CN114426574A - 新型冠状病毒中和性人源单克隆抗体及其应用 - Google Patents
新型冠状病毒中和性人源单克隆抗体及其应用 Download PDFInfo
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Abstract
本发明公开了一种抗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，具体地指一种新型冠状病毒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。
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抗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，抗体命名为F1-B5，其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，F1-B5的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，F1-B5的重链可变区具有SEQ ID NO.4所示的氨基酸序列。可选地，F1-B5的重链可变区具有SEQ ID NO.3所示的核酸序列。
本发明还提供了F1-B5的重链，所述重链包括重链可变区和重链恒定区，F1-B5的重链可变区如上所述，F1-B5的重链恒定区具有如SEQ ID NO.6所示的氨基酸序列。可选地，对应核酸序列如SEQ ID NO.5所示。
再次，本发明提供的新型冠状病毒的中和性人源单克隆F1-B5抗体，其重链可变区如上所述。
优选地，F1-B5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，F1-B5的LCDR1、LCDR2、LCDR3的核酸编码序列依次为：SEQ ID NO.19、SEQID NO.21、SEQ ID NO.23。
优选地，F1-B5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，F1-B5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，F1-B5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。
本发明还提供了一种新型冠状病毒抗体的重链可变区，抗体命名为F1-B3，其重链可变区的互补决定区CDR具有如下氨基酸序列：
SEQ ID NO.32所示的HCDR1；
SEQ ID NO.34所示的HCDR2；
SEQ ID NO.36所示的HCDR3。
上述方案中，优选地，F1-B3的HCDR1、HCDR2、HCDR3的核酸编码序列依次为：SEQ IDNO.31、SEQ ID NO.33、SEQ ID NO.35。
优选地，F1-B3的重链可变区具有SEQ ID NO.28所示的氨基酸序列。可选地，F1-B3的重链可变区具有SEQ ID NO.27所示的核酸序列。
本发明还提供了F1-B3的重链，所述重链包括重链可变区和重链恒定区，F1-B3的重链可变区如上所述，F1-B3的重链恒定区具有如SEQ ID NO.30所示的氨基酸序列。可选地，对应核酸序列如SEQ ID NO.29所示。
再次，本发明提供的新型冠状病毒的中和性人源单克隆F1-B3抗体，其重链可变区如上所述。
优选地，F1-B3的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.44所示的LCDR1；
SEQ ID NO.46所示的LCDR2；
SEQ ID NO.48所示的LCDR3。
可选地，F1-B3的LCDR1、LCDR2、LCDR3的核酸编码序列依次为：SEQ ID NO.43、SEQID NO.45、SEQ ID NO.47。
优选地，F1-B3抗体的轻链可变区具有SEQ ID NO.40所示的氨基酸序列。
优选地，F1-B3抗体还具有氨基酸序列如SEQ ID NO.42所示的轻链恒定区。
进一步优选地，F1-B3抗体的重链可变区和恒定区的氨基酸序列如SEQ ID NO.26所示，轻链可变区和恒定区的氨基酸序列如SEQ ID NO.38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抗体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。
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 through one-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，得到了能中和新型冠状病毒的抗体Fab F1-B5(以下简称：F1-B5)和FabF1-B3(以下简称：F1-B3)，后续并进行鉴定分析。
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。数据分析表明，这两株抗体具有不同的表位，如果联用，中和效果更有优势，为后续抗体联用奠定基础，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F1-B5和F1-B3抗体纯化后的SDS-PAGE图；
其中Marker泳道为分子量标准，F1-B5泳道为纯化后的F1-B5，F1-B3泳道为纯化后的F1-B3。
图3为ELISA测定F1-B5和F1-B3与新型冠状病毒WH-RBD-TFc蛋白的结合情况分析图。
图4为F1-B5和F1-B3对新冠病毒的中和活性分析图。
图5为IgG-FB5与Fab-F1-B3的竞争ELISA表位分析图。
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,DimitrovDS.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F1-B5和F1-B3。
F1-B5的序列清单
F1-B3的序列清单
实施例3：F1-B5和F1-B3的表达纯化
按照已有文献(Zhu Z,Dimitrov DS.Methods Mol Biol.2009；525:129-4)对F1-B5和F1-B3进行表达和纯化。构建F1-B5和F1-B3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10gMOPS，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F1-B5和F1-B3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F1-B5和F1-B3与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F1-B5和F1-B3，37℃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。F1-B5和F1-B3与新型冠状病毒囊膜蛋白受体结合域结合的EC50为63nM和12nM，如图3a和3b。
实施例5：F1-B5Fab和F1-B3 Fab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4a和4b所示，F1-B5 Fab和F1-B3 Fab具有中和活性。
实施例6：F1-B5IgG和F1-B3 Fab竞争ELISA表位分析
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，一抗稀释方法：固定F1-B3 Fab的终摩尔浓度为30nM,梯度稀释的F1-B5IgG，将其两者混合，加入96孔板中，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。F1-B5IgG与F1-B3并无竞争关系，说明这两个抗体具有不同的表位，如图5所示。
序列表
<110> 中国科学院武汉病毒研究所
<120> 新型冠状病毒中和性人源单克隆抗体及其应用
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Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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
