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.
Advaccine Biopharmaceuticals Suzhou Co., Ltd., Suzhou, China.
Cell Rep. 2023 May 30;42(5):112503. doi: 10.1016/j.celrep.2023.112503. Epub 2023 May 3.
Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (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 identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow 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 exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.
新兴的循环严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)变体对抗体产生明显逃逸作用,从而推动了广谱中和抗体(bNAb)的鉴定。然而,bNAb 在抗体进化过程中如何获得更高的中和广度仍不清楚。在这里,我们从一名恢复期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,尤其是针对奥密克戎亚谱系。结构分析直观地显示了 XG005 与奥密克戎刺突结合界面,揭示了体细胞突变如何赋予 XG005 更高的中和效力和广度。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 单次给药,在 BA.2 和 BA.5 挑战的小鼠中表现出很高的治疗效果。我们的研究结果提供了一个自然的例子,说明了体细胞超突变在 SARS-CoV-2 中和广度和效力方面的重要性。