A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants

查看全文 作　　者：Zhenlin [1,2,3]Yang;Yulu [4]Wang;Yujia [4]Jin;Yuanfei [4]Zhu;Yanling [2,4]Wu;Cheng [4]Li;Yu [4]Kong;Wenping [4]Song;Xiaolong [4]Tian;Wuqiang [5]Zhan;Ailing [2,4]Huang;Shanshan [4]Zhou;Shuai [4]Xia;Xiaoxu [6]Tian;Chao [6]Peng;Cuicui [1,3]Chen;Yibing [4]Shi;Gaowei [4]Hu;Shujuan [4]Du;Yuyan [4]Wang;Youhua [4]Xie;Shibo [4]Jiang;Lu [4]Lu;Lei [5]Sun;Yuanlin [1,3,7]Song;Tianlei [2,4]Ying

机构地区：[1]Department of Pulmonary Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China;[2]Shanghai Engineering Research Center for Synthetic Immunology,Shanghai 200032,China;[3]Shanghai Key Laboratory of Lung Inflammation and Injury,Shanghai 200032,China;[4]MOE/NHC Key Laboratory of Medical Molecular Virology,Shanghai Institute of Infectious Disease and Biosecurity,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai 200032,China;[5]The Fifth People’s Hospital of Shanghai,Fudan University and Shanghai Key Laboratory of Medical Epigenetics,Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China;[6]National Facility for Protein Science in Shanghai,Zhangjiang Lab,Shanghai Advanced Research Institute,Chinese Academy of Science,Shanghai 201210,China;[7]Department of Pulmonary Medicine,Shanghai Respiratory Research Institute,Shanghai 200032,China

出　　处：《Signal Transduction and Targeted Therapy》索引2021年第6卷第12期,共8页

基　　金：This work was supported by grants from the National Key R&D Program of China(2019YFA0904400);National Natural Science Foundation of China(32070938,82041003,81822027,81630090,81902108);Chinese Academy of Medical Sciences(2019PT350002);Shanghai Municipal Health Commission(GWV-10.2-YQ06,GWV-10.2-XD01);Science and Technology Commission of Shanghai Municipality(20411950402,20XD1401200,18DZ2210200,20DZ2254600,20DZ2261200). 摘　　要：The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants.Here we show that the bivalency of an affinity maturated fully human singledomain antibody(n3113.1-Fc)exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus,and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2(ACE2)humanized mice.The crystal structure of n3113 in complex with the receptor-binding domain(RBD)of SARS-CoV-2,combined with the cryo-EM structures of n3113 and spike ecto-domain,reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2.The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion,expanding our recognition of neutralization by antibodies against SARS-CoV-2.Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2)for n3113.1-Fc with Y58L mutation,demonstrating the potential of n3113.1-Fc(Y58L)as a promising candidate for clinical development to treat COVID-19. 关键词：ACE2 VARIANTS authentic

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A non-ACE2 competing human single-domain antibody confers broad neutralization against SARS-CoV-2 and circulating variants

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