Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Fifth People's Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Nat Commun. 2024 Jun 15;15(1):5127. doi: 10.1038/s41467-024-49096-1.
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.
新冠病毒的奥密克戎亚变种 BQ.1.1、XBB.1.5 和 XBB.1.16 以其逃避免疫反应的能力而闻名。在这里，我们分离出一种中和抗体 7F3，它能够中和所有测试过的 SARS-CoV-2 变体，包括 BQ.1.1、XBB.1.5 和 XBB.1.16。7F3 靶向受体结合基序（RBM）区域，并广泛结合 37 种 RBD 突变蛋白。我们使用 7F3 和交叉中和抗体 GW01 开发了 IgG 样双特异性抗体 G7-Fc。G7-Fc 对所有 28 种测试的 SARS-CoV-2 变体和沙贝病毒表现出强大的中和活性，为 K18-ACE 和 BALB/c 雌性小鼠的 XBB.1 感染提供了强大的预防和治疗效果。G7-Fc 与奥密克戎 XBB 刺突（S）三聚体复合物的冷冻电镜结构分析揭示了三聚体-二聚体构象，G7-Fc 协同靶向两个不同的 RBD 表位并阻断 ACE2 结合。对 7F3 和 LY-CoV1404 表位的比较分析突出了 7F3 结合的 RBM 区域中一个独特且高度保守的表位，有利于中和免疫逃避的奥密克戎变体 XBB.1.16。G7-Fc 有望成为对抗 SARS-CoV-2 的潜在预防措施，特别是针对循环和新兴变体。
