A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses

Yingdan Wang, Aihua Hao, Ping Ji, Yunping Ma, Zhaoyong Zhang, Jiali Chen, Qiyu Mao, Xinyi Xiong, Palizhati Rehati, Yajie Wang, Yanqun Wang, Yumei Wen, Lu Lu, Zhenguo Chen, Jincun Zhao (), Fan Wu (), Jinghe Huang () and Lei Sun ()
Additional contact information
Yingdan Wang: Fudan University
Aihua Hao: Fudan University
Ping Ji: Fudan University
Yunping Ma: Fudan University
Zhaoyong Zhang: the First Affiliated Hospital of Guangzhou Medical University
Jiali Chen: Fudan University
Qiyu Mao: Fudan University
Xinyi Xiong: the First Affiliated Hospital of Guangzhou Medical University
Palizhati Rehati: Fudan University
Yajie Wang: Fudan University
Yanqun Wang: the First Affiliated Hospital of Guangzhou Medical University
Yumei Wen: Fudan University
Lu Lu: Fudan University
Zhenguo Chen: Fudan University
Jincun Zhao: the First Affiliated Hospital of Guangzhou Medical University
Fan Wu: Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital
Jinghe Huang: Fudan University
Lei Sun: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants.

Date: 2024
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DOI: 10.1038/s41467-024-49096-1

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