CN113388029A - 针对新型冠状病毒的中和性人源单克隆抗体及其应用 - Google Patents
针对新型冠状病毒的中和性人源单克隆抗体及其应用 Download PDFInfo
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Abstract
本发明公开了一种针对新型冠状病毒的中和性人源单克隆抗体，该抗体能够特异性地识别新型冠状病毒抗原，在活病毒上具有较好的中和活性。其针对的表位主要是新型冠状病毒的受体结合域。此外，可将本发明的抗体制成预防和治疗新型冠状病毒的抗体药物，从而在临床中用于预防和治疗新型冠状病毒感染引起的疾病。
Description
技术领域
本发明涉及生物技术领域，具体地指一种针对新型冠状病毒的中和性人源单克隆抗体及其应用。
背景技术
冠状病毒属于套式病毒目冠状病毒科，为有包膜的单股正链RNA病毒，冠状病毒在不同物种内能够引起呼吸道、肠道、肝、肾以及神经系统不同严重程度的疾病。截止2020年3月1日，新型冠状病毒(2019-nCoV，SARS-CoV-2)已在60多个国家传播，确诊病例超过87,000例，死亡2,980例。
冠状病毒在病毒侵入过程中，病毒表面的囊膜糖蛋白(spike glycoprotein，S蛋白)是产生单克隆抗体的靶点。S蛋白在功能上分为两个区域，其中包含受体结合域(receptor binding domain，RBD)的S1亚基负责与宿主细胞的结合，而S2亚基则负责介导病毒与宿主膜的融合。系统分析进化分析表明SARS-CoV-2与SARS-CoV类似，已有文献证明SARS-CoV-2利用与SARS-CoV相同的宿主受体(血管紧张素转换酶2，ACE2)侵入宿主细胞。
针对新型冠状病毒，目前尚无特效的抗病毒药物，也无有效的预防疫苗。中和性抗体可以阻断病毒与靶细胞结合，诱导补体、免疫细胞杀死被病毒染的细胞，在新型冠状病毒防控中具有极大优势。因此，研发针对新型冠状病毒的中和抗体对新型冠状病毒的防治具有重要的意义。
发明内容
本发明的目的在于应对新型冠状病毒的防治，提供一种效果较好的针对新型冠状病毒的中和性人源单克隆抗体及其应用。
为实现上述目的，首先，本发明提供了一种新型冠状病毒抗体的重链可变区，所述重链可变区的互补决定区CDR具有如下氨基酸序列：
SEQ ID NO.8所示的HCDR1；
SEQ ID NO.10所示的HCDR2；
SEQ ID NO.12所示的HCDR3。
上述方案中，优选地，所述HCDR1、HCDR2、HCDR3的核酸编码序列依次为：SEQ IDNO.7、SEQ ID NO.9、SEQ ID NO.11。
优选地，所述重链可变区具有SEQ ID NO.4所示的氨基酸序列。可选地，所述重链可变区具有SEQ ID NO.3所示的核酸序列。
其次，本发明还提供了一种新型冠状病毒抗体的重链，所述重链包括重链可变区和重链恒定区，所述重链可变区如上所述，所述重链恒定区具有如SEQ ID NO.6所示的的氨基酸序列。
可选地，所述重链恒定区具有SEQ ID NO.5所示的核酸序列。
再次，本发明还提供了一种新型冠状病毒的中和性人源单克隆抗体，所述抗体的重链可变区如上所述。
优选地，所述抗体的轻链可变区的互补决定区CDR具有如下氨基酸序列：
SEQ ID NO.20所示的LCDR1；
SEQ ID NO.22所示的LCDR2；
SEQ ID NO.24所示的LCDR3。
可选地，所述LCDR1、LCDR2、LCDR3的核酸编码序列依次为：SEQ ID NO.19、SEQ IDNO.21、SEQ ID NO.23。
优选地，所述抗体的轻链可变区具有SEQ ID NO.16所示的氨基酸序列。
优选地，所述抗体还具有氨基酸序列如SEQ ID NO.18所示的轻链恒定区。
进一步优选地，所述抗体的重链可变区和恒定区的氨基酸序列如SEQ ID NO.2所示，轻链可变区和恒定区的氨基酸序列如SEQ ID NO.14所示。
再次，本发明还提供了一种新型冠状病毒的中和性人源单克隆IgG抗体，所述抗体的重链氨基酸序列如SEQ ID NO.26所示。
可选地，所述抗体的轻链氨基酸序列如SEQ ID NO.30所示。
最后，本发明还提供了上述新型冠状病毒抗体的重链可变区或重链在制备抗新型冠状病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。以及上述新型冠状病毒的中和性人源单克隆抗体/IgG抗体在制备抗新型冠状病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
