Rational Development of a Human Antibody Cocktail That Deploys Multiple Functions to Confer Pan-SARS-CoVs Protection

Overview

Journal Cell Res

Specialty Cell Biology

Date 2020 Dec 2

PMID 33262452

Citations 56

Authors

Hangping Yao

Yao Sun

Yong-Qiang Deng

Nan Wang

Yongcong Tan

Na-Na Zhang

Xiao-Feng Li

Chao Kong

Yan-Peng Xu

Qi Chen

Tian-Shu Cao

Hui Zhao

Xintian Yan

Lei Cao

Zhe Lv

Dandan Zhu

Rui Feng

Nanping Wu

Wenhai Zhang

Yuhao Hu

Keda Chen

Rong-Rong Zhang

Qingyu Lv

Shihui Sun

Yunhua Zhou

Run Yan

Guan Yang

Xinglu Sun

Chanjuan Liu

Xiangyun Lu

Linfang Cheng

Hongying Qiu

Xing-Yao Huang

Tianhao Weng

Danrong Shi

Weidong Jiang

Junbin Shao

Lei Wang

Jie Zhang

Tao Jiang

Guojun Lang

Cheng-Feng Qin

Lanjuan Li

Xiangxi Wang

Affiliations

Soon will be listed here.

Abstract

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.

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