Ser Gly Tyr Tyr Trp Ile
1 5 10
<210> 24
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的LCDR1的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(11)
<400> 24
Ser Gly Asp Ala Leu Pro Lys Gln Tyr Ala Tyr
1 5 10
<210> 25
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的LCDR2的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(7)
<400> 25
Lys Thr Ser Glu Arg Pro Ser
1 5
<210> 26
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的LCDR3的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(10)
<400> 26
Gln Ser Ala Asp Ser Ser Gly Phe Tyr Val
1 5 10
<210> 27
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的重链可变区的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(123)
<400> 27
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Leu Ser Leu Ser Thr Ser
20 25 30
Gly Val Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Pro Glu
35 40 45
Trp Leu Ala Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Ser Pro Ser
50 55 60
Leu Thr Ser Arg Leu Ser Ile Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala His Pro Arg Tyr Tyr Gly Asp Ser Ser Gly Tyr Tyr Trp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 28
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的轻链可变区的氨基酸序列
<220>
<221> DOMAIN
<222> (1)..(107)
<400> 28
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Gln Tyr Ala
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Met Tyr
35 40 45
Lys Thr Ser Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Asp Ser Ser Gly Phe Tyr
85 90 95
Val Phe Gly Thr Gly Thr Gln Val Thr Val Leu
100 105
<210> 29
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的重链可变区的编码核苷酸序列
<220>
<221> misc_feature
<222> (1)..(369)
<400> 29
caaatcactc taaaggaaag tggtccaact ctcgtgaaac ccacccagac cctgacactg 60
acctgtacct tctccggcct gtctctgagc acatctggag tctccgtggg ctggatccgg 120
cagcctcctg gcaaggctcc tgagtggctg gccctgatct actgggacga cgacaagaga 180
tacagccctt ccctgacatc tagactgtcc atcaccaagg acacctccaa gaaccaagtg 240
gtgctgacca tgaccaacat ggatcctgtg gataccgcta cctactactg cgcccaccca 300
cggtactacg gcgactcctc tggctactat tggatctggg gccagggcac catggtgacc 360
gtgtcctct 369
<210> 30
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> 中和抗体YB13-208的轻链可变区的编码核苷酸序列
<220>
<221> misc_feature
<222> (1)..(321)
<400> 30
agttatgaac taactcaacc accaagtgtg tccgtgtccc ctggccagac cgctcggatc 60
acctgttctg gcgacgccct gcctaagcag tacgcctact ggtatcagca gaaaccagga 120
caagctcctg tggtcgtgat gtacaagacc tccgagagac cttctggcat ccccgaaaga 180
tttagcggat cctcctctgg cacaacagtg accctgacca tctccggcgt gcaggccgag 240
gacgaggccg actactactg ccagtctgct gattctagcg gcttctacgt gttcggcacc 300
ggcacccagg tgaccgtgct g 321
Claims (12)
1.一种与冠状病毒 S蛋白结合的人源中和抗体或其抗原结合片段，其包含重链可变区和轻链可变区，
所述重链可变区包含：氨基酸序列分别如SEQ ID NO:11、SEQ ID NO:12和SEQ ID NO:13所示的HCDR1、HCDR2和HCDR3；
所述轻链可变区包含：氨基酸序列分别如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:16所示的LCDR1、LCDR2和LCDR3。
2.根据权利要求1所述的人源中和抗体或其抗原结合片段，其特征在于，其包含重链可变区和轻链可变区：
所述重链可变区包含如SEQ ID NO:17所示的氨基酸序列，或与SEQ ID NO:17所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列；和所述轻链可变区包含如SEQ ID NO:18所示的氨基酸序列，或与SEQ ID NO:18所示的氨基酸序列具有至少95％，96％，97％，98％或99％序列同一性的氨基酸序列。
3.如权利要求1或2所述的人源中和抗体或其抗原结合片段，其中所述抗原结合片段选自Fab、Fab '、Fab '-SH、Fv、scFv、F(ab ')2、双抗体。
4.多核苷酸，其编码权利要求1至3任一所述的与冠状病毒 S蛋白结合的人源中和抗体或其抗原结合片段。
5.根据权利要求4所述的多核苷酸，其特征在于，所述多核苷酸具有如SEQ ID NO:19和/或SEQ ID NO:20的核苷酸序列。
6.一种核酸构建体，其包含权利要求4或5所述的多核苷酸。
7.一种表达载体，其包含权利要求6所述的核酸构建体。
8.一种转化的细胞，其包括权利要求4或5所述的多核苷酸、权利要求6所述的核酸构建体或权利要求7所述的表达载体。
9.一种药物组合物，其包含权利要求1至3任一项所述的与冠状病毒 S蛋白结合的人源中和抗体或其抗原结合片段、权利要求4或5所述的多核苷酸、权利要求6所述的核酸构建体、权利要求7所述的表达载体或权利要求8所述的转化的细胞，以及药学上可接受的载体和/或赋形剂。
10.根据权利要求9所述的药物组合物，其特征在于，所述药物组合物为鼻喷剂、口服制剂或栓剂的形式。
11.根据权利要求9所述的药物组合物，其特征在于，所述药物组合物为胃肠外制剂的形式。
12.一种权利要求1至3任一项所述的与冠状病毒 S蛋白结合的人源中和抗体或其抗原结合片段、权利要求4或5所述的多核苷酸、权利要求6所述的核酸构建体、权利要求7所述的表达载体、权利要求8所述的转化的细胞或权利要求9至11任一所述的药物组合物在制备预防或治疗或检测或诊断新冠病毒感染的药物中的应用；
其中，所述新冠病毒为SARS-CoV-2原始毒株和/或SARS-CoV-2变异毒株；
所述SARS-CoV-2变异毒株选自Alpha (B.1.1.7)、Beta (B.1.351)、Gamma (P.1)、Lambda(C.37)、Delta (B.1.617.2)和Omicron（B.1.1.529）毒株中的一种或几种。
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