115 120
<210> 5
<211> 321
<212> DNA
<213> 重链恒定区CH1的核酸序列(Artificial Sequence)
<400> 5
gcctccacca 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 acaaaactag t 321
<210> 6
<211> 107
<212> PRT
<213> 重链恒定区CH1的氨基酸序列(Artificial Sequence)
<400> 6
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 Ser
100 105
<210> 7
<211> 24
<212> DNA
<213> 重链可变区的HCDR1的核酸序列(Artificial Sequence)
<400> 7
ggattcaccg tcagtagcaa ctac 24
<210> 8
<211> 8
<212> PRT
<213> 重链可变区的HCDR1的氨基酸序列(Artificial Sequence)
<400> 8
Gly Phe Thr Val Ser Ser Asn Tyr
1 5
<210> 9
<211> 21
<212> DNA
<213> 重链可变区的HCDR2的核酸序列(Artificial Sequence)
<400> 9
atttatagcg gtggtagcac a 21
<210> 10
<211> 7
<212> PRT
<213> 重链可变区的HCDR2的氨基酸序列(Artificial Sequence)
<400> 10
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 11
<211> 45
<212> DNA
<213> 重链可变区的HCDR3的核酸序列(Artificial Sequence)
<400> 11
gcgagggggg atggttcgga cgactactac tacggtatgg acgtc 45
<210> 12
<211> 15
<212> PRT
<213> 重链可变区的HCDR3的氨基酸序列(Artificial Sequence)
<400> 12
Ala Arg Gly Asp Gly Ser Asp Asp Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 13
<211> 651
<212> DNA
<213> 轻链可变区和恒定区VL+CL的核酸序列(Artificial Sequence)
<400> 13
caggctgtgc tgactcagcc gtcctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacgtcggg gcaggttatg atgtacactg gtaccagcag 120
cttccaggaa cagcccccaa actcctcatc tatggtaaca gtaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtggctcg 300
gtgttcggcg gagggaccaa 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
agctacctga gcctgacgcc tgagcagtgg aagtcccaca aaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggccccta cagaatgttc a 651
<210> 14
<211> 217
<212> PRT
<213> 轻链可变区和恒定区VL+CL的氨基酸序列(Artificial Sequence)
<400> 14
Gln Ala Val Leu Thr Gln Pro Ser Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Val Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
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 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 Lys 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> 15
<211> 333
<212> DNA
<213> 轻链可变区VL的核酸序列(Artificial Sequence)
<400> 15
caggctgtgc tgactcagcc gtcctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacgtcggg gcaggttatg atgtacactg gtaccagcag 120
cttccaggaa cagcccccaa actcctcatc tatggtaaca gtaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtggctcg 300
gtgttcggcg gagggaccaa gctgaccgtc cta 333
<210> 16
<211> 111
<212> PRT
<213> 轻链可变区VL的氨基酸序列(Artificial Sequence)
<400> 16
Gln Ala Val Leu Thr Gln Pro Ser Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Val Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
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> 17
<211> 318
<212> DNA
<213> 轻链恒定区CL的核酸序列(Artificial Sequence)
<400> 17
ggtcagccca aggctgcccc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa 60
gccaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120
gcctggaagg cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180
caaagcaaca acaagtacgc ggccagcagc tacctgagcc tgacgcctga gcagtggaag 240
tcccacaaaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300
gcccctacag aatgttca 318
<210> 18
<211> 106
<212> PRT
<213> 轻链恒定区CL的氨基酸序列(Artificial Sequence)
<400> 18
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 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的核酸序列(Artificial Sequence)
<400> 19
actgggagca gctccaacgt cggggcaggt tatgatgtac ac 42
<210> 20
<211> 14
<212> PRT
<213> 轻链可变区的LCDR1的氨基酸序列(Artificial Sequence)
<400> 20
Thr Gly Ser Ser Ser Asn Val Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 21
<211> 21
<212> DNA
<213> 轻链可变区的LCDR2的核酸序列(Artificial Sequence)
<400> 21
ggtaacagta atcggccctc a 21
<210> 22
<211> 7
<212> PRT
<213> 轻链可变区的LCDR2的氨基酸序列(Artificial Sequence)
<400> 22