本发明提供的上述抗新型冠状病毒的中和性人源单克隆抗体，是通过以下方法得到：
利用实验室已构建的抗体Fab噬菌体展示文库(按参考文献：Zhu Z,DimitrovDS.Construction of a large
human phage-displayed Fab library throughone-step cloning.Methods Mol Biol.2009；525:129-4中所述的方法构建)，以哺乳动物细胞表达的新型冠状病毒病毒囊膜蛋白受体结合域为抗原，经过4轮筛选，从第四轮筛选中挑选单克隆进行鉴定，得到了一种能中和新型冠状病毒的抗体Fab F1-A3(以下简称：Fab-F1-A3)，后续并进行鉴定分析。在Fab-F1-A3基础上，我们构建成IgG(IgG-F1-A3)形式并进行后续理化性质和中和活性评价。
本发明的有益效果：所提供的抗体能够特异性识别新型冠状病毒抗原重组蛋白，对于活病毒具有较好的中和活性。其针对的表位主要是新型冠状病毒的S蛋白的受体结合域RBD。此外，可将本发明的抗体制成预防和治疗新型冠状病毒的抗体药物，从而在临床中用于预防和治疗新型冠状病毒引起的疾病。
附图说明
图1为新型冠状病毒受体结合域蛋白表达纯化后的SDS-PAGE图；
其中Marker泳道为分子量标准，WH-RBD-TFc泳道为SARS-CoV-2的RBD蛋白。
图2为Fab-F1-A3抗体纯化后的SDS-PAGE图；
其中Marker泳道为分子量标准，Fab-F1-A3泳道为纯化后的F1-A3。
图3为ELISA测定Fab-F1-A3与新型冠状病毒WH-RBD-TFc蛋白的结合情况分析图。
图4为Fab-F1-A3对新冠病毒的中和活性分析图。
图5为IgG-F1-A3抗体纯化后的SDS-PAGE图；
其中Marker泳道为分子量标准，IgG-F1-A3还原泳道为纯化后的IgG-F1-A3变性还原形式，IgG-F1-A3非还原泳道为纯化后的IgG-F1-A3非还原形式。
图6为ELISA测定IgG-F1-A3与新型冠状病毒WH-RBD-TFc蛋白的结合情况分析图。
图7为生物膜干涉技术(BLI)测定IgG-F1-A3与新型冠状病毒WH-RBD-TFc蛋白的结合。
图8为IgG-F1-A3对新冠病毒的中和活性分析图。
具体实施方式
以下结合附图和具体实施例对本发明作进一步的详细描述。以下实施例是在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
本发明所提及的抗体Fab噬菌体展示文库，其构建过程如参考文献：Zhu Z,Dimitrov DS.Construction of a large
human phage-displayed Fab librarythrough one-step cloning.Methods Mol Biol.2009；525:129-4中所述的方法构建。
实施例1：表达并纯化新型冠状病毒受体结合域(RBD)蛋白
将新型冠状病毒SARS-CoV-2的spike glycoprotein(S蛋白)基因序列(GenBank:QHR63250.2)的胞外域氨基酸序列(319-541)和N端来源于albumin的信号肽、C端凝血酶位点及人源IgG1的Fc片段标签构建到pSectag2A载体上，具体过程为，将新型冠状病毒囊膜S蛋白(GenBank:QHR63250.2)中的受体结合域(receptor binding domian，RBD，氨基酸从319到541)(WH-RBD)、凝血酶位点(T)及人源IgG1的Fc片段(Fc)基因融合后，通过同源重组的方法，构建到pSecTag2A载体(ThermoFisherScientific，货号：V90020)的酶切位点SfiI处，成功得到载体pSectag2A-WH-RBD-TFc。采用哺乳动物细胞293F表达体系表达。转染前1天将293F细胞(控制细胞密度为5×105个/ml)40mL接种于125mL悬浮细胞培养瓶。将40μg质粒(pSectag2A-WH-RBD-TFc)稀释于4mL培养基中轻轻混匀，再将60μL PEI(polyethylenimine)稀释于培养液中，轻轻浑匀。室温孵育20分钟后将它们逐滴加入细胞中。将细胞放入悬浮培养箱中，250转/分钟，37℃下8％CO2悬浮培养。
120小时后收集培养基上清，用Goat Anti-human-IgG Fc Antibody作为抗体通过蛋白免疫印迹(Western Blot)检测pSectag2A-WH-RBD-TFc的表达。
