Structure and function analysis of a potent human neutralizing antibody CA521FALA against SARS-CoV-2

Deyong Song,Changlin Dou,Hongguang Xu,Qiaoping Wang,Baiping Sun,Chuangchuang Dong,Zhenduo Shen,Guangying Du,Jie Jiao,Kailin Wang,Ying Li,Chunjie Sha,Yong‐Qiang Deng ,Ruiying Wang,Xiu Liu,Jun Lü ,Wenbo Wang,Lan Wang,Jingwei Tian,Wanhui Liu,Yanyan Zhao,Ning Zong ,Chuan Liu

doi:10.1038/s42003-021-02029-w

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic, which has resulted in more than two million deaths at 2021 February . There is currently no approved therapeutics for treating COVID-19. The SARS-CoV-2 Spike protein is considered a key therapeutic target by many researchers. Here we describe the identification of several monoclonal antibodies that target SARS-CoV-2 Spike protein. One human antibody, CA521FALA, demonstrated neutralization potential by immunizing human antibody transgenic mice. CA521FALA showed potent SARS-CoV-2-specific neutralization activity against SARS-CoV-2 pseudovirus and authentic SARS-CoV-2 infection in vitro. CA521FALA also demonstrated having a long half-life of 9.5 days in mice and 9.3 days in rhesus monkeys. CA521FALA inhibited SARS-CoV-2 infection in SARS-CoV-2 susceptible mice at a therapeutic setting with virus titer of the lung reduced by 4.5 logs. Structural analysis by cryo-EM revealed that CA521FALA recognizes an epitope overlapping with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 RBD in the Spike protein. CA521FALA blocks the interaction by binding all three RBDs of one SARS-CoV-2 spike trimer simultaneously. These results demonstrate the importance for antibody-based therapeutic interventions against COVID-19 and identifies CA521FALA a promising antibody that reacts with SARS-CoV-2 Spike protein to strongly neutralize its activity.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic, which has resulted in more than two million deaths at 2021 February
This may be due in part to antibody-dependent enhancement (ADE) which could lead to acute respiratory injury and is a potential risk for antibody therapeutic developed against SARS-CoV infection[24]
Cryo-electron microscopy characterization of the complexes formed by Spike protein and CA521FALA IgG/Fab showed that it recognizes a patch of residues overlapping with angiotensinconverting enzyme 2 (ACE2)-binding sites in the SARS-CoV-2 receptor-binding domain (RBD) of the Spike protein

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic, which has resulted in more than two million deaths at 2021 February. CA521FALA blocks the interaction by binding all three RBDs of one SARS-CoV-2 spike trimer simultaneously These results demonstrate the importance for antibody-based therapeutic interventions against COVID-19 and identifies CA521FALA a promising antibody that reacts with SARS-CoV-2 Spike protein to strongly neutralize its activity. Given that ADE is a potential risk for antibody therapeutics against SARS-CoV-2 infection we introduced FALA mutation to potentially abrogate the effect in these neutralizing MAbs. One human MAb designated CA521FALA demonstrated potent SARS-CoV-2-specific neutralization activity in vitro and in vivo and had no risk of ADE. Structural analysis reveals that the CA521FALA can block the interaction by binding all three RBDs of one SARS-CoV-2 spike protein simultaneously whether it was in “up” or “down” conformations and the cryo-EM structures provided evidence of bivalent binding of full-length IgG with two adjacent RBDs

Methods

Results

Conclusion