CN114805560A - 纳米抗体r14的构建体及其应用 - Google Patents
纳米抗体r14的构建体及其应用 Download PDFInfo
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Abstract
本发明提供了基于特异性结合SARS‑CoV‑2RBD的纳米抗体R14的构建体(包括多价纳米抗体和纳米抗体融合蛋白)、其相关产品及其应用;本发明的基于特异性结合SARS‑CoV‑2RBD的纳米抗体R14的构建体(包括多价纳米抗体和纳米抗体融合蛋白)能有效抑制SARS‑CoV‑2感染及其变异毒株感染,可以雾化给药,能直达肺部,起效较快,且半衰期长,为临床上预防或治疗新冠病毒及其变异株感染提供了更有效的治疗策略。
Description
本申请是申请日为2022年3月21日,申请号为202210278872.9,发明名称为“纳米抗体R14的构建体及其应用”的发明专利申请的分案申请。
技术领域
本发明涉及生物医药领域,具体涉及纳米抗体R14的构建体及其应用,更具体地,涉及基于特异性结合SARS-CoV-2RBD的纳米抗体R14的多价纳米抗体、纳米抗体融合蛋白、编码其的多核苷酸、包含该多核苷酸的核酸构建体、包含该核酸构建体的表达载体、包含上述多核苷酸、核酸构建体或表达载体的转化的细胞以及包含上述任一项产品的药物组合物及其在制备用于预防或治疗新型冠状病毒的药物中的应用、在制备用于检测新型冠状病毒或诊断新型冠状病毒感染的试剂或试剂盒中的应用。
背景技术
新型冠状病毒(SARS-CoV-2)、严重急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)等同属冠状病毒科(family Coronaviridae),是针对人类呼吸系统的主要病原体,主要通过飞沫、气溶胶和接触等方式传播,其传染性强,因此这类引起呼吸系统疾病的病毒严重危害公共卫生安全,尤其近年来呼吸性传染病频发、病毒不断变异。
当前的新冠肺炎疫情暴发推动了各种疫苗和抗病毒药物的开发,其中接种疫苗可有效预防严重传染疾病的发生,但是疫苗的适用对象为未感染人群,且研发周期长,临床研究过程复杂。而对于确诊患者而言,只能通过抗病毒药物进行治疗,其中一种抗病毒药物是治疗性抗体药物,主要指中和抗体;中和抗体药物主要是通过与病原微生物表面的抗原结合,阻止病原微生物表达的特定分子与细胞表面受体结合,达到“中和”的效果。SARS-CoV-2病毒表面具有糖基化的刺突蛋白(spike protein,S),该S蛋白能与宿主细胞受体蛋白ACE2相互作用并触发膜融合,因此阻断S蛋白与ACE2的结合是治疗新冠病毒感染的有效途径。
常规单克隆抗体,一般通过静脉注射给药,然而,通过静脉注射途径给药的单克隆抗体从全身循环进入肺部的药物浓度非常低,大大降低了中和抗体本身的抗病毒效果,导致不能有效降低肺部的病毒载量。新型冠状病毒最初感染上呼吸道,它与免疫系统的第一次相互作用主要发生在呼吸道黏膜表面,鉴于此,对于通过呼吸道感染的新冠病毒而言,在关注血清抗体的同时,还有必要从黏膜免疫的角度去思考、设计和开发合适的抗体类药物。例如,雾化给药可使抗体药物在呼吸道内达到更高的局部浓度,能在病毒入侵时更有效地阻断病毒感染。
纳米抗体作为治疗性药物已备受关注,例如,由Ablynx公司研发的纳米抗体药物Caplacizumab(CabliviTM)用于治疗获得性血栓性血小板减少性紫癜,是首个获批上市的纳米抗体药物;再如,纳米抗体候选药物ALX-0171是一种用于治疗小儿呼吸道合胞病毒(RSV)感染的三价形式的纳米抗体,采用雾化给药,已进入临床Ⅱ期阶段 (https://clinicaltrials.gov),这些都提示:纳米抗体药物具有安全性、可行性。
因此,开发针对新型冠状病毒的、适于呼吸道黏膜免疫的纳米抗体药物具有潜在的临床应用价值与前景。
发明内容
发明目的
本发明的目的在于提供基于特异性结合SARS-CoV-2RBD的纳米抗体R14的构建体(包括多价纳米抗体和纳米抗体融合蛋白)、编码其的多核苷酸、包含该多核苷酸的核酸构建体、包含该核酸构建体的表达载体、包含上述多核苷酸、核酸构建体或表达载体的转化的细胞以及包含上述任一项产品的药物组合物及其在制备用于预防或治疗新型冠状病毒的药物中的应用、在制备用于检测新型冠状病毒或诊断新型冠状病毒感染的试剂或试剂盒中的应用。
本发明的基于特异性结合SARS-CoV-2RBD的纳米抗体R14的构建体(包括多价纳米抗体和纳米抗体融合蛋白),能有效抑制SARS-CoV-2感染及其变异毒株感染,可以雾化给药,能直达肺部,起效较快且半衰期长,为新冠病毒及其变异株感染提供了更有效的治疗策略。
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,本发明提供了一种多价纳米抗体,其包括两条以上、特异性结合 SARS-CoV-2RBD的纳米抗体,其中,所述特异性结合SARS-CoV-2RBD的纳米抗体包括以下CDR:
氨基酸序列如SEQ ID NO:1(即,GFTLDYYAIG)所示的CDR1,
氨基酸序列如SEQ ID NO:2(即,CISSSDGSTSYADSVKG)所示的CDR2,以及
氨基酸序列如SEQ ID NO:3(即,TPATYYSGRYYYQCPAGGMDY)所示的CDR3。
在具体实施方案中,所述特异性结合SARS-CoV-2RBD的纳米抗体还包括4个框架区FR1-4,所述FR1-4与所述CDR1、CDR2和CDR3按顺序交错排列;
优选地,所述FR1-4的氨基酸序列分别如SEQ ID NO:4(即,QVQLQESGGGLVQPGGSLRLSCAVS)、SEQ ID NO:5(即,WFRQAPGKEREGVS)、 SEQ ID NO:6(即,RFTISRDNAKNTVYLQMNSLKPEDTALYYCAA)和SEQ ID NO:7 (即,WGQGTQVTVSS)所示。
在优选的具体实施方案中,所述特异性结合SARS-CoV-2RBD的纳米抗体具有如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;优选地,所述纳米抗体的氨基酸序列如以下SEQ ID NO:8所示:
在优选的具体实施方案I中,所述多价纳米抗体由两条以上、优选地三条所述特异性结合SARS-CoV-2RBD的纳米抗体通过Linker连接构成;
其中,所述Linker为(GGGGS)n,其中,n=1,2,3,或4,优选地,n=2或3。
作为具体实施方案I的进一步优选,所述多价纳米抗体为三价纳米抗体,具有如SEQ ID NO:9所示的氨基酸序列:
QVQLQESGGGLVQPGGSLRLSCAVSGFTLDYYAIGWFRQAPGKEREGVSCISSSD GSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAATPATYYSGRYYYQC PAGGMDYWGQGTQVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSQVQLQESGGGL VQPGGSLRLSCAVSGFTLDYYAIGWFRQAPGKEREGVSCISSSDGSTSYADSVKGRFTI SRDNAKNTVYLQMNSLKPEDTALYYCAATPATYYSGRYYYQCPAGGMDYWGQGTQ VTVSSGGGGSGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVQPGGSLRLSCAVSG FTLDYYAIGWFRQAPGKEREGVSCISSSDGSTSYADSVKGRFTISRDNAKNTVYLQMN SLKPEDTALYYCAATPATYYSGRYYYQCPAGGMDYWGQGTQVTVSS(SEQ ID NO:9)。
在优选的具体实施方案II中,所述多价纳米抗体为由以下融合蛋白形成的IgM五聚体,所述融合蛋白从N端到C端的结构如式(I)所示:
A-L-B(I)
其中,
A为单条、所述特异性结合SARS-CoV-2RBD的纳米抗体,或者为如上述优选的具体实施方案I中所述的多价纳米抗体;
B为人源IgM的Fc片段;优选地,所述人源IgM的Fc片段具有如SEQ ID NO:10(即,VIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTD QVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVPDQD TAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNA TFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPARE QLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSI LTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY) 所示的氨基酸序列,或与SEQID NO:10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;
L为(GGGGS)m,其中,m=0,1,2,3,或4。
作为上述融合蛋白的优选实施方案,其具有如SEQ ID NO:11所示的氨基酸序列:
QVQLQESGGGLVQPGGSLRLSCAVSGFTLDYYAIGWFRQAPGKEREGVSCISSSD GSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAATPATYYSGRYYYQC PAGGMDYWGQGTQVTVSSVIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQI QVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVD HRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWT RQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKY VTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGK PTLYNVSLVMSDTAGTCY(SEQ ID NO:11)。
第二方面,本发明提供了一种纳米抗体融合蛋白,所述纳米抗体融合蛋白从N端到C端的结构如式(I)所示:
A-L-B (I)
其中,
A为单条、特异性结合SARS-CoV-2RBD的纳米抗体,所述特异性结合SARS-CoV-2RBD的纳米抗体如上述第一方面中所定义;或者,A为根据上述第一方面的优选的具体实施方案I中所述的多价纳米抗体,即,由两条以上、优选地三条所述特异性结合SARS-CoV-2RBD的纳米抗体通过Linker连接构成的多价纳米抗体,其中,所述Linker 为(GGGGS)n,其中,n=1,2,3,或4,优选地,n=2或3;
B为人源IgM的Fc片段;优选地,所述人源IgM的Fc片段具有如SEQ ID NO:10所示的氨基酸序列,或与SEQ ID NO:10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;
L为(GGGGS)m,其中,m=0,1,2,3,或4。
作为上述融合蛋白的优选实施方案,其具有如SEQ ID NO:11所示的氨基酸序列。
第三方面,本发明提供了一种多核苷酸,其编码如上述第一方面所述的多价纳米抗体,或者编码如上述第二方面所述的纳米抗体融合蛋白。
在具体实施方案中,所述多核苷酸为DNA或mRNA;
优选地,所述多核苷酸编码根据上述第一方面的优选的具体实施方案I的多价纳米抗体,进一步优选地,所述多核苷酸包括如SEQ ID NO:12(即, CAAGTGCAACTGCAGGAGAGCGGCGGAGGCCTGGTCCAACCTGGCGGCAGCCTG CGGCTGTCTTGTGCTGTGTCTGGATTCACCCTGGATTACTATGCCATCGGCTGGTTT AGACAGGCCCCTGGCAAGGAACGGGAAGGCGTTAGCTGCATCAGCTCTTCCGACG GCTCTACCAGCTACGCTGATTCTGTGAAGGGCCGCTTCACAATCAGCAGAGATAAT GCCAAAAACACGGTGTACCTGCAGATGAACAGCCTGAAGCCCGAGGACACCGCC CTGTACTATTGCGCTGCCACACCCGCCACCTACTACAGCGGCAGATACTACTATCAG TGTCCTGCCGGAGGCATGGATTACTGGGGACAGGGCACCCAGGTGACAGTGAGCA GCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGTGGTGGCGGCGGATCCGGCGGC GGAGGCAGCGGCGGCGGGGGCAGCCAGGTGCAGCTGCAGGAGAGCGGCGGCGG CCTGGTGCAGCCTGGAGGCAGCCTGAGACTGAGCTGTGCCGTGTCCGGTTTCACC CTGGACTACTACGCCATTGGATGGTTCAGACAGGCTCCAGGCAAGGAAAGAGAAG GCGTGTCCTGTATCAGCTCTTCTGATGGATCTACATCTTACGCCGACAGCGTGAAG GGCAGGTTCACCATCTCCAGAGACAATGCCAAGAACACCGTGTACCTGCAGATGA ACAGCCTGAAACCTGAGGATACCGCACTTTATTACTGCGCCGCCACCCCTGCTACA TACTACAGCGGAAGATACTACTACCAGTGCCCCGCCGGCGGCATGGACTACTGGG GCCAGGGCACCCAGGTCACAGTGAGCAGCGGCGGCGGCGGCTCCGGCGGAGGCG GCTCTGGTGGCGGCGGAAGCGGAGGCGGAGGCAGCGGCGGCGGAGGCTCTCAGG TGCAGCTGCAGGAGTCCGGCGGCGGGCTGGTGCAGCCAGGCGGCAGCCTGAGAC TGAGCTGCGCCGTGTCTGGCTTTACACTGGACTACTACGCCATCGGCTGGTTCCGG CAGGCCCCTGGCAAAGAGCGGGAAGGCGTGTCTTGCATCAGCAGCAGCGACGGC AGCACCAGCTACGCCGACAGCGTCAAGGGAAGATTCACCATCTCCCGGGACAACG CCAAGAACACAGTGTACCTGCAAATGAACAGCCTCAAGCCCGAGGACACCGCCCT GTACTACTGCGCCGCTACCCCTGCCACATACTACTCTGGCAGATACTACTACCAGTG CCCTGCCGGCGGCATGGACTACTGGGGCCAGGGCACACAGGTGACCGTGTCCAGC) 所示的核苷酸序列;