在检测到pSectag2A-WH-RBD-TFc表达后，扩大细胞培养与转染规模，大量表达受体结合域蛋白。收集培养基上清，用ProteinA填料纯化目的蛋白，随后用截留分子量为10kDa的超滤离心管超滤置换缓冲液，经SDS-PAGE验证其纯度。如图1。
实施例2：利用噬菌体Fab展示库筛选
利用抗体Fab噬菌体展示库，以哺乳动物细胞293F表达体系表达的新型冠状病毒spike glycoprotein(S)的受体结合域为抗原，通过免疫磁珠法进行噬菌体Fab库的淘选，特异性的噬菌体被抗原捕获，用PBS+0.05％Tween-20清洗，经过4轮筛选，以及单克隆鉴定测序得到了一株体外活病毒上具有中和活性的克隆，命名为Fab-F1-A3。
Fab-F1-A3的序列清单
实施例3：Fab-F1-A3的表达纯化
按照已有文献(Zhu Z,Dimitrov DS.Methods Mol Biol.2009；525:129-4)对Fab-F1-A3进行表达和纯化。构建Fab-F1-A3原核表达载体，转化入E.coli HB2151。再接种菌种于含100μg/ml氨苄的SB培养基(1L培养基中含30g胰蛋白胨、20g酵母提取物和10g MOPS，pH值用NaOH调至7.0)中，待OD600达到0.7～1.0时加入IPTG至终浓度为200μg/ml，于37℃、220rpm的条件下进行诱导表达14～16h。4℃、6000rpm、15min离心收集菌体，弃培养基，沉淀重悬于1×PBS中，再经多粘菌素B(polymyxin B)处理45min后离心收集上清。用Ni-NTA填料纯化，经SDS-PAGE验证其纯度。随后用截留分子量为10kD的超滤离心管超滤置换缓冲液。所得到的Fab-F1-A3蛋白C-末端含6×His标签和FLAG标签，经SDS-PAGE验证其纯度，如图2。
实施例4：ELISA测定Fab-F1-A3和新型冠状病毒囊膜蛋白受体结合域RBD蛋白的结合
将囊膜蛋白受体结合域(WH-RBD-TFc)(4μg/mL)包被在ELISA板上，并用Fc蛋白做阴性对照，4℃孵育过夜后用PBS+3％milk于37℃封闭2h，之后用PBST(PBS+0.05％Tween20)洗3次，加入梯度稀释的Fab-F1-A3，37℃孵育90min后用PBST(PBS+0.05％Tween 20)洗5次，再加辣根过氧化物酶(HRP)标记的鼠抗FLAG单克隆抗体于37℃孵育40min后，用PBST洗5次，再加入ABTS进行检测。Fab-F1-A3与新型冠状病毒囊膜蛋白受体结合域结合的EC50为4nM，如图3。
实施例5：Fab-F1-A3对SARS-CoV-2毒株的中和活性
铺Vero细胞，按3×105/孔铺于12孔板，在37℃下，5％CO2培养箱培养过夜，第二天用2.5-DMEM(DMEM+2.5％FBS)稀释抗体和新冠病毒，抗体梯度稀释2μM起始，3倍梯度稀释，6个梯度，并设置对照(不加蛋白只加病毒)，将稀释的病毒与抗体混合于37℃孵育1h，弃12孔板的培养基，将病毒抗体混合液加入12孔板Vero细胞中37℃感染1h，弃上清，加1mL的2.5-DMEM+0.9％羟甲基纤维素37℃5％CO2培养2-3天。之后用1mL的20％甲醛固定1h或者更久，弃上清，用水洗涤细胞，0.5％结晶紫孵育5min，弃结晶紫，用水洗涤细胞直至水变无色，晾干计噬斑数，分析中和活性。
结果如图4所示，Fab-F1-A3具有较高的中和活性。
实施例6：IgG-F1-A3的构建与表达纯化
将筛选获得中和性抗体Fab-F1-A3的重链可变区(VH)和轻链(VL+CL)构建到载体pVITRO2-neo-mcs上。具体过程为：将Fab-F1-A3的重链可变区(VH)(SEQ ID NO:3)与信号肽(Immunglobulin heavy chain,partial[Musmusculusdomesticus]GenBank:AAA16913.1)通过PCR方法延伸一起，利用酶切位点EcoRI和XhoI构建到pVITRO2-neo-mcs，测序成功后，将通过PCR获得的信号肽(Immunoglobulin light chain variable region,partial[Homosapiens]GenBank:QDF61488.1)-轻链(VL+CL)(SEQ ID NO:30)，再利用酶切位点BamHI和XbaI将其轻链构建到重链测序成功的载体pVITRO2-neo-mcs上，构建成功的质粒(命名：IgG-F1-A3质粒)做转染。