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 23
<211> 33
<212> DNA
<213> 轻链可变区的LCDR3的核酸序列(Artificial Sequence)
<400> 23
cagtcctatg acagcagcct gagtggctcg gtg 33
<210> 24
<211> 11
<212> PRT
<213> 轻链可变区的LCDR3的氨基酸序列(Artificial Sequence)
<400> 24
Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Val
1 5 10
<210> 25
<211> 678
<212> DNA
<213> 重链VH+CH1核酸序列(Artificial Sequence)
<400> 25
caggtgcagc tgcaggagtc cgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccaggggagg ggctggagtg ggtctcatcc attagtagta gtagtagtta catatactac 180
gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaaag 300
tggctaagag gggcttttga tatctggggc caagggacca cggtcaccgt ctcctcagcc 360
tccaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgtgaca aaactagt 678
<210> 26
<211> 226
<212> PRT
<213> 重链VH+CH1氨基酸序列(Artificial Sequence)
<400> 26
Gln Val Gln Leu Gln 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 Glu Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Leu Arg Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr Ser
225
<210> 27
<211> 357
<212> DNA
<213> 重链可变区VH核酸序列(Artificial Sequence)
<400> 27
caggtgcagc tgcaggagtc cgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120
ccaggggagg ggctggagtg ggtctcatcc attagtagta gtagtagtta catatactac 180
gcagactcag tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggaaag 300
tggctaagag gggcttttga tatctggggc caagggacca cggtcaccgt ctcctca 357
<210> 28
<211> 119
<212> PRT
<213> 重链可变区VH的氨基酸序列(Artificial Sequence)
<400> 28
Gln Val Gln Leu Gln 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 Glu Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Trp Leu Arg Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 29
<211> 321
<212> DNA
<213> 重链恒定区CH1的核酸序列(Artificial Sequence)
<400> 29
gcctccacca 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 acaaaactag t 321
<210> 30
<211> 107
<212> PRT
<213> 重链恒定区CH1的氨基酸序列(Artificial Sequence)
<400> 30
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 Ser
100 105
<210> 31
<211> 21
<212> DNA
<213> 重链可变区的HCDR1的核酸序列(Artificial Sequence)
<400> 31
ggattcaccg tcagtagcaa c 21
<210> 32
<211> 7
<212> PRT
<213> 重链可变区的HCDR1的氨基酸序列(Artificial Sequence)
<400> 32
Gly Phe Thr Val Ser Ser Asn
1 5
<210> 33
<211> 18
<212> DNA
<213> 重链可变区的HCDR2的核酸序列(Artificial Sequence)
<400> 33
agtagtagta gtagttac 18
<210> 34
<211> 6
<212> PRT
<213> 重链可变区的HCDR2的氨基酸序列(Artificial Sequence)
<400> 34
Ser Ser Ser Ser Ser Tyr
1 5
<210> 35
<211> 30
<212> DNA
<213> 重链可变区的HCDR3的核酸序列(Artificial Sequence)
<400> 35
ggaaagtggc taagaggggc ttttgatatc 30
<210> 36
<211> 10
<212> PRT
<213> 重链可变区的HCDR3的氨基酸序列(Artificial Sequence)
<400> 36
Gly Lys Trp Leu Arg Gly Ala Phe Asp Ile
1 5 10
<210> 37
<211> 651
<212> DNA
<213> 轻链可变区和恒定区VL+CL的核酸序列(Artificial Sequence)
<400> 37
aattttatgc tgactcagcc ccactctatg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccg gcagcagtgg cagcattgcc aacaactatg tgcagtggta ccggcagcgc 120
ccgggcagtg cccccatcac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagtag cacccattgg 300
gtgttcggcg gagggaccaa 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
agctacctga gcctgacgcc tgagcagtgg aagtcccaca aaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggccccta cagaatgttc a 651
<210> 38
<211> 217
<212> PRT
<213> 轻链可变区和恒定区VL+CL的氨基酸序列(Artificial Sequence)
<400> 38
Asn Phe Met Leu Thr Gln Pro His Ser Met Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Gly Ser Ser Gly Ser Ile Ala Asn Asn
20 25 30
Tyr Val Gln Trp Tyr Arg Gln Arg Pro Gly Ser Ala Pro Ile 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 Thr His Trp 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 Lys 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> 39
<211> 333
<212> DNA
