期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2204256119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
This study developed a rational antibody cocktail containing three cross-neutralizing antibodies that can bind to the receptor-binding domain of SARS-CoV and SARS-CoV-2. Cryo-electron microscopy structures of the triple-antibody cocktail in complex with the spike proteins of prototyped SARS-CoV-2, Delta, Omicron, and SARS-CoV defined three nonoverlapping conserved neutralizing epitopes. This knowledge will facilitate the development of broad-acting antibody therapeutics and vaccines against SARS-CoV-2 and emerging variants.
Antibody therapeutics for the treatment of COVID-19 have been highly successful. However, the recent emergence of the Omicron variant has posed a challenge, as it evades detection by most existing SARS-CoV-2 neutralizing antibodies (nAbs). Here, we successfully generated a panel of SARS-CoV-2/SARS-CoV cross-neutralizing antibodies by sequential immunization of the two pseudoviruses. Of the potential candidates, we found that nAbs X01, X10, and X17 offer broad neutralizing potential against most variants of concern, with X17 further identified as a Class 5 nAb with undiminished neutralization against the Omicron variant. Cryo-electron microscopy structures of the three antibodies together in complex with each of the spike proteins of the prototypical SARS-CoV, SARS-CoV-2, and Delta and Omicron variants of SARS-CoV-2 defined three nonoverlapping conserved epitopes on the receptor-binding domain. The triple-antibody mixture exhibited enhanced resistance to viral evasion and effective protection against infection of the Beta variant in hamsters. Our findings will aid the development of antibody therapeutics and broad vaccines against SARS-CoV-2 and its emerging variants.