采用哺乳动物细胞293F表达体系表达。转染前1天将293F细胞(控制细胞密度为5×105个/ml)40mL接种于125mL悬浮细胞培养瓶。将40μg质粒(IgG-F1-A3质粒)稀释于4mL培养基中轻轻混匀，再将60μL PEI(polyethylenimine)稀释于培养液中，轻轻浑匀。室温孵育20分钟后将它们逐滴加入细胞中。将细胞放入悬浮培养箱中，250转/分钟，37℃下8％CO2悬浮培养。
120小时后收集培养基上清，用Goat Anti-human-IgG Fc Antibody作为抗体通过蛋白免疫印迹(Western Blot)检测IgG-F1-A3的表达。
在检测到IgG-F1-A3表达后，扩大细胞培养与转染规模，大量表达受体结合域蛋白。收集培养基上清，用ProteinA填料纯化目的蛋白，随后用截留分子量为10kDa的超滤离心管超滤置换缓冲液，经SDS-PAGE验证其纯度及形式。如图5。
IgG-F1-A3的序列清单
实施例6：ELISA测定IgG-F1-A3和新型冠状病毒囊膜蛋白受体结合域RBD蛋白的结合
将囊膜蛋白受体结合域(WH-RBD-TFc)(4μg/mL)包被在ELISA板上，并用无关蛋白做阴性对照，4℃孵育过夜后用PBS+3％milk于37℃封闭2h，之后用PBST(PBS+0.05％Tween20)洗3次，加入梯度稀释的IgG-F1-A3，37℃孵育90min后用PBST(PBS+0.05％Tween 20)洗5次，再加辣根过氧化物酶(HRP)标记的羊抗人IgG(Fab)抗体于37℃孵育40min后，用PBST洗5次，再加入ABTS进行检测。IgG-F1-A3与新型冠状病毒囊膜蛋白受体结合域结合的EC50约为0.78nM，如图6。
实施例7：为生物膜干涉技术(BLI)测定IgG-F1-A3与新型冠状病毒囊膜蛋白受体结合域RBD蛋白的结合
根据Sulfo-NHS-LC-Biotin试剂说明书先将新型冠状病毒囊膜蛋白受体结合域(WH-RBD-TFc)生物素化，固定Biotin-WH-RBD-TFc浓度为40μg/ml，将抗体IgG-F1-A3梯度稀释缓冲Buffer(PBS+0.01％Tween 20+0.1％BSA)中，上机测结合和解离，并计算亲和力，分析得：结合强，解离慢，亲和力高，亲和力KD(M)为1.299E-11，如图7。
实施例8：IgG-F1-A3对SARS-CoV-2毒株的中和活性
铺Vero细胞，按3×105/孔铺于12孔板，在37℃下，5％CO2培养箱培养过夜，第二天用2.5-DMEM(DMEM+2.5％FBS)稀释抗体和新冠病毒，抗体梯度稀释50μg/ml起始，3倍梯度稀释，12个梯度，并设置对照(不加蛋白只加病毒)，将稀释的病毒与抗体混合于37℃孵育1h，弃12孔板的培养基，将病毒抗体混合液加入12孔板Vero细胞中37℃感染1h，弃上清，加1mL的2.5-DMEM+0.9％羟甲基纤维素37℃5％CO2培养2-3天。之后用1mL的20％甲醛固定1h或者更久，弃上清，用水洗涤细胞，0.5％结晶紫孵育5min，弃结晶紫，用水洗涤细胞直至水变无色，晾干计噬斑数，分析中和活性。结果如图8所示，IgG-F1-A3具有较高的中和活性。
序列表
<110> 中国科学院武汉病毒研究所
<120> 针对新型冠状病毒的中和性人源单克隆抗体及其应用
<130> 200623
<150> 2020101682484
<151> 2020-03-12
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Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 19
<211> 42
<212> DNA
<213> 轻链可变区的LCDR1 DNA(Artificial Sequence)
<400> 19
actgggaacg gcgccaacat cggaatgggt tatgatgtcc ac 42
<210> 20
<211> 14
<212> PRT
<213> 轻链可变区的LCDR1 PRT(Artificial Sequence)
<400> 20
Thr Gly Asn Gly Ala Asn Ile Gly Met Gly Tyr Asp Val His
1 5 10
<210> 21
<211> 21
<212> DNA
<213> 轻链可变区的LCDR2 DNA(Artificial Sequence)
<400> 21
ggaaacacca atcggccctc a 21
<210> 22
<211> 7
<212> PRT
<213> 轻链可变区的LCDR2 PRT(Artificial Sequence)