<213> 轻链可变区VL的核酸序列(Artificial Sequence)
<400> 39
aattttatgc tgactcagcc ccactctatg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccg gcagcagtgg cagcattgcc aacaactatg tgcagtggta ccggcagcgc 120
ccgggcagtg cccccatcac tgtgatctat gaggataacc aaagaccctc tggggtccct 180
gatcggttct ctggctccat cgacagctcc tccaactctg cctccctcac catctctgga 240
ctgaagactg aggacgaggc tgactactac tgtcagtctt atgatagtag cacccattgg 300
gtgttcggcg gagggaccaa gctgaccgtc cta 333
<210> 40
<211> 111
<212> PRT
<213> 轻链可变区VL的氨基酸序列(Artificial Sequence)
<400> 40
Asn Phe Met Leu Thr Gln Pro His Ser Met Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Thr Ile Ser Cys Thr Gly Ser Ser Gly Ser Ile Ala Asn Asn
20 25 30
Tyr Val Gln Trp Tyr Arg Gln Arg Pro Gly Ser Ala Pro Ile 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 Thr His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 41
<211> 318
<212> DNA
<213> 轻链恒定区CL的核酸序列(Artificial Sequence)
<400> 41
ggtcagccca aggctgcccc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa 60
gccaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120
gcctggaagg cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180
caaagcaaca acaagtacgc ggccagcagc tacctgagcc tgacgcctga gcagtggaag 240
tcccacaaaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300
gcccctacag aatgttca 318
<210> 42
<211> 106
<212> PRT
<213> 轻链恒定区CL的氨基酸序列(Artificial Sequence)
<400> 42
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 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> 43
<211> 39
<212> DNA
<213> 轻链可变区的LCDR1的核酸序列(Artificial Sequence)
<400> 43
accggcagca gtggcagcat tgccaacaac tatgtgcag 39
<210> 44
<211> 13
<212> PRT
<213> 轻链可变区的LCDR1的氨基酸序列(Artificial Sequence)
<400> 44
Thr Gly Ser Ser Gly Ser Ile Ala Asn Asn Tyr Val Gln
1 5 10
<210> 45
<211> 21
<212> DNA
<213> 轻链可变区的LCDR2的核酸序列(Artificial Sequence)
<400> 45
gaggataacc aaagaccctc t 21
<210> 46
<211> 7
<212> PRT
<213> 轻链可变区的LCDR2的氨基酸序列(Artificial Sequence)
<400> 46
Glu Asp Asn Gln Arg Pro Ser
1 5
<210> 47
<211> 30
<212> DNA
<213> 轻链可变区的LCDR3的核酸序列(Artificial Sequence)
<400> 47
cagtcttatg atagtagcac ccattgggtg 30
<210> 48
<211> 10
<212> PRT
<213> 轻链可变区的LCDR3的氨基酸序列(Artificial Sequence)
<400> 48
Gln Ser Tyr Asp Ser Ser Thr His Trp Val
1 5 10
Claims (10)
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。
2.一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.32所示的HCDR1；
SEQ ID NO.34所示的HCDR2；
SEQ ID NO.36所示的HCDR3。
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2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.28所示的氨基酸序列。
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或3所述，所述重链恒定区具有如SEQ ID NO.6所示的氨基酸序列；
或所述重链可变区如权利要求2或4所述，所述重链恒定区具有如SEQ ID NO.30所示的氨基酸序列。
6.一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或3所示，其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；
或所述抗体的重链可变区如权利要求2或4所示，其轻链可变区的互补决定区CDR具有如下氨基酸序列：
SEQ ID NO.44所示的LCDR1；
SEQ ID NO.46所示的LCDR2；
SEQ ID NO.48所示的LCDR3。
7.根据权利要求6所述新型冠状病毒的中和性人源单克隆抗体，其特征在于：当所述抗体的重链可变区如权利要求1或3所示，其轻链可变区具有SEQ ID NO.16所示的氨基酸序列；
或当所述抗体的重链可变区如权利要求2或4所示，其轻链可变区具有SEQ ID NO.40所示的氨基酸序列。
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：当所述抗体的轻链可变区氨基酸序列如SEQ ID NO.16所示，轻链恒定区氨基酸序列如SEQ ID NO.18所示；
或当所述抗体的轻链可变区氨基酸序列如SEQ ID NO.40所示，轻链恒定区氨基酸序列如SEQ ID NO.42所示。
9.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。
10.权利要求6～8任一项所述新型冠状病毒抗体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。
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| WO2019039891A1 (ko) * | 2017-08-23 | 2019-02-28 | 대한민국(관리부서 질병관리본부장) | 중동호흡기증후군 코로나바이러스의 스파이크 단백질에 대한 단일클론항체 및 이의 용도 |
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| CN111592595A (zh) * | 2020-04-27 | 2020-08-28 | 南京医科大学 | 抗新型冠状病毒SARS-Cov-2的中和性抗体及其应用 |
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