优选地,所述多核苷酸编码如上述第二方面所述的纳米抗体融合蛋白,进一步优选地,所述多核苷酸包括如SEQ ID NO:13(即, CAGGTGCAGCTGCAGGAGTCTGGAGGAGGCTTGGTGCAGCCTGGGGGGTCTCTG AGACTCTCCTGTGCAGTCTCTGGATTTACTTTGGATTATTATGCCATAGGCTGGTTCCGCCAGGCCCCAGGGAAGGAGCGTGAGGGGGTCTCATGTATTAGTAGTAGTGATG GTAGCACATCGTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAC GCCAAAAACACGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACAGCCC TTTATTACTGTGCAGCAACCCCTGCTACATACTATAGTGGACGTTACTACTACCAAT GTCCCGCGGGGGGCATGGACTACTGGGGCCAGGGGACCCAGGTGACCGTGAGCT CTGTGATCGCCGAGCTGCCCCCCAAGGTGAGCGTGTTCGTGCCCCCTAGAGACGG CTTCTTCGGCAACCCTAGAAAGAGCAAGCTGATCTGCCAAGCCACCGGCTTCTCC CCTAGACAGATCCAAGTGAGCTGGCTGAGAGAGGGCAAGCAAGTGGGCAGCGGC GTCACAACAGACCAAGTGCAAGCCGAGGCCAAGGAGAGCGGCCCCACCACCTAC AAGGTGACAAGCACCCTGACCATCAAGGAGAGCGACTGGCTGGGGCAGAGCATG TTCACCTGCAGAGTGGACCACAGAGGCCTGACCTTTCAGCAGAACGCTAGCAGCA TGTGCGTGCCCGACCAAGACACCGCCATCAGAGTGTTCGCCATCCCCCCTAGCTTC GCTAGCATCTTCCTGACCAAGAGCACCAAGCTGACCTGCCTCGTGACCGATCTGA CCACCTACGACAGCGTGACCATCAGCTGGACAAGACAGAACGGCGAGGCCGTGA AGACCCACACCAACATCAGCGAGAGCCACCCCAACGCCACCTTCAGCGCCGTGGGCGAGGCTAGCATCTGCGAGGACGACTGGAACAGCGGCGAGAGATTCACCTGCA CCGTGACCCACACCGACCTGCCTAGCCCCCTGAAGCAGACCATCAGCAGACCCAA GGGCGTGGCCCTGCACAGACCCGACGTGTACCTGCTGCCCCCCGCTAGAGAGCAG CTGAACCTGAGAGAGAGCGCCACCATCACCTGCCTGGTGACCGGCTTTAGCCCCG CTGACGTGTTCGTGCAGTGGATGCAGAGAGGGCAGCCCCTGAGCCCCGAGAAGTA CGTGACAAGCGCCCCCATGCCCGAGCCCCAAGCCCCCGGCAGATACTTCGCCCAC AGCATCCTGACCGTGAGCGAGGAAGAGTGGAACACCGGCGAGACCTACACCTGC GTGGTGGCCCACGAGGCCCTGCCCAACAGAGTGACCGAGAGAACCGTGGACAAG AGCACCGGCAAGCCCACCCTGTACAACGTGAGCCTGGTGATGAGCGACACCGCCG GCACCTGCTAC)所示的核苷酸序列。
第四方面,本发明提供了一种核酸构建体,其包含如上述第三方面所述的多核苷酸,以及任选地,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,本发明提供了一种表达载体,其包含如上述第四方面所述的核酸构建体。
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。
第七方面,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多价纳米抗体、如上述第二方面所述的纳米抗体融合蛋白、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。
在具体实施方案中,所述药物组合物可以为鼻喷剂、口服制剂、栓剂或胃肠外制剂的形式;
优选地,所述鼻喷剂选自气雾剂、喷雾剂和粉雾剂;
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;
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。
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。
第八方面,本发明提供了一种如上述第一方面所述的多价纳米抗体、如上述第二方面所述的纳米抗体融合蛋白、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、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用于预防和/或治疗新型冠状病毒感染的药物中的应用。
在具体实施方案中,所述新型冠状病毒可以为SARS-CoV-2原始毒株和/或 SARS-CoV-2变异毒株;
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)、Kappa(B.1.617.1)、Delta(B.1.617.2)毒株、Omicron(B.1.1.529)亚型BA.1毒株或Omicron (B.1.1.529)亚型BA.2毒株,进一步优选为Delta(B.1.617.2)毒株、Omicron(B.1.1.529)亚型BA.1毒株或Omicron(B.1.1.529)亚型BA.2毒株。
第九方面,本发明提供了一种如上述第一方面所述的多价纳米抗体、如上述第二方面所述的纳米抗体融合蛋白、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在制备用于检测新型冠状病毒或用于诊断新型冠状病毒感染的试剂或试剂盒中的应用。
在具体实施方案中,所述新型冠状病毒可以为SARS-CoV-2原始毒株和/或SARS-CoV-2变异毒株;
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)、 Kappa(B.1.617.1)、Delta(B.1.617.2)毒株、Omicron(B.1.1.529)亚型BA.1毒株或Omicron (B.1.1.529)亚型BA.2毒株,进一步优选为Delta(B.1.617.2)毒株、Omicron(B.1.1.529)亚型BA.1毒株或Omicron(B.1.1.529)亚型BA.2毒株。
第十方面,本发明提供了一种新型冠状病毒检测试剂盒,其包括如上述第一方面所述的多价纳米抗体、如上述第二方面所述的纳米抗体融合蛋白、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。
有益效果
本发明针对新冠病毒进行纳米抗体构建体的药物开发,本发明的基于纳米抗体R14 的构建体均能以高亲和力与SARS-CoV-2RBD结合,能以高中和活性中和SARS-CoV-2 原型毒株和一系列变异毒株的假病毒和活病毒,这些均表明:基于纳米抗体R14的构建体是能够以高亲和力与SARS-CoV-2RBD结合的、并具有高中和活性的新型冠状病毒 (SARS-CoV-2)纳米抗体。
特别是,发明人通过一系列实验证明,本发明的基于纳米抗体R14的三价纳米抗体(TR14)和IgM五聚体形式(MR14)相对于其单体(即,纳米抗体R14)具有明显提高的中和活性和显著延长的半衰期,其实现了黏膜免疫,可以限制病毒的繁殖和进一步跨越黏膜屏障,控制了病毒的黏膜传播,为新型冠状病毒的临床预防、治疗提供了潜在的可雾化给药的抗体新药,并可实现新型冠状病毒的灵敏、可靠检测。
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1中所构建的纳米抗体构建体TR14和MR14的结构示意图;
图2是本发明实施例1中所记载的R14蛋白分子筛层析和SDS-PAGE鉴定结果图;
图3是本发明实施例1中所记载的TR14蛋白分子筛层析和SDS-PAGE鉴定结果图;
图4是本发明实施例1中所记载的MR14蛋白分子筛层析和SDS-PAGE鉴定结果图;
图5是本发明实施例2中所记载的SARS-CoV-2RBD-his蛋白(A)、变异毒株Omicron(B.1.1.529)亚型BA.1的RBD-his蛋白(B)和Omicron(B.1.1.529)亚型BA.2的RBD-his蛋白(C)的SDS-PAGE鉴定结果图。
图6是本发明实施例5中所测定的三种抗体中和SARS-CoV-2原型毒株假病毒感染的效果示意图。
图7是本发明实施例5中所测定的三种抗体中和SARS-CoV-2变异毒株Delta(B.1.617.2)假病毒感染的效果示意图。
图8是本发明实施例5中所测定的三种抗体中和SARS-CoV-2变异毒株Omicron(B.1.1.529)亚型BA.1假病毒感染的效果示意图。
图9是本发明实施例5中所测定的三种抗体中和SARS-CoV-2变异毒株Omicron(B.1.1.529)亚型BA.2假病毒感染的效果示意图。
图10是本发明实施例7中所测定的三种抗体在雾化前、后对假病毒的中和活性;其中,A为纳米抗体R14在雾化前、后对SARS-CoV-2原型毒株假病毒的中和活性结果, B为纳米抗体构建体TR14对SARS-CoV-2变异毒株Delta(B.1.617.2)假病毒的中和活性结果,C为纳米抗体构建体MR14对SARS-CoV-2变异毒株Delta(B.1.617.2)假病毒的中和活性结果。
图11是本发明实施例8中所测定的三种抗体在血液中的半衰期。
图12是本发明实施例8中所使用的雾化系统。
图13是本发明实施例8中所测定的三种抗体在肺部的半衰期。
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
“纳米抗体”,即“重链单域抗体”,该类抗体只包含一个重链可变区(VHH,variabledomain of heavy chain of heavy-chain antibody),相比于其他抗体,轻链天然缺失。
由于纳米抗体自身的生物物理优势,可以很容易地对其进行雾化并通过吸入器直接递送到肺部,从而治疗呼吸系统病毒引起的感染,被认为是非常有潜力的抗体类药物。
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纳米抗体与SARS-CoV-2RBD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,TRIzol购自Invitrogen,Superscript II First-Strand Synthesis Systemfor RT-PCR试剂盒购自Invitrogen。
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,例如,pCAGGS载体购自MiaoLingPlasmid;293F细胞、HEK293T细胞等购自 ATCC;Series Sensor Chip SA芯片购自GE Healthcare;Vero细胞购自ATCC CCL81。
一些合成类生物材料,例如引物、序列等需要人工合成的材料,均委托合成公司完成,例如,本发明中的TR14的编码序列由南京金斯瑞生物科技有限公司合成。
实施例1:基于纳米抗体R14的三价形式(TR14)和IgM五聚体形式(MR14)抗体的构建、表达与纯化
本实施例中的单价纳米抗体及其三价形式和IgM五聚体形式的结构示意图如图1所示。
所采用的基础纳米抗体R14为本实验室通过用SARS-CoV-2RBD蛋白和SARS-CoV-2NTD蛋白同时免疫羊驼、构建抗体文库、利用噬菌体展示技术筛选而得;单价纳米抗体R14的氨基酸序列如SEQ ID NO:8所示,其能以高亲和力、特异性地结合 SARS-CoV-2RBD(结合常数小于1E-10M),并且在假病毒中和实验中,能以高中和活性中和SARS-CoV-2假病毒,这些均表明:R14纳米抗体是能够以高亲和力与 SARS-CoV-2RBD结合的、并具有高中和活性的新型冠状病毒(SARS-CoV-2)羊驼源纳米抗体。
在上述单价纳米抗体R14的编码序列(如SEQ ID NO:14所示)的5’端连接信号肽(ATMHSSALLCCLVLLTGVRA,SEQ ID NO:15)、3’端连上6个组氨酸标签(hexa-His-tag) 的编码序列及翻译终止密码子TGA,通过限制性内切酶位点EcoRI和XhoI,将其构建入 pCAGGS载体(购自Invitrogen)中,然后将所得重组载体转染至293F细胞(购自Invitrogen) 中,进行R14-his蛋白的表达。含有目的蛋白的细胞培养液经镍离子亲和层析(HisTrap TM excel((GE Healthcare))和凝胶过滤层析(SuperdexTM 75Increase 10/300GL column(GEHealthcare))纯化后,可以获得较纯的目的蛋白。R14-his蛋白的SDS-PAGE鉴定大小为15KD左右,结果如图2所示。
通过两段(GGGGS)3序列,将三个如SEQ ID NO:14所示的纳米抗体R14链的编码序列通过头尾相连形式串联(由南京金斯瑞生物科技有限公司直接合成),在其5’端连接信号肽(ATMHSSALLCCLVLLTGVRA,SEQ ID NO:15)、3’端连上6个组氨酸标签 (hexa-His-tag)的编码序列及翻译终止密码子TGA,通过限制性内切酶位点EcoRI和XhoI,将其构建入pCAGGS载体(购自Invitrogen)中,然后将所得重组载体转染至293F细胞(购自Invitrogen)中,进行TR14-his蛋白的表达。含有目的蛋白的细胞培养液经镍离子亲和层析(HisTrap TM excel((GE Healthcare))和凝胶过滤层析(SuperdexTM 200Increase 10/300GL column(GEHealthcare))纯化后,可以获得较纯的目的蛋白。TR14-his蛋白的SDS-PAGE 鉴定大小为50KD左右,结果如图3所示。
