Deciphering a reliable synergistic bispecific strategy of rescuing antibodies for SARS-CoV-2 escape variants, including BA.2.86, EG.5.1, and JN.1
Zhou Tong,
Jianyu Tong,
Wenwen Lei,
Yufeng Xie,
Yingzi Cui,
Guowen Jia,
Shihua Li,
Zezhong Zhang,
Zhimin Cheng,
Xiao Xing,
Haiyun Ma,
Lan Deng,
Rong Zhang,
Xin Zhao,
Kefang Liu,
Qihui Wang,
Jianxun Qi,
Haomin Huang,
Rui Song,
Zhaoming Su,
Guizhen Wu,
Jing Lou,
George Fu Gao
Affiliations
Zhou Tong
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shanxi Academy of Advanced Research and Innovation, Xinhua Road, Taiyuan, Shanxi 030032, China
Jianyu Tong
Shanxi Academy of Advanced Research and Innovation, Xinhua Road, Taiyuan, Shanxi 030032, China
Wenwen Lei
NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
Yufeng Xie
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Yingzi Cui
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Guowen Jia
The State Key Laboratory of Biotherapy, Frontiers Medical Center of Tianfu Jincheng Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China
Shihua Li
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Zezhong Zhang
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Zhimin Cheng
Shanxi Academy of Advanced Research and Innovation, Xinhua Road, Taiyuan, Shanxi 030032, China
Xiao Xing
Shanxi Academy of Advanced Research and Innovation, Xinhua Road, Taiyuan, Shanxi 030032, China
Haiyun Ma
The State Key Laboratory of Biotherapy, Frontiers Medical Center of Tianfu Jincheng Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China
Lan Deng
Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., a 3SBio, Inc., company, 399 Libing Road, Shanghai 201203, China
Rong Zhang
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Xin Zhao
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Kefang Liu
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Qihui Wang
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Jianxun Qi
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Haomin Huang
Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., a 3SBio, Inc., company, 399 Libing Road, Shanghai 201203, China
Rui Song
Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
Zhaoming Su
The State Key Laboratory of Biotherapy, Frontiers Medical Center of Tianfu Jincheng Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China
Guizhen Wu
NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Corresponding author
Summary: The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most therapeutic mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in this study. It could effectively restore the neutralizing activity of the bsAb when any of its single mAbs is escaped by variants. This synergy is primarily attributed to the binding angle of receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking and promoting cryptic epitope exposure that classical antibody cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, and RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. This study not only shifts the paradigm in understanding antibody interactions but paves the way for developing more effective therapeutic antibodies against rapidly mutating SARS-CoV-2, with Dia-19 already showing promise against emerging variants like BA.2.86, EG.5.1, and JN.1.
