Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2021,（1）
• 所属期刊栏目: ARTICLES
• 页码范围: 25-36
• 页数: 12页
• 语种: 英文

摘要

Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined.Here,we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2.On the basis of our previously identified humanized cross-neutralizing antibody H014,we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner,P17,which confers effective protection in animal model.Cryo-EM studies dissected the nature of the P17 epitope,which is SARS-CoV-2 specific and distinctly different from that of H014.High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17,together with functional investigations revealed that in a two-antibody cocktail,synergistic neutralization was achieved by S1 shielding and conformational locking,thereby blocking receptor attachment and viral membrane fusion,conferring high potency as well as robustness against viral mutation escape.Furthermore,cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.