通过同源重组的方式,将纳米抗体R14的编码序列(如SEQ ID NO:14所示)与人源IgM抗体的Fc的编码序列(如SEQ ID NO:16所示)连接,在其5’端连接信号肽(ATMHSSALLCCLVLLTGVRA,SEQ ID NO:15)、3’端连上翻译终止密码子TGA,通过限制性内切酶位点EcoRI和XhoI,将其构建入pCAGGS载体(购自Invitrogen),获得 pCAGGS-R14-IgM Fc重组表达载体。将J链(Joining chain)的编码序列(如SEQ ID NO:17 所示)的3’端连上翻译终止密码子TGA,通过限制性内切酶位点EcoRI和XhoI,将其构建入pCAGGS载体(购自Invitrogen),获得pCAGGS-J chain重组表达载体。将上述两种重组表达载体pCAGGS-R14-IgM Fc与pCAGGS-J chain共转染至293F细胞(购自Invitrogen) 中,进行R14-IgM Fc融合蛋白和J链的表达,二者再进行自组装,形成IgM形式的MR14 蛋白。所得MR14蛋白通过HiTrapTMIgM Purification HP(GE Healthcare)和SuperoseTM6 increase 10/300GL(GEHealthcare)纯化,再经SDS-PAGE进行鉴定。MR14蛋白的 SDS-PAGE鉴定大小为70KD左右,结果如图4所示。
实施例2:SARS-CoV-2及其变异毒株RBD的表达与纯化
在SARS-CoV-2原始毒株的RBD蛋白(其氨基酸序列如SEQ ID NO:18所示)的编码序列的3’端连上6个组氨酸标签(hexa-His-tag)的编码序列及翻译终止密码子TGA,通过限制性内切酶位点EcoRI和XhoI,将其构建入pCAGGS载体(购自Invitrogen)中,然后将所得重组载体转染至293F细胞(购自Invitrogen)中,进行SARS-CoV-2RBD-his蛋白的表达。
分别在SARS-CoV-2变异毒株Omicron(B.1.1.529)亚型BA.1的RBD蛋白(其氨基酸序列如SEQ ID NO:19所示)的编码序列和Omicron(B.1.1.529)亚型BA.2的RBD蛋白(其氨基酸序列如SEQ ID NO:20所示)的编码序列的3’端分别连上6个组氨酸标签 (hexa-His-tag)的编码序列及翻译终止密码子TGA,通过bac-to-bac杆状病毒表达系统 (Invitrogen)进行表达。将含有目的基因的pFastbac1质粒转化至DH10Bac感受态细胞中, 生成重组杆粒(bacmids)。将重组杆粒bacmids转染至Sf9细胞中进行病毒的扩增,并在Hi5 细胞中进行蛋白表达。表达48h后,收集Hi5细胞上清液,使用HisTrap TM excel(GE Healthcare)通过镍亲和层析纯化可溶性蛋白。
含有目的蛋白的细胞培养液经镍离子亲和层析柱HisTrap TM excel(GEHealthcare)和凝胶过滤层析SuperdexTM 200Increase 10/300GL column(GE Healthcare)纯化后,可以获得较纯的目的蛋白。SARS-CoV-2RBD-his蛋白、变异毒株Omicron(B.1.1.529)亚型BA.1 的RBD-his蛋白和Omicron(B.1.1.529)亚型BA.2的RBD-his蛋白的SDS-PAGE鉴定大小为 30KD左右,分别如图5A~C所示。
实施例3:表面等离子共振技术检测各抗体与SARS-CoV-2原始毒株及其变异株的RBD蛋白的结合能力
表面等离子共振分析利用Biacore 8K(Biacore Inc.)进行。具体步骤如下:
分别将上述实施例所制备的单价纳米抗体R14及其构建体TR14和MR14进行生物素化,然后固定到Series Sensor Chip SA芯片(Cytiva Life Sciences)上;用PBST缓冲液(2.7 mM KCl,137mM NaCl,4.3mM Na2HPO4,1.4mM KH2PO4,0.05%吐温)分别将上述实施例所制备的SARS-CoV-2原始毒株及其变异株的RBD蛋白进行倍比稀释,从低浓度到高浓度逐一上样至芯片。结合动力学常数的计算是利用BIAevaluation software 8K (Biacore,Inc.)软件进行的。各抗体与各RBD之间的平衡解离常数(KD)如表1所示,表 1结果表明:单价纳米抗体R14及其构建体TR14和MR14都能够和SARS-CoV-2原型毒株及变异毒株Omicron亚型BA.1、Omicron亚型BA.2的RBD蛋白以较高的亲和力结合。
表1、单价纳米抗体R14及其构建体TR14和MR14与SARS-CoV-2原始毒株及变异毒株的RBD之间的亲和性结果
实施例4:SARS-CoV-2原始毒株及变异毒株假病毒的包装
1)分别将编码SARS-CoV-2原始毒株(WT)及变异毒株Delta(B.1.617.2)、Omicron(B.1.1.529)亚型BA.1和Omicron(B.1.1.529)亚型BA.2的S蛋白后18位氨基酸的基因去掉,S蛋白其余序列进行合成(由苏州金唯智提供合成服务),得到SARS-CoV-2-WT-S-del18、B.1.617.2-S-del18、B.1.1.529-BA.1-S-del18和B.1.1.529-BA.2-S-del18基因的核苷酸序列,序列分别如SEQ ID NO:21~24所示。
2)分别将1)中获得的该蛋白基因克隆到pCAGGS载体上,得到表达质粒 pCAGGS-SARS-CoV-2-WT-S-del18、pCAGGS-B.1.617.2-S-del18、pCAGGS- B.1.1.529-BA.1-S-del18和pCAGGS-B.1.1.529-BA.2-S-del18。
SARS-CoV-2原始毒株及变异毒株假病毒的包装步骤如下:
a.细胞准备:在10cm细胞培养皿中铺HEK293T细胞(购自ATCC CRL-3216),使第二天细胞汇合密度至80%左右。培养液为含10%FBS的DMEM培养基。
b.转染:取上述步骤2)中的各S蛋白的表达质粒,用PEI转染30μg质粒/10cm细胞培养皿,目的质粒与PEI按1:3比例混匀后转染,4-6h换培养液(含10%FBS的DMEM培养基),37℃培养24h。
c.加毒:将假病毒包装骨架病毒G*VSV-delG(购自武汉枢密脑科学技术有限公司)加入上述转染后的HEK293T细胞,37℃孵育2h,换培养液(含10%FBS的DMEM培养基),并加入VSV-G抗体(表达该抗体的杂交瘤细胞购自ATCC细胞库),在培养箱中继续培养 30h。
d.收毒:收上清3000rpm离心10min,在超净工作台中经0.45μm无菌滤器过滤,去除细胞碎片,分装,-80℃冰箱冻存。
分别得到SARS-CoV-2原型毒株(SARS-CoV-2WT)及变异毒株Delta(B.1.617.2)、Omicron(B.1.1.529)亚型BA.1、Omicron(B.1.1.529)亚型BA.2的假病毒。
实施例5:抗体中和假病毒感染的检测
将经纯化的单价纳米抗体R14及其构建体TR14和MR14(由实施例1制得)分别以 5倍倍比稀释至第9个梯度(2.56pg/mL),将稀释液与1.6×104TCID50实施例4获得的一系列SARS-CoV-2原始毒株及变异毒株的假病毒分别混合,在37℃混合孵育1h,然后加入到预先接种Vero细胞(购自ATCC CCL81)的96孔板中。孵育18~20小时后,通过CQ1 ConfocalQuantitative Image Cytometer(Yokogawa)检测。根据带GFP荧光的细胞数,计算抗体对上述一系列SARS-CoV-2原型毒株及变异毒株Delta、BA.1和BA.2的假病毒的中和能力,其结果分别如图6~9所示,结果统计如表2;结果显示,相对于单价纳米抗体R14,其构建体TR14和MR14的假病毒中和效果均得以提高。
表2、单价纳米抗体R14及其构建体TR14和MR14对SARS-CoV-2原始毒株及变异毒株的假病毒的中和能力
注:IC50(μg/mL)为抗体的半抑制浓度。
实施例6:抗体中和活病毒感染的检测
本实施例中,通过基于细胞病变效应(CPE)的活病毒中和试验,测定各抗体对新冠病毒活病毒的中和效果。具体步骤如下:
将经纯化的单价纳米抗体R14及其TR14和MR14(由实施例1制得)分别以2倍倍比稀释至第11个梯度,每个梯度4个重复孔,每孔50μL,将稀释液与等体积的100 TCID50的SARS-CoV-2原始毒株或其变异毒株Delta、Omicron亚型BA.1于37℃孵育。1 小时后,将混合物加入到悬浮的Vero细胞中,并在37℃下继续孵育3天。观察和记录细胞病变情况。使用GraphPad Prism 7.0计算纳米抗体及其构建体的IC50。实验均在中国疾病预防控制中心的生物安全三级实验室(BSL3)中进行。
单价纳米抗体R14及其TR14和MR14对新冠病毒原始毒株及其变异毒株的活病毒中和效果见表3,表3结果显示:TR14和MR14对新冠病毒原始毒株及变异毒株的活病毒均具有良好的抑制效果。
表3、单价纳米抗体R14及其构建体TR14和MR14对SARS-CoV-2原始毒株及变异毒株的活病毒的中和能力
注:IC50(μg/mL)为抗体的半抑制浓度。#表示在测定的最低浓度0.001μg/mL时,对活病毒仍具有100%的抑制效果。
实施例7:抗体雾化前后稳定性的检测
使用Aerogen Solo(Aerogen Inc.,Chicago,USA)雾化器,分别将单价纳米抗体R14及其构建体TR14和MR14进行雾化,然后使用含有20mL PBS的全玻璃SKC(Eighty Four,PA,USA)收集雾化后的抗体,并按实施例5所述进行假病毒中和试验。结果如图10所示,其中,A为纳米抗体R14在雾化前、后对SARS-CoV-2原型毒株假病毒的中和活性结果,B为纳米抗体构建体TR14对SARS-CoV-2变异毒株Delta(B.1.617.2)假病毒的中和活性结果,C为纳米抗体构建体MR14对SARS-CoV-2变异毒株Delta(B.1.617.2)假病毒的中和活性结果。图10结果表明:本发明的纳米抗体构建体TR14和MR14在雾化前、后对新冠病毒原型毒株或其变异毒株的假病毒的中和活性保持稳定,提示它们均适于通过雾化途径给药。
实施例8:抗体半衰期的测定
通过腹腔注射的方式,研究纳米抗体R14及其构建体TR14和MR14在血液中的半衰期,具体程序如下:将6-8周雌性SPF级BALB/c小鼠(购自维通利华(Vital River))用异氟醚麻醉,并通过腹腔注射分别缓慢注射200μl 2mg/mL(20mg/kg体重)的R14、TR14 和MR14。分别在注射后1小时、6小时、10小时、24小时、48小时、72小时和96小时,通过眼眶采血收集血液样品。离心后,取上清,通过ELISA测定确定血清中抗体的浓度。使用软件PKSolver计算纳米抗体R14及其构建体TR14和MR14的半衰期(t1/2)。 R14、TR14和MR14在血液中的半衰期的结果如图11所示,图11结果显示:相对于单价抗体R14,构建体TR14和MR14表现出明显延长的半衰期,这有利于提高抗体在体内的抗病毒效果。
接下来,又通过雾化给药的方式,研究纳米抗体R14及其构建体TR14和MR14在肺部的停留时间。使用雾化系统(如图12所示),分别雾化20mg/ml的三种抗体R14、 TR14和MR14,使小鼠在雾化仓中持续暴露10分钟后,通过腹腔注射的方式,用三溴乙醇麻醉小鼠,分别在0小时、1小时、6小时和24小时收集支气管肺泡灌洗液,通过 ELISA测定灌洗液中的抗体浓度,并使用PKSolver计算纳米抗体在肺中的半衰期(t1/2)。 R14、TR14和MR14在肺部半衰期的结果如图13所示,图13结果显示:相对于单价抗体R14,构建体TR14和MR14表现出明显延长的半衰期,这有利于提高抗体通过雾化途径给药后在体内的抗病毒效果。
上述结果表明,本发明的基于纳米抗体R14的构建体TR14和MR14具有开发成为治疗新型冠状病毒及其变异毒株感染的高中和活性抗体药物、特别是雾化药物的潜力。
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。
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Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Thr Pro Ala
245 250 255
Thr Tyr Tyr Ser Gly Arg Tyr Tyr Tyr Gln Cys Pro Ala Gly Gly Met
260 265 270
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
305 310 315 320
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly
325 330 335
Phe Thr Leu Asp Tyr Tyr Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly
340 345 350
Lys Glu Arg Glu Gly Val Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr
355 360 365
Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
370 375 380
Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
385 390 395 400
Thr Ala Leu Tyr Tyr Cys Ala Ala Thr Pro Ala Thr Tyr Tyr Ser Gly
405 410 415
Arg Tyr Tyr Tyr Gln Cys Pro Ala Gly Gly Met Asp Tyr Trp Gly Gln
420 425 430
Gly Thr Gln Val Thr Val Ser Ser
435 440
<210> 10
<211> 349
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<220>
<221> MISC_FEATURE
<223> 人源IgM的Fc片段
<400> 10
Val Ile Ala Glu Leu Pro Pro Lys Val Ser Val Phe Val Pro Pro Arg
1 5 10 15
Asp Gly Phe Phe Gly Asn Pro Arg Lys Ser Lys Leu Ile Cys Gln Ala
20 25 30
Thr Gly Phe Ser Pro Arg Gln Ile Gln Val Ser Trp Leu Arg Glu Gly
35 40 45
Lys Gln Val Gly Ser Gly Val Thr Thr Asp Gln Val Gln Ala Glu Ala
