Three epitope-distinct human antibodies from RenMab mice neutralize SARS-CoV-2 and cooperatively minimize the escape of mutants

• Main Authors: Jianhui Nie, Jingshu Xie, Shuo Liu, Jiajing Wu, Chuan Liu, Jianhui Li, Yacui Liu, Meiyu Wang, Huizhen Zhao, Yabo Zhang, Jiawei Yao, Lei Chen, Yuelei Shen, Yi Yang, Hong-Wei Wang, Youchun Wang, Weijin Huang
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-07-01
• Series: Cell Discovery
• Online Access: https://doi.org/10.1038/s41421-021-00292-z

Abstract Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 3.8 million deaths to date. Neutralizing antibodies are effective therapeutic measures. However, many naturally occurring mutations at the receptor-binding domain (RBD) have emerged, and some of them can evade existing neutralizing antibodies. Here, we utilized RenMab, a novel mouse carrying the entire human antibody variable region, for neutralizing antibody discovery. We obtained several potent RBD-blocking antibodies and categorized them into four distinct groups by epitope mapping. We determined the involved residues of the epitope of three representative antibodies by cryo-electron microscopy (Cryo-EM) studies. Moreover, we performed neutralizing experiments with 50 variant strains with single or combined mutations and found that the mixing of three epitope-distinct antibodies almost eliminated the mutant escape. Our study provides a sound basis for the rational design of fully human antibody cocktails against SARS-CoV-2 and pre-emergent coronaviral threats.