<400> 22
Gly Asn Thr Asn Arg Pro Ser
1 5
<210> 23
<211> 33
<212> DNA
<213> 轻链可变区的LCDR3 DNA(Artificial Sequence)
<400> 23
cagtcctatg acggcaacct aagggcttcg gtg 33
<210> 24
<211> 11
<212> PRT
<213> 轻链可变区的LCDR3 PRT(Artificial Sequence)
<400> 24
Gln Ser Tyr Asp Gly Asn Leu Arg Ala Ser Val
1 5 10
<210> 25
<211> 1353
<212> DNA
<213> 重链VH+CH1+ Hinge+CH2+CH3 DNA(Artificial Sequence)
<400> 25
caggtgcagc tggtggagtc tggaggaggc ttggtccagc 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 tgaggacacg gctgtgtatt actgtgcgag gggggatggt 300
tcggacgact actactacgg tatggacgtc tggggccaag ggaccacggt caccgtgagc 360
tcagcttcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1080
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320
acgcagaaga gcctctccct gtctccgggt aaa 1353
<210> 26
<211> 451
<212> PRT
<213> 重链VH+CH1+ Hinge+CH2+CH3 PRT(Artificial Sequence)
<400> 26
Gln 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 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 Gly Asp Gly Ser Asp Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 27
<211> 990
<212> DNA
<213> 重链恒定区CH1+ Hinge+CH2+CH3 DNA(Artificial Sequence)
<400> 27
gcttccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960
cagaagagcc tctccctgtc tccgggtaaa 990
<210> 28
<211> 330
<212> PRT
<213> 重链恒定区CH1+ Hinge+CH2+CH3 PRT(Artificial Sequence)
<400> 28
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 29
<211> 651
<212> DNA
<213> IgG 轻链VL+CL DNA(Artificial Sequence)
<400> 29
cagtctgtcg tgacgcagcc gccctcagtg tctggggccc aagggcagag ggtcttcatc 60
tcctgcactg ggaacggcgc caacatcgga atgggttatg atgtccactg gtatcagcaa 120
cttccaggga gagcccccaa actcctcatc tttggaaaca ccaatcggcc ctcaggggtc 180
cctgaccgat tctctgcctc caggtctggc acgtcagcct ccctggccat cactgggctc 240
cagactgcgg atgaggctga ctattactgc cagtcctatg acggcaacct aagggcttcg 300
gtgttcggcg gcgggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 360
actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 420
ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 480
aaggcgggag tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc 540
agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggccccta cagaatgttc a 651
<210> 30
<211> 217
<212> PRT
<213> IgG 轻链VL+CL PRT(Artificial Sequence)
<400> 30
Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Gly Ala Gln Gly Gln
1 5 10 15
Arg Val Phe Ile Ser Cys Thr Gly Asn Gly Ala Asn Ile Gly Met Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Arg Ala Pro Lys Leu
35 40 45
Leu Ile Phe Gly Asn Thr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Ala Ser Arg Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Thr Ala Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Gly Asn
85 90 95
Leu Arg Ala Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 31
<211> 318
<212> DNA
<213> IgG 轻链恒定区CL DNA(Artificial Sequence)
<400> 31
ggtcagccca aggctgcccc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa 60
gccaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120
gcctggaagg cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180
caaagcaaca acaagtacgc ggccagcagc tatctgagcc tgacgcctga gcagtggaag 240
tcccacagaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300
gcccctacag aatgttca 318
<210> 32
<211> 106
<212> PRT
<213> IgG 轻链恒定区CL PRT(Artificial Sequence)
<400> 32
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
Claims (18)
1.一种新型冠状病毒抗体的重链可变区，其特征在于：
所述重链可变区的互补决定区CDR具有如下氨基酸序列：
SEQ ID NO.8所示的HCDR1；
SEQ ID NO.10所示的HCDR2；
SEQ ID NO.12所示的HCDR3。
2.根据权利要求1所述新型冠状病毒抗体的重链可变区，其特征在于：所述HCDR1、HCDR2、HCDR3的核酸编码序列依次为：SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11。
3.根据权利要求1所述新型冠状病毒抗体的重链可变区，其特征在于：所述重链可变区具有SEQ ID NO.4所示的氨基酸序列。
4.根据权利要求1所述新型冠状病毒抗体的重链可变区，其特征在于：所述重链可变区具有SEQ ID NO.3所示的核酸序列。
5.一种新型冠状病毒抗体的重链，所述重链包括重链可变区和重链恒定区，其特征在于：所述重链可变区如权利要求1所述，所述重链恒定区具有如SEQ ID NO.6所示的氨基酸序列。
6.权利要求5所述新型冠状病毒抗体的重链，其特征在于：所述重链恒定区具有SEQ IDNO.5所示的核酸序列。
7.一种新型冠状病毒的中和性人源单克隆抗体，其特征在于：所述抗体的重链可变区如权利要求1所述。
8.根据权利要求7所述新型冠状病毒的中和性人源单克隆抗体，其特征在于：所述抗体的轻链可变区的互补决定区CDR具有如下氨基酸序列：