50 55 60
Lys Glu Ser Gly Pro Thr Thr Tyr Lys Val Thr Ser Thr Leu Thr Ile
65 70 75 80
Lys Glu Ser Asp Trp Leu Gly Gln Ser Met Phe Thr Cys Arg Val Asp
85 90 95
His Arg Gly Leu Thr Phe Gln Gln Asn Ala Ser Ser Met Cys Val Pro
100 105 110
Asp Gln Asp Thr Ala Ile Arg Val Phe Ala Ile Pro Pro Ser Phe Ala
115 120 125
Ser Ile Phe Leu Thr Lys Ser Thr Lys Leu Thr Cys Leu Val Thr Asp
130 135 140
Leu Thr Thr Tyr Asp Ser Val Thr Ile Ser Trp Thr Arg Gln Asn Gly
145 150 155 160
Glu Ala Val Lys Thr His Thr Asn Ile Ser Glu Ser His Pro Asn Ala
165 170 175
Thr Phe Ser Ala Val Gly Glu Ala Ser Ile Cys Glu Asp Asp Trp Asn
180 185 190
Ser Gly Glu Arg Phe Thr Cys Thr Val Thr His Thr Asp Leu Pro Ser
195 200 205
Pro Leu Lys Gln Thr Ile Ser Arg Pro Lys Gly Val Ala Leu His Arg
210 215 220
Pro Asp Val Tyr Leu Leu Pro Pro Ala Arg Glu Gln Leu Asn Leu Arg
225 230 235 240
Glu Ser Ala Thr Ile Thr Cys Leu Val Thr Gly Phe Ser Pro Ala Asp
245 250 255
Val Phe Val Gln Trp Met Gln Arg Gly Gln Pro Leu Ser Pro Glu Lys
260 265 270
Tyr Val Thr Ser Ala Pro Met Pro Glu Pro Gln Ala Pro Gly Arg Tyr
275 280 285
Phe Ala His Ser Ile Leu Thr Val Ser Glu Glu Glu Trp Asn Thr Gly
290 295 300
Glu Thr Tyr Thr Cys Val Val Ala His Glu Ala Leu Pro Asn Arg Val
305 310 315 320
Thr Glu Arg Thr Val Asp Lys Ser Thr Gly Lys Pro Thr Leu Tyr Asn
325 330 335
Val Ser Leu Val Met Ser Asp Thr Ala Gly Thr Cys Tyr
340 345
<210> 11
<211> 479
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<220>
<221> MISC_FEATURE
<223> 一种纳米抗体融合蛋白的氨基酸序列
<400> 11
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 Val Ser Gly Phe Thr Leu Asp Tyr Tyr
20 25 30
Ala Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ser Cys Ile Ser Ser Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Ala Thr Pro Ala Thr Tyr Tyr Ser Gly Arg Tyr Tyr Tyr Gln Cys
100 105 110
Pro Ala Gly Gly Met Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
115 120 125
Ser Ser Val Ile Ala Glu Leu Pro Pro Lys Val Ser Val Phe Val Pro
130 135 140
Pro Arg Asp Gly Phe Phe Gly Asn Pro Arg Lys Ser Lys Leu Ile Cys
145 150 155 160
Gln Ala Thr Gly Phe Ser Pro Arg Gln Ile Gln Val Ser Trp Leu Arg
165 170 175
Glu Gly Lys Gln Val Gly Ser Gly Val Thr Thr Asp Gln Val Gln Ala
180 185 190
Glu Ala Lys Glu Ser Gly Pro Thr Thr Tyr Lys Val Thr Ser Thr Leu
195 200 205
Thr Ile Lys Glu Ser Asp Trp Leu Gly Gln Ser Met Phe Thr Cys Arg
210 215 220
Val Asp His Arg Gly Leu Thr Phe Gln Gln Asn Ala Ser Ser Met Cys
225 230 235 240
Val Pro Asp Gln Asp Thr Ala Ile Arg Val Phe Ala Ile Pro Pro Ser
245 250 255
Phe Ala Ser Ile Phe Leu Thr Lys Ser Thr Lys Leu Thr Cys Leu Val
260 265 270
Thr Asp Leu Thr Thr Tyr Asp Ser Val Thr Ile Ser Trp Thr Arg Gln
275 280 285
Asn Gly Glu Ala Val Lys Thr His Thr Asn Ile Ser Glu Ser His Pro
290 295 300
Asn Ala Thr Phe Ser Ala Val Gly Glu Ala Ser Ile Cys Glu Asp Asp
305 310 315 320
Trp Asn Ser Gly Glu Arg Phe Thr Cys Thr Val Thr His Thr Asp Leu
325 330 335
Pro Ser Pro Leu Lys Gln Thr Ile Ser Arg Pro Lys Gly Val Ala Leu
340 345 350
His Arg Pro Asp Val Tyr Leu Leu Pro Pro Ala Arg Glu Gln Leu Asn
355 360 365
Leu Arg Glu Ser Ala Thr Ile Thr Cys Leu Val Thr Gly Phe Ser Pro
370 375 380
Ala Asp Val Phe Val Gln Trp Met Gln Arg Gly Gln Pro Leu Ser Pro
385 390 395 400
Glu Lys Tyr Val Thr Ser Ala Pro Met Pro Glu Pro Gln Ala Pro Gly
405 410 415
Arg Tyr Phe Ala His Ser Ile Leu Thr Val Ser Glu Glu Glu Trp Asn
420 425 430
Thr Gly Glu Thr Tyr Thr Cys Val Val Ala His Glu Ala Leu Pro Asn
435 440 445
Arg Val Thr Glu Arg Thr Val Asp Lys Ser Thr Gly Lys Pro Thr Leu
450 455 460
Tyr Asn Val Ser Leu Val Met Ser Asp Thr Ala Gly Thr Cys Tyr
465 470 475
<210> 12
<211> 1320
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> 一种三价纳米抗体的编码序列
<400> 12
caagtgcaac tgcaggagag cggcggaggc ctggtccaac ctggcggcag cctgcggctg 60
tcttgtgctg tgtctggatt caccctggat tactatgcca tcggctggtt tagacaggcc 120
cctggcaagg aacgggaagg cgttagctgc atcagctctt ccgacggctc taccagctac 180
gctgattctg tgaagggccg cttcacaatc agcagagata atgccaaaaa cacggtgtac 240
ctgcagatga acagcctgaa gcccgaggac accgccctgt actattgcgc tgccacaccc 300
gccacctact acagcggcag atactactat cagtgtcctg ccggaggcat ggattactgg 360
ggacagggca cccaggtgac agtgagcagc ggaggaggcg gcagcggcgg aggcggcagt 420
ggtggcggcg gatccggcgg cggaggcagc ggcggcgggg gcagccaggt gcagctgcag 480
gagagcggcg gcggcctggt gcagcctgga ggcagcctga gactgagctg tgccgtgtcc 540
ggtttcaccc tggactacta cgccattgga tggttcagac aggctccagg caaggaaaga 600
gaaggcgtgt cctgtatcag ctcttctgat ggatctacat cttacgccga cagcgtgaag 660
ggcaggttca ccatctccag agacaatgcc aagaacaccg tgtacctgca gatgaacagc 720
ctgaaacctg aggataccgc actttattac tgcgccgcca cccctgctac atactacagc 780
ggaagatact actaccagtg ccccgccggc ggcatggact actggggcca gggcacccag 840
gtcacagtga gcagcggcgg cggcggctcc ggcggaggcg gctctggtgg cggcggaagc 900
ggaggcggag gcagcggcgg cggaggctct caggtgcagc tgcaggagtc cggcggcggg 960
ctggtgcagc caggcggcag cctgagactg agctgcgccg tgtctggctt tacactggac 1020
tactacgcca tcggctggtt ccggcaggcc cctggcaaag agcgggaagg cgtgtcttgc 1080
atcagcagca gcgacggcag caccagctac gccgacagcg tcaagggaag attcaccatc 1140
tcccgggaca acgccaagaa cacagtgtac ctgcaaatga acagcctcaa gcccgaggac 1200
accgccctgt actactgcgc cgctacccct gccacatact actctggcag atactactac 1260
cagtgccctg ccggcggcat ggactactgg ggccagggca cacaggtgac cgtgtccagc 1320
<210> 13
<211> 1437
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> 一种纳米抗体融合蛋白的编码序列
<400> 13
caggtgcagc tgcaggagtc tggaggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag tctctggatt tactttggat tattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgtgaggg ggtctcatgt attagtagta gtgatggtag cacatcgtat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaaaaa cacggtgtat 240
ctgcaaatga acagcctgaa acctgaggac acagcccttt attactgtgc agcaacccct 300
gctacatact atagtggacg ttactactac caatgtcccg cggggggcat ggactactgg 360
ggccagggga cccaggtgac cgtgagctct gtgatcgccg agctgccccc caaggtgagc 420
gtgttcgtgc cccctagaga cggcttcttc ggcaacccta gaaagagcaa gctgatctgc 480
caagccaccg gcttctcccc tagacagatc caagtgagct ggctgagaga gggcaagcaa 540
gtgggcagcg gcgtcacaac agaccaagtg caagccgagg ccaaggagag cggccccacc 600
acctacaagg tgacaagcac cctgaccatc aaggagagcg actggctggg gcagagcatg 660
ttcacctgca gagtggacca cagaggcctg acctttcagc agaacgctag cagcatgtgc 720
gtgcccgacc aagacaccgc catcagagtg ttcgccatcc cccctagctt cgctagcatc 780
ttcctgacca agagcaccaa gctgacctgc ctcgtgaccg atctgaccac ctacgacagc 840
gtgaccatca gctggacaag acagaacggc gaggccgtga agacccacac caacatcagc 900
