Potently neutralizing and protective human antibodies against SARS-CoV-2.
Potently neutralizing and protective human antibodies against SARS-CoV-2.
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DOI：
10.1038/s41586-020-2548-6
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发表时间：
2020-08
期刊：
影响因子：
64.8
通讯作者：
Crowe JE Jr
中科院分区：
文献类型：
--
作者：
Zost SJ;Gilchuk P;Case JB;Binshtein E;Chen RE;Nkolola JP;Schäfer A;Reidy JX;Trivette A;Nargi RS;Sutton RE;Suryadevara N;Martinez DR;Williamson LE;Chen EC;Jones T;Day S;Myers L;Hassan AO;Kafai NM;Winkler ES;Fox JM;Shrihari S;Mueller BK;Meiler J;Chandrashekar A;Mercado NB;Steinhardt JJ;Ren K;Loo YM;Kallewaard NL;McCune BT;Keeler SP;Holtzman MJ;Barouch DH;Gralinski LE;Baric RS;Thackray LB;Diamond MS;Carnahan RH;Crowe JE Jr
COVID-19大流行是对全球健康的重大威胁，对此医疗对策有限。此外，我们目前缺乏对体液免疫机制的深入了解。从靶向刺突（S）糖蛋白的更大组人单克隆抗体（mAb）中，我们鉴定了几种表现出强效中和活性并完全阻断S（SRBD）受体结合结构域与人ACE 2（hACE 2）相互作用的抗体。竞争结合，结构和功能的研究允许聚类的单克隆抗体到类识别不同的表位上的SRBD以及不同的构象状态的S三聚体。识别非重叠位点COV 2 -2196和COV 2 -2130的有效中和mAb同时结合S并协同中和真实的SARS-CoV-2病毒。在SARS-CoV-2感染的两种小鼠模型中，单独被动转移COV 2 -2196或COV 2 -2130或两种mAb的组合保护小鼠免于体重减轻，并减少肺部的病毒负荷和炎症。此外，被动转移两种最有效的ACE 2阻断mAb（COV 2 -2196或COV 2 -2381）作为单一疗法保护恒河猴免受SARS-CoV-2感染。这些结果确定了SRBD上的保护性表位，并为合理的疫苗设计和稳健的免疫治疗药物的选择提供了基于结构的框架。
The COVID-19 pandemic is a major threat to global health for which there are limited medical countermeasures. Moreover, we currently lack a thorough understanding of mechanisms of humoral immunity. From a larger panel of human monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein, we identified several that exhibited potent neutralizing activity and fully blocked the receptor-binding domain of S (SRBD) from interacting with human ACE2 (hACE2). Competition-binding, structural, and functional studies allowed clustering of the mAbs into classes recognizing distinct epitopes on the SRBD as well as distinct conformational states of the S trimer. Potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two mouse models of SARS-CoV-2 infection, passive transfer of either COV2-2196 or COV2-2130 alone or a combination of both mAbs protected mice from weight loss and reduced viral burden and inflammation in the lung. In addition, passive transfer of each of two of the most potently ACE2 blocking mAbs (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutics.
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影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
DOI：
10.1073/pnas.1510199112
发表时间：
2015-08-18
影响因子：
11.1
作者：
Corti, Davide;Zhao, Jincun;Lanzavecchia, Antonio
通讯作者：
Lanzavecchia, Antonio
影响因子：
48
作者：
Bepler, Tristan;Morin, Andrew;Berger, Bonnie
通讯作者：
Berger, Bonnie
影响因子：
3
作者：
Mastronarde, DN
通讯作者：
Mastronarde, DN
影响因子：
56.9
作者：
Chandrashekar, Abishek;Liu, Jinyan;Barouch, Dan H.
通讯作者：
Barouch, Dan H.