SEQ ID NO.20所示的LCDR1；
SEQ ID NO.22所示的LCDR2；
SEQ ID NO.24所示的LCDR3。
9.根据权利要求8所述新型冠状病毒的中和性人源单克隆抗体，其特征在于：所述LCDR1、LCDR2、LCDR3的核酸编码序列依次为：SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23。
10.根据权利要求7所述新型冠状病毒的中和性人源单克隆抗体，其特征在于：所述抗体的轻链可变区具有SEQ ID NO.16所示的氨基酸序列。
11.根据权利要求7所述新型冠状病毒的中和性人源单克隆抗体，其特征在于：所述抗体还具有氨基酸序列如SEQ ID NO.18所示的轻链恒定区。
12.根据权利要求7所述新型冠状病毒的中和性人源单克隆抗体，其特征在于：所述抗体的重链可变区和恒定区的氨基酸序列如SEQ ID NO.2所示，轻链可变区和恒定区的氨基酸序列如SEQ ID NO.14所示。
13.一种新型冠状病毒的中和性人源单克隆IgG抗体，其特征在于：所述抗体的重链氨基酸序列如SEQ ID NO.26所示。
14.根据权利要求13所述新型冠状病毒的中和性人源单克隆IgG抗体，其特征在于：所述抗体的轻链氨基酸序列如SEQ ID NO.30所示。
15.权利要求1～4任一项所述新型冠状病毒抗体的重链可变区在制备抗新型冠状病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
16.权利要求5或6所述新型冠状病毒抗体的重链在制备抗新型冠状病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
17.权利要求7～12任一项所述新型冠状病毒的中和性人源单克隆抗体在制备抗新型冠状病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
18.权利要求13或14所述新型冠状病毒的中和性人源单克隆IgG抗体在制备抗新型冠状病毒的重组蛋白、载体、免疫偶联物、多核苷酸、遗传工程化的宿主细胞、药物中的应用。
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| CN114031685A (zh) * | 2022-01-10 | 2022-02-11 | 中国人民解放军军事科学院军事医学研究院 | 一种全人源抗新冠病毒广谱中和抗体zw2g10及应用 |
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| CN113912709B (zh) * | 2021-09-28 | 2022-06-17 | 深圳国家感染性疾病临床医学研究中心 | 新型冠状病毒单克隆抗体及其应用 |
| CN114031685A (zh) * | 2022-01-10 | 2022-02-11 | 中国人民解放军军事科学院军事医学研究院 | 一种全人源抗新冠病毒广谱中和抗体zw2g10及应用 |
| CN114031685B (zh) * | 2022-01-10 | 2022-03-25 | 中国人民解放军军事科学院军事医学研究院 | 一种全人源抗新冠病毒中和抗体zw2g10及应用 |
| WO2023151312A1 (zh) * | 2022-02-14 | 2023-08-17 | 北京昌平实验室 | 乙型冠状病毒广谱中和抗体及其应用 |
| CN114349855A (zh) * | 2022-03-18 | 2022-04-15 | 百斯医学诊断科技(北京)有限公司 | 新型冠状病毒Delta突变株特异性抗体及其应用 |
| CN114349855B (zh) * | 2022-03-18 | 2022-06-28 | 百斯医学诊断科技(北京)有限公司 | 新型冠状病毒Delta突变株特异性抗体及其应用 |
| CN114805562A (zh) * | 2022-05-07 | 2022-07-29 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化纳米抗体及其应用 |
| CN115160434A (zh) * | 2022-05-26 | 2022-10-11 | 广东菲鹏制药股份有限公司 | 人源化单域抗体及其应用和药物 |
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