gagagccacc ccaacgccac cttcagcgcc gtgggcgagg ctagcatctg cgaggacgac 960
tggaacagcg gcgagagatt cacctgcacc gtgacccaca ccgacctgcc tagccccctg 1020
aagcagacca tcagcagacc caagggcgtg gccctgcaca gacccgacgt gtacctgctg 1080
ccccccgcta gagagcagct gaacctgaga gagagcgcca ccatcacctg cctggtgacc 1140
ggctttagcc ccgctgacgt gttcgtgcag tggatgcaga gagggcagcc cctgagcccc 1200
gagaagtacg tgacaagcgc ccccatgccc gagccccaag cccccggcag atacttcgcc 1260
cacagcatcc tgaccgtgag cgaggaagag tggaacaccg gcgagaccta cacctgcgtg 1320
gtggcccacg aggccctgcc caacagagtg accgagagaa ccgtggacaa gagcaccggc 1380
aagcccaccc tgtacaacgt gagcctggtg atgagcgaca ccgccggcac ctgctac 1437
<210> 14
<211> 390
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> 纳米抗体R14 VHH链的编码序列
<400> 14
caggtgcagc tgcaggagtc tggaggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag tctctggatt tactttggat tattatgcca taggctggtt ccgccaggcc 120
ccagggaagg agcgtgaggg ggtctcatgt attagtagta gtgatggtag cacatcgtat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acgccaaaaa cacggtgtat 240
ctgcaaatga acagcctgaa acctgaggac acagcccttt attactgtgc agcaacccct 300
gctacatact atagtggacg ttactactac caatgtcccg cggggggcat ggactactgg 360
ggcaaaggga cccaggtgac cgtgagctct 390
<210> 15
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<220>
<221> MISC_FEATURE
<223> 信号肽序列
<400> 15
Ala Thr Met His Ser Ser Ala Leu Leu Cys Cys Leu Val Leu Leu Thr
1 5 10 15
Gly Val Arg Ala
20
<210> 16
<211> 1047
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> 人源IgM抗体的Fc的编码序列
<400> 16
gtgatcgccg agctgccccc caaggtgagc gtgttcgtgc cccctagaga cggcttcttc 60
ggcaacccta gaaagagcaa gctgatctgc caagccaccg gcttctcccc tagacagatc 120
caagtgagct ggctgagaga gggcaagcaa gtgggcagcg gcgtcacaac agaccaagtg 180
caagccgagg ccaaggagag cggccccacc acctacaagg tgacaagcac cctgaccatc 240
aaggagagcg actggctggg gcagagcatg ttcacctgca gagtggacca cagaggcctg 300
acctttcagc agaacgctag cagcatgtgc gtgcccgacc aagacaccgc catcagagtg 360
ttcgccatcc cccctagctt cgctagcatc ttcctgacca agagcaccaa gctgacctgc 420
ctcgtgaccg atctgaccac ctacgacagc gtgaccatca gctggacaag acagaacggc 480
gaggccgtga agacccacac caacatcagc gagagccacc ccaacgccac cttcagcgcc 540
gtgggcgagg ctagcatctg cgaggacgac tggaacagcg gcgagagatt cacctgcacc 600
gtgacccaca ccgacctgcc tagccccctg aagcagacca tcagcagacc caagggcgtg 660
gccctgcaca gacccgacgt gtacctgctg ccccccgcta gagagcagct gaacctgaga 720
gagagcgcca ccatcacctg cctggtgacc ggctttagcc ccgctgacgt gttcgtgcag 780
tggatgcaga gagggcagcc cctgagcccc gagaagtacg tgacaagcgc ccccatgccc 840
gagccccaag cccccggcag atacttcgcc cacagcatcc tgaccgtgag cgaggaagag 900
tggaacaccg gcgagaccta cacctgcgtg gtggcccacg aggccctgcc caacagagtg 960
accgagagaa ccgtggacaa gagcaccggc aagcccaccc tgtacaacgt gagcctggtg 1020
atgagcgaca ccgccggcac ctgctac 1047
<210> 17
<211> 477
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> J链的编码序列
<400> 17
atgaagaacc acctgctgtt ctggggcgtg ctggccgtgt tcatcaaggc cgtgcacgtg 60
aaggcccaag aggacgagag aatcgtgctg gtggacaaca agtgcaagtg cgctagaatc 120
acaagcagaa tcatcagaag cagcgaggac cccaacgagg acatcgtgga gagaaacatc 180
agaatcatcg tgcccctgaa caacagagag aacatcagcg accccacaag ccccctgaga 240
acaagattcg tgtaccacct gagcgacctg tgcaagaagt gcgaccccac cgaggtggag 300
ctggacaatc agatcgtgac cgccacacag agcaacatct gcgacgagga cagcgccacc 360
gagacctgct acacctacga cagaaacaag tgctacaccg ccgtggtgcc cctggtgtac 420
ggcggcgaga ccaagatggt ggagaccgcc ctgacccccg acgcctgcta ccccgac 477
<210> 18
<211> 238
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<220>
<221> MISC_FEATURE
<223> SARS-CoV-2原始毒株的RBD蛋白的氨基酸序列
<400> 18
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Arg
1 5 10 15
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
20 25 30
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
35 40 45
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
50 55 60
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
65 70 75 80
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
85 90 95
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
100 105 110
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
115 120 125
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
130 135 140
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
145 150 155 160
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
165 170 175
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
180 185 190
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
195 200 205
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
210 215 220
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe
225 230 235
<210> 19
<211> 261
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<220>
<221> MISC_FEATURE
<223> 变异毒株Omicron (B.1.1.529)亚型BA.1的RBD蛋白的氨基酸序列
<400> 19
Met Leu Leu Val Asn Gln Ser His Gln Gly Phe Asn Lys Glu His Thr
1 5 10 15
Ser Lys Met Val Ser Ala Ile Val Leu Tyr Val Leu Leu Ala Ala Ala
20 25 30
Ala His Ser Ala Phe Ala Arg Val Gln Pro Thr Glu Ser Ile Val Arg
35 40 45
Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Asp Glu Val Phe Asn Ala
50 55 60
Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn
65 70 75 80
Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Leu Ala Pro Phe Phe Thr
85 90 95
Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe
100 105 110
Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg
115 120 125
Gln Ile Ala Pro Gly Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys
130 135 140
Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Lys
145 150 155 160
Leu Asp Ser Lys Val Ser Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
165 170 175
Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
180 185 190
Tyr Gln Ala Gly Asn Lys Pro Cys Asn Gly Val Ala Gly Phe Asn Cys
195 200 205
Tyr Phe Pro Leu Arg Ser Tyr Ser Phe Arg Pro Thr Tyr Gly Val Gly
210 215 220
His Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala
225 230 235 240
Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn
245 250 255
Lys Cys Val Asn Phe
260
<210> 20
<211> 261
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Polypeptide
<220>
<221> MISC_FEATURE
<223> 变异毒株Omicron (B.1.1.529)亚型BA.2的RBD蛋白的氨基酸序列
<400> 20
Met Leu Leu Val Asn Gln Ser His Gln Gly Phe Asn Lys Glu His Thr
1 5 10 15
Ser Lys Met Val Ser Ala Ile Val Leu Tyr Val Leu Leu Ala Ala Ala
20 25 30
Ala His Ser Ala Phe Ala Arg Val Gln Pro Thr Glu Ser Ile Val Arg
35 40 45
Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Asp Glu Val Phe Asn Ala
50 55 60
Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn
65 70 75 80
Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Phe Ala Pro Phe Phe Ala
85 90 95
Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe
100 105 110
Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asn Glu Val Ser
115 120 125
Gln Ile Ala Pro Gly Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys
130 135 140
Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Lys
145 150 155 160
Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
165 170 175
Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
180 185 190
Tyr Gln Ala Gly Asn Lys Pro Cys Asn Gly Val Ala Gly Phe Asn Cys
195 200 205
Tyr Phe Pro Leu Arg Ser Tyr Gly Phe Arg Pro Thr Tyr Gly Val Gly
210 215 220
His Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala
225 230 235 240
Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn
245 250 255
Lys Cys Val Asn Phe
260
<210> 21
<211> 3789
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> SARS-CoV-2-WT-S-del18基因的核苷酸序列
<400> 21
atgttcgtgt tcctggtgct gctgcccctg gtgagcagcc aatgcgtgaa cctgaccaca 60
agaacacagc tgccccccgc ctacaccaac agcttcacaa gaggcgtgta ctaccccgac 120
aaggtgttca gaagcagcgt cctccacagc acccaagacc tgttcctgcc cttcttcagc 180
aacgtgacct ggttccacgc catcagcggc accaacggca ccaagagatt cgacaacccc 240
gtgctgccct tcaacgacgg cgtgtacttc gctagcaccg agaagagcaa catcatcaga 300
ggctggatct tcggcaccac cctggacagc aaaacacaga gcctgctgat cgtgaacaac 360
gccacaaacg tggtgatcaa ggtgtgcgag tttcagttct gcaacgaccc cttcctgggc 420
gtgtaccaca agaacaacaa gagctggatg gagagcgagt tccgggtgta cagcagcgcc 480
aacaactgca ccttcgagta cgtgagccaa cccttcctga tggacctgga gggcaagcaa 540
ggcaatttta agaacctgag agagttcgtg ttcaagaaca tcgacggcta cttcaagatc 600
tacagcaagc acacccccat caacctggtg agagacctgc cccaaggctt cagcgccctg 660
gagcccctgg tggacctgcc catcggcatc aacatcacaa gatttcagac cctgctggcc 720
ctgcacagaa gctatctgac ccccggcgac agcagcagcg gctggaccgc cggcgccgcc 780
gcttactacg tgggctacct gcagcctaga accttcctgc tgaagtacaa cgagaacggc 840
acaatcaccg acgccgtcga ctgcgccctg gaccccctga gcgagaccaa gtgcaccctg 900
aagagcttca ccgtggagaa gggcatctat cagacaagca acttcagagt gcagcccacc 960
gagagcatcg tgagattccc caacatcacc aacctgtgcc ccttcggcga ggtgttcaac 1020
gccacaagat tcgctagcgt gtacgcctgg aacagaaaga gaatcagcaa ctgcgtggcc 1080
gactacagcg tgctgtacaa cagcgctagc ttcagcacct tcaagtgcta cggcgtcagc 1140
cccaccaagc tgaacgacct gtgcttcacc aacgtgtacg ccgacagctt cgtgatcaga 1200
ggcgacgagg tgagacagat cgcccccggg cagaccggca agatcgccga ctacaactac 1260
aagctgcccg acgacttcac cggctgcgtg atcgcctgga acagcaacaa cctggactcc 1320
aaggtgggcg gcaactacaa ctacctgtac agactgttca gaaagagcaa cctgaagccc 1380
ttcgagagag acatcagcac cgagatctac caagccggca gcaccccctg caacggcgtg 1440
gagggcttca actgctactt ccccctgcag agctacggct ttcagcccac ctacggcgtg 1500
ggctatcagc cctacagagt ggtcgtgctg agcttcgagc tgctgcacgc ccccgccacc 1560
gtgtgcggcc ccaagaagag caccaacctg gtgaagaaca agtgcgtgaa cttcaacttc 1620
aacggcctca ccgggaccgg cgtgctgacc gagagcaaca agaagttcct gcctttccaa 1680
cagttcggca gagacatcga cgacaccacc gacgccgtca gagaccctca gaccctggag 1740
atcctggaca tcacaccctg cagcttcggc ggcgtgagcg tgatcacccc cggcaccaac 1800
acaagcaacc aagtggccgt gctgtaccaa ggcgtgaact gcaccgaggt gcccgtggcc 1860
atccacgccg atcagctgac ccccacctgg agagtgtaca gcaccggcag caacgtgttt 1920
cagacaagag ccggctgcct gatcggcgcc gagcacgtga acaacagcta cgagtgcgac 1980
atccccatcg gcgccggcat ctgcgctagc tatcagacac agaccaacag ccacagaaga 2040
gctagaagcg tggctagcca aagcatcatc gcctacacca tgagcctggg cgccgagaac 2100
agcgtggcct acagcaacaa cagcatcgcc atccccacca acttcaccat cagcgtgacc 2160
accgaaatcc tgcctgtgag catgaccaag acaagcgtgg actgcaccat gtacatctgc 2220
ggcgacagca ccgagtgcag caacctgctc ctgcagtacg gcagcttctg cattcagctg 2280
aacagagccc tgaccggcat cgccgtggag caagacaaga acacccaaga ggtgttcgcc 2340
caagtgaagc agatctacaa gacccccccc atcaaggact tcggcggctt caacttcagc 2400
caaatcctgc ctgaccctag caagcctagc aagagaagct tcatcgagga cctgctgttc 2460
aacaaggtga ccctggccga cgccggcttc atcaagcagt acggcgactg cctgggcgac 2520
atcgccgcta gagacctgat ctgcgctcag aagttcaacg gcctgaccgt gctgcccccc 2580
ctgctgaccg acgagatgat cgctcagtac acaagcgccc tgctcgctgg caccatcaca 2640
agcgggtgga ccttcggcgc cggggccgcc ctgcagatcc ccttcgccat gcagatggcc 2700
tacagattca acggcatcgg cgtgacacag aacgtgctgt acgagaatca gaagctgatc 2760
gccaatcagt tcaacagcgc catcggcaag atccaagaca gcctgagcag caccgctagc 2820
gccctgggca agctgcaaga cgtggtgaat cagaacgccc aagccctgaa caccctggtg 2880
aagcagctga gcagcaactt cggcgccatc agcagcgtgc tgaacgacat cctggctaga 2940
ctggacaagg tggaggccga ggtgcagatc gatagactga tcaccggcag actgcagagc 3000
ctgcagacct acgtgacaca gcagctgatc agagccgccg agatcagagc tagcgccaac 3060
ctggccgcca ccaagatgag cgagtgcgtg ctggggcaga gcaagagagt ggacttctgc 3120
ggcaagggct accacctgat gagcttccct cagagcgccc cccacggcgt ggtgttcctg 3180
cacgtgacct acgtgcccgc ccaagagaag aacttcacca ccgcccccgc catctgccac 3240
gacggcaagg cccacttccc tagagagggc gtgttcgtga gcaacggcac ccactggttc 3300
gtgacacaga gaaacttcta cgagcctcag atcatcacca cccacaacac cttcgtgagc 3360
ggcaactgcg acgtggtgat cggcatcgtg aacaacaccg tgtacgaccc tctgcagccc 3420
gagctggaca gcttcaagga ggagctggac aagtacttca agaaccacac aagccccgac 3480
gtggacctgg gcgacatcag cgggatcaac gctagcgtgg tgaacattca gaaggaaatc 3540
gacagactga atgaggtggc caagaacctg aacgagagcc tgatcgacct gcaagagctg 3600
ggcaagtacg agcagtacat caagtggccc tggtacatct ggctgggctt catcgccggc 3660
ctgatcgcca tcgtgatggt gaccatcatg ctgtgctgca tgacaagctg ctgctcctgt 3720
ctgaaggggt gctgcagctg cggcagctgc tgcaaggact acaaggacga tgacgacaag 3780
ggcccctga 3789
<210> 22
<211> 3792
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> B.1.617.2-S-del18基因的核苷酸序列
<400> 22
atgttcgtgt tcctcgtgct cctgcctctg gtgtctagcc agtgcgtgaa cctgagaaca 60
cggacccagc tccctcccgc ctacacaaac tctttcaccc ggggcgtgta ctaccccgac 120
aaggtgttcc ggtctagcgt gctccactct acacaggacc tgttcctccc tttcttcagc 180
aacgtgacat ggttccacgc catccacgtg tctggcacaa acggcacaaa gcggttcgac 240
aaccccgtgc tccctttcaa cgacggcgtg tacttcgcca gcaccgagaa gtctaacatt 300
atccggggct ggattttcgg caccacactc gactctaaga cacagtccct cctgattgtg 360
aacaacgcca caaacgtggt gattaaggtg tgcgagttcc agttctgcaa cgaccctttc 420
ctggacgtgt actaccacaa gaacaacaag tcttggatgg agtctggcgt gtactctagc 480
gccaacaact gcaccttcga gtacgtgtcc cagcctttcc tcatggacct ggagggcaag 540
cagggcaact tcaagaacct gagagagttc gtgttcaaga acattgacgg ctacttcaag 600
atttactcta agcacacccc aattaacctc gtgagggacc tccctcaggg cttctccgtg 660
ttagaaccac tggtggacct ccctattggc attaacatca cacgcttcca gacactgctc 720
gccctccacc ggtcttacct gaccccaggc gactctagct ctggctggac agccggcgcc 780
