抗体进化过程中的偶然体细胞突变赋予对新冠病毒奥密克戎变种的广泛中和能力。
Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants.
作者信息
Wu Jianbo, Chen Zhenguo, Gao Yidan, Wang Zegen, Wang Jiarong, Chiang Bing-Yu, Zhou Yunjiao, Han Yuru, Zhan Wuqiang, Xie Minxiang, Jiang Weiyu, Zhang Xiang, Hao Aihua, Xia Anqi, He Jiaying, Xue Song, Mayer Christian T, Wu Fan, Wang Bin, Zhang Lunan, Sun Lei, Wang Qiao
机构信息
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
These authors contributed equally.
出版信息
bioRxiv. 2022 Dec 13:2022.12.12.520172. doi: 10.1101/2022.12.12.520172.
Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.
新出现的循环严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体对抗体的显著逃避促使人们寻找广泛中和抗体（bNAb）。然而，bNAb在抗体进化过程中如何获得增强的中和广度仍不清楚。在此，我们从一名康复个体中鉴定出一个克隆相关的抗体家族。其中一个成员XG005对SARS-CoV-2变体表现出强大而广泛的中和活性，而其他成员的中和广度和效力则显著降低，尤其是对奥密克戎亚谱系。对XG005-奥密克戎刺突蛋白结合界面的结构分析揭示了关键的体细胞突变如何赋予XG005更高的中和效力和广度。单次注射具有延长半衰期、降低抗体依赖性增强（ADE）效应和提高抗体产品质量的XG005，在受BA.2和BA.5攻击的小鼠中显示出高治疗效果。我们的结果提供了一个自然实例，以表明体细胞超突变在抗体进化过程中对SARS-CoV-2中和广度和效力的重要性。
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