gccgcctact acgtgggcta cctgcagcct aggaccttcc tcctgaagta caacgagaac 840
ggcacaatta ccgacgccgt ggactgcgcc ctggacccac tgtccgagac aaagtgcaca 900
ctgaagtcct tcacagtgga gaagggcatt taccagacat ctaacttccg ggtgcagcct 960
acagagtcta ttgtgcggtt cccaaacatc acaaacctgt gccctttcgg cgaggtgttc 1020
aacgccaccc ggttcgcctc tgtgtacgcc tggaaccgga agcggatctc taactgcgtg 1080
gccgactact ccgtgctgta caactccgcc tctttctcta cattcaagtg ctacggcgtg 1140
tcccctacaa agctgaacga cctgtgcttc accaacgtgt acgccgactc tttcgtgatt 1200
agaggcgacg aggtgaggca gattgccccc ggccagacag gcaagatcgc cgactacaac 1260
tacaagctgc ccgacgactt cacaggctgc gtgatcgcct ggaactctaa caacctggac 1320
tctaaggtgg gcggcaacta caactacaga tacagactgt tccggaagtc taacctgaag 1380
ccattcgaga gggacattag caccgagatt taccaggccg gctctaagcc atgcaacggc 1440
gtggagggct tcaactgcta cttcccactg cagtcctacg gcttccagcc tacaaacggc 1500
gtgggctacc agccttaccg ggtggtggtg ctgtctttcg agctgctcca cgcccccgcc 1560
acagtgtgcg gcccaaagaa gagcacaaac ctcgtgaaga acaagtgcgt gaacttcaac 1620
ttcaacggcc tcacaggcac aggcgtgctc accgagtcta acaagaagtt cctccctttc 1680
cagcagttcg gccgcgacat tgccgacacc accgacgccg tgcgggaccc tcagacactg 1740
gaaattctcg acatcacccc ttgcagcttc ggcggcgtgt ccgtgatcac cccaggcaca 1800
aacacatcta accaggtggc cgtgctgtac cagggcgtga actgcaccga ggtgccagtg 1860
gccatccacg ccgaccagct caccccaaca tggagggtgt acagcacagg ctctaacgtg 1920
ttccagaccc gggccggctg cctcattggc gccgagcacg tgaacaactc ttacgagtgc 1980
gacatcccta ttggcgccgg catttgcgcc tcttaccaga cccagacaaa ctctagacgg 2040
agagcccggt ctgtggcctc tcagagcatt attgcctaca ccatgtctct gggcgccgag 2100
aactctgtgg cctactctaa caactctatt gccatcccta caaacttcac aatttctgtg 2160
accaccgaga ttctcccagt gtctatgacc aagacatctg tggactgcac catgtacatt 2220
tgcggcgact ccaccgagtg ctctaacctc ctgctccagt acggctcttt ctgcacccag 2280
ctcaaccgcg ccctgacagg catcgccgtg gagcaggaca agaacaccca ggaggtgttc 2340
gcccaggtga agcagattta caagaccccc ccaattaagg acttcggcgg cttcaacttc 2400
tctcagattc tccccgaccc atccaagcct agcaagcggt ccttcattga ggacctcctg 2460
ttcaacaagg tgacactggc cgacgccggc ttcattaagc agtacggcga ctgcctgggc 2520
gacattgccg cccgggacct gatttgcgcc cagaagttca acggcctcac agtgctcccc 2580
ccactgctca ccgacgagat gattgcccag tacacatctg ccctcctggc cggcacaatt 2640
acatctggct ggaccttcgg cgccggcgcc gccctgcaga tccctttcgc catgcagatg 2700
gcctaccgct tcaacggcat cggcgtgaca cagaacgtgc tgtacgagaa ccagaagctg 2760
atcgccaacc agttcaacag cgccattggc aagattcagg actctctgag cagcacagcc 2820
agcgccctgg gcaagctgca gaacgtggtg aaccagaacg cccaggccct gaacacactg 2880
gtgaagcagc tgtcttctaa cttcggcgcc atttctagcg tgctgaacga cattctgtcg 2940
cggctggaca aggtggaggc cgaggtgcag attgacaggc tcatcacagg cagactgcag 3000
tctctgcaga catacgtgac ccagcagctg attagagccg ccgagattag agcctccgcc 3060
aacctggccg ccaccaagat gagcgagtgc gtgctcggcc agtctaagcg ggtggacttc 3120
tgcggcaagg gctaccacct catgtctttc cctcagtccg cccctcacgg cgtggtgttc 3180
ctccacgtga catacgtgcc cgcccaggag aagaacttca ccacagcccc cgccatttgc 3240
cacgacggca aggcccactt ccctagggag ggcgtgttcg tgtctaacgg cacccactgg 3300
ttcgtgaccc agcggaactt ctacgagcct cagattatta ccacagacaa cacattcgtg 3360
agcggcaact gcgacgtggt gattggcatt gtgaacaaca cagtgtacga cccactgcag 3420
cctgagttgg actctttcaa ggaggaactc gacaagtact tcaagaacca cacatctcct 3480
gacgtggacc tgggcgacat tagcggcatt aacgcctctg tggtgaacat tcagaaggag 3540
attgacagac tgaacgaggt ggccaagaac ctgaacgagt ctctcattga cctgcaggag 3600
ctgggcaagt acgagcagta cattaagtgg ccttggtaca tttggctggg cttcattgcc 3660
ggcctgatcg ccattgtgat ggtgaccatc atgctgtgct gcatgacatc ttgctgcagc 3720
tgcctgaagg gctgctgctc ttgcggctct tgctgcaagg actacaagga cgacgatgac 3780
aagggacctt aa 3792
<210> 23
<211> 3795
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> B.1.1.529-BA.1-S-del18基因的核苷酸序列
<400> 23
atgttcgtgt tcctcgtgct cctgcctctg gtgtctagcc agtgcgtgaa cctgaccaca 60
cggacccagc tccctcccgc ctacacaaac tctttcaccc ggggcgtgta ctaccccgac 120
aaggtgttcc ggtctagcgt gctccactct acacaggacc tgttcctccc tttcttcagc 180
aacgtgacat ggttccacgt gatctctggc acaaacggca caaagcggtt cgacaacccc 240
gtgctccctt tcaacgacgg cgtgtacttc gccagcattg agaagtctaa cattatccgg 300
ggctggattt tcggcaccac actcgactct aagacacagt ccctcctgat tgtgaacaac 360
gccacaaacg tggtgattaa ggtgtgcgag ttccagttct gcaacgaccc tttcctggac 420
cacaagaaca acaagtcttg gatggagtct gagttcagag tgtactctag cgccaacaac 480
tgcaccttcg agtacgtgtc ccagcctttc ctcatggacc tggagggcaa gcagggcaac 540
ttcaagaacc tgagagagtt cgtgttcaag aacattgacg gctacttcaa gatttactct 600
aagcacaccc caattattgt gagggaacca gaagacctcc ctcagggctt ctccgcctta 660
gaaccactgg tggacctccc tattggcatt aacatcacac gcttccagac actgctcgcc 720
ctccaccggt cttacctgac cccaggcgac tctagctctg gctggacagc cggcgccgcc 780
gcctactacg tgggctacct gcagcctagg accttcctcc tgaagtacaa cgagaacggc 840
acaattaccg acgccgtgga ctgcgccctg gacccactgt ccgagacaaa gtgcacactg 900
aagtccttca cagtggagaa gggcatttac cagacatcta acttccgggt gcagcctaca 960
gagtctattg tgcggttccc aaacatcaca aacctgtgcc ctttcgacga ggtgttcaac 1020
gccacccggt tcgcctctgt gtacgcctgg aaccggaagc ggatctctaa ctgcgtggcc 1080
gactactccg tgctgtacaa cctggcccct ttcttcacat tcaagtgcta cggcgtgtcc 1140
cctacaaagc tgaacgacct gtgcttcacc aacgtgtacg ccgactcttt cgtgattaga 1200
ggcgacgagg tgaggcagat tgcccccggc cagacaggca acatcgccga ctacaactac 1260
aagctgcccg acgacttcac aggctgcgtg atcgcctgga actctaacaa gctggactct 1320
aaggtgtctg gcaactacaa ctacctgtac agactgttcc ggaagtctaa cctgaagcca 1380
ttcgagaggg acattagcac cgagatttac caggccggca acaagccatg caacggcgtg 1440
gccggcttca actgctactt cccactgcgc tcctactcct tccggcctac atacggcgtg 1500
ggccaccagc cttaccgggt ggtggtgctg tctttcgagc tgctccacgc ccccgccaca 1560
gtgtgcggcc caaagaagag cacaaacctc gtgaagaaca agtgcgtgaa cttcaacttc 1620
aacggcctca agggcacagg cgtgctcacc gagtctaaca agaagttcct ccctttccag 1680
cagttcggcc gcgacattgc cgacaccacc gacgccgtgc gggaccctca gacactggaa 1740
attctcgaca tcaccccttg cagcttcggc ggcgtgtccg tgatcacccc aggcacaaac 1800
acatctaacc aggtggccgt gctgtaccag ggcgtgaact gcaccgaggt gccagtggcc 1860
atccacgccg accagctcac cccaacatgg agggtgtaca gcacaggctc taacgtgttc 1920
caaacccggg ccggctgcct cattggcgcc gagtacgtga acaactctta cgagtgcgac 1980
atccctattg gcgccggcat ttgcgcctct taccagaccc agacaaagtc tcaccggaga 2040
gcccggtctg tggcctctca gagcattatt gcctacacca tgtctctggg cgccgagaac 2100
tctgtggcct actctaacaa ctctattgcc atccctacaa acttcacaat ttctgtgacc 2160
accgagattc tcccagtgtc tatgaccaag acatctgtgg actgcaccat gtacatttgc 2220
ggcgactcca ccgagtgctc taacctcctg ctccagtacg gctctttctg cacccagctc 2280
aagcgcgccc tgacaggcat cgccgtggag caggacaaga acacccagga ggtgttcgcc 2340
caggtgaagc agatttacaa gaccccccca attaagtact tcggcggctt caacttctct 2400
cagattctcc ccgacccatc caagcctagc aagcggtcct tcattgagga cctcctgttc 2460
aacaaggtga cactggccga cgccggcttc attaagcagt acggcgactg cctgggcgac 2520
attgccgccc gggacctgat ttgcgcccag aagttcaagg gcctcacagt gctcccccca 2580
ctgctcaccg acgagatgat tgcccagtac acatctgccc tcctggccgg cacaattaca 2640
tctggctgga ccttcggcgc cggcgccgcc ctgcagatcc ctttcgccat gcagatggcc 2700
taccgcttca acggcatcgg cgtgacacag aacgtgctgt acgagaacca gaagctgatc 2760
gccaaccagt tcaacagcgc cattggcaag attcaggact ctctgagcag cacagccagc 2820
gccctgggca agctgcagga cgtggtgaac cacaacgccc aggccctgaa cacactggtg 2880
aagcagctgt cttctaagtt cggcgccatt tctagcgtgc tgaacgacat tttctcgcgg 2940
ctggacaagg tggaggccga ggtgcagatt gacaggctca tcacaggcag actgcagtct 3000
ctgcagacat acgtgaccca gcagctgatt agagccgccg agattagagc ctccgccaac 3060
ctggccgcca ccaagatgag cgagtgcgtg ctcggccagt ctaagcgggt ggacttctgc 3120
ggcaagggct accacctcat gtctttccct cagtccgccc ctcacggcgt ggtgttcctc 3180
cacgtgacat acgtgcccgc ccaggagaag aacttcacca cagcccccgc catttgccac 3240
gacggcaagg cccacttccc tagggagggc gtgttcgtgt ctaacggcac ccactggttc 3300
gtgacccagc ggaacttcta cgagcctcag attattacca cagacaacac attcgtgagc 3360
ggcaactgcg acgtggtgat tggcattgtg aacaacacag tgtacgaccc actgcagcct 3420
gagttggact ctttcaagga ggaactcgac aagtacttca agaaccacac atctcctgac 3480
gtggacctgg gcgacattag cggcattaac gcctctgtgg tgaacattca gaaggagatt 3540
gacagactga acgaggtggc caagaacctg aacgagtctc tcattgacct gcaggagctg 3600
ggcaagtacg agcagtacat taagtggcct tggtacattt ggctgggctt cattgccggc 3660
ctgatcgcca ttgtgatggt gaccatcatg ctgtgctgca tgacatcttg ctgcagctgc 3720
ctgaagggct gctgctcttg cggctcttgc tgcaaggact acaaggacga cgatgacaag 3780
ggaccttaac tcgag 3795
<210> 24
<211> 2913
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Polynucleotide
<220>
<221> misc_feature
<223> B.1.1.529-BA.2-S-del18基因的核苷酸序列
<400> 24
atgttcgtgt tcctcgtgct cctgcctctg gtgtctagcc agtgcgtgaa cctgatcaca 60
cggacccaga gctacacaaa ctctttcacc cggggcgtgt actaccccga caaggtgttc 120
cggtctagcg tgctccactc tacacaggac ctgttcctcc ctttcttcag caacgtgaca 180
tggttccacg ccatccacgt gtctggcaca aacggcacaa agcggttcga caaccccgtg 240
ctccctttca acgacggcgt gtacttcgcc agcaccgaga agtctaacat tatccggggc 300
tggattttcg gcaccacact cgactctaag acacagtccc tcctgattgt gaacaacgcc 360
acaaacgtgg tgattaaggt gtgcgagttc cagttctgca acgacccttt cctggacgtg 420
tactaccaca agaacaacaa gtcttggatg gagtctgagt tcagagtgta ctctagcgcc 480
aacaactgca ccttcgagta cgtgtcccag cctttcctca tggacctgga gggcaagcag 540
ggcaacttca agaacctgag agagttcgtg ttcaagaaca ttgacggcta cttcaagatt 600
tactctaagc acaccccaat taacctcggc agggacctcc ctcagggctt ctccgcctta 660
gaaccactgg tggacctccc tattggcatt aacatcacac gcttccagac actgctcgcc 720
ctccaccggt cttacctgac cccaggcgac tctagctctg gctggacagc cggcgccgcc 780
gcctactacg tgggctacct gcagcctagg accttcctcc tgaagtacaa cgagaacggc 840
acaattaccg acgccgtgga ctgcgccctg gacccactgt ccgagacaaa gtgcacactg 900
aagtccttca cagtggagaa gggcatttac cagacatcta acttccgggt gcagcctaca 960
gagtctattg tgcggttccc aaacatcaca aacctgtgcc ctttcgacga ggtgttcaac 1020
gccacccggt tcgcctctgt gtacgcctgg aaccggaagc ggatctctaa ctgcgtggcc 1080
gactactccg tgctgtacaa cttcgccccc ttcttcgcct tcaagtgcta cggcgtgtcc 1140
cctacaaagc tgaacgacct gtgcttcacc aacgtgtacg ccgactcttt cgtgattaga 1200
ggcaacgagg tgagccagat tgcccccggc cagacaggca acatcgccga ctacaactac 1260
aagctgcccg acgacttcac aggctgcgtg atcgcctgga actctaacaa gctggactct 1320
aaggtgggcg gcaactacaa ctacctgtac agactgttcc ggaagtctaa cctgaagcca 1380
ttcgagaggg acattagcac cgagatttac caggccggca acaagccatg caacggcgtg 1440
gccggcttca actgctactt cccactgcgg tcctacggct tccggcctac atacggcgtg 1500
ggccaccagc cttaccgggt ggtggtgctg tctttcgagc tgctccacgc ccccgccaca 1560
gtgtgcggcc caaagaagag cacaaacctc gtgaagaaca agtgcgtgaa cttcaacttc 1620
aacggcctca caggcacagg cgtgctcacc gagtctaaca agaagttcct ccctttccag 1680
cagttcggcc gcgacattgc cgacaccacc gacgccgtgc gggaccctca gacactggaa 1740
attctcgaca tcaccccttg cagcttcggc ggcgtgtccg tgatcacccc aggcacaaac 1800
acatctaacc aggtggccgt gctgtaccag ggcgtgaact gcaccgaggt gccagtggcc 1860
atccacgccg accagctcac cccaacatgg agggtgtaca gcacaggctc taacgtgttc 1920
cagacccggg ccggctgcct cattggcgcc gagtacgtga acaactctta cgagtgcgac 1980
atccctattg gcgccggcat ttgcgcctct taccagaccc agacaaagtc tcaccggaga 2040
gcccggtctg tggcctctca gagcattatt gcctacacca tgtctctggg cgccgagaac 2100
tctgtggcct actctaacaa ctctattgcc atccctacaa acttcacaat ttctgtgacc 2160
accgagattc tcccagtgtc tatgaccaag acatctgtgg actgcaccat gtacatttgc 2220
ggcgactcca ccgagtgctc taacctcctg ctccagtacg gctctttctg cacccagctc 2280
aagcgcgccc tgacaggcat cgccgtggag caggacaaga acacccagga ggtgttcgcc 2340
caggtgaagc agatttacaa gaccccccca attaagtact tcggcggctt caacttctct 2400
cagattctcc ccgacccatc caagcctagc aagcggtcct tcattgagga cctcctgttc 2460
aacaaggtga cactggccga cgccggcttc attaagcagt acggcgactg cctgggcgac 2520
attgccgccc gggacctgat ttgcgcccag aagttcaacg gcctcacagt gctcccccca 2580
ctgctcaccg acgagatgat tgcccagtac acatctgccc tcctggccgg cacaattaca 2640
tctggctgga ccttcggcgc cggcgccgcc ctgcagatcc ctttcgccat gcagatggcc 2700
taccgcttca acggcatcgg cgtgacacag aacgtgctgt acgagaacca gaagctgatc 2760
gccaaccagt tcaacagcgc cattggcaag attcaggact ctctgagcag cacagccagc 2820
gccctgggca agctgcagga cgtggtgaac cacaacgccc aggccctgaa cacactggtg 2880
aagcagctgt cttctaagtt cggcgccatt agc 2913
Claims (8)
1.一种由以下纳米抗体融合蛋白形成的IgM五聚体在制备用于预防或治疗新冠病毒感染的药物中的应用,其特征在于,所述纳米抗体融合蛋白从N端到C端的结构如式(I)所示:
A-L-B (I)
其中,
A为特异性结合SARS-CoV-2RBD的纳米抗体;
B为人源IgM的Fc片段;
L为(GGGGS)m,其中,m=0,1,2,3,或4。
2.根据权利要求1所述的应用,其特征在于,所述特异性结合SARS-CoV-2RBD的纳米抗体包括以下CDR:氨基酸序列如SEQ ID NO:1所示的CDR1,氨基酸序列如SEQ ID NO:2所示的CDR2,以及氨基酸序列如SEQ ID NO:3所示的CDR3。
3.根据权利要求2所述的应用,其特征在于,所述特异性结合SARS-CoV-2 RBD的纳米抗体还包括4个框架区FR1-4,所述FR1-4与所述CDR1、CDR2和CDR3按顺序交错排列;
优选地,所述FR1-4分别如SEQ ID NO:4、5、6、7所示。
4.根据权利要求1-3任一项所述的应用,其特征在于,所述特异性结合SARS-CoV-2 RBD的纳米抗体具有如SEQ ID NO:8所示的氨基酸序列。
5.根据权利要求1-4任一项所述的应用,其特征在于,所述人源IgM的Fc片段具有如SEQID NO:10所示的氨基酸序列。
6.根据权利要求1-5任一项所述的应用,其特征在于,所述纳米抗体融合蛋白具有如SEQ ID NO:11所示的氨基酸序列。
7.根据权利要求1-6任一项所述的应用,其特征在于,所述新冠病毒为SARS-CoV-2原始毒株和/或SARS-CoV-2变异毒株;
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)、Kappa(B.1.617.1)、Delta(B.1.617.2)毒株、Omicron(B.1.1.529)亚型BA.1毒株和/或Omicron(B.1.1.529)亚型BA.2毒株。
8.根据权利要求1-7任一项所述的应用,其特征在于,所述药物为鼻喷剂、口服制剂、栓剂或胃肠外制剂的形式;
优选地,所述鼻喷剂选自气雾剂、喷雾剂和粉雾剂;
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;
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。
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