Yu Lei, Wang Yajie, Liu Yuanchen, Xing Xiaomin, Li Chen, Wang Xun, Shi Jialu, Ma Wentai, Li Jiayan, Chen Yanjia, Qiao Rui, Zhao Xiaoyu, Tian Shilei, Gao Ming, Wen Shuhua, Xue Yingxue, Qiu Tianyi, Yu Hongjie, Guan Yongjun, Chu Hin, Sun Lei, Wang Pengfei
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Commun Biol. 2025 Mar 6;8(1):378. doi: 10.1038/s42003-025-07769-7.
The emergence of various SARS-CoV-2 variants presents challenges for antibody therapeutics, emphasizing the need for more potent and broadly neutralizing antibodies. Here, we employed an unbiased screening approach and successfully isolated two antibodies from individuals with only exposure to ancestral SARS-CoV-2. One of these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum of SARS-CoV-2 variants, including the latest KP.2, KP.3 and XEC, with consistent IC values ranging from ~1 to 5 ng/mL. It also displayed broad neutralization activity against SARS-CoV and related sarbecoviruses. Structural analysis revealed that these antibodies target shared hotspot but mutation-resistant epitopes, with their Fabs locking receptor binding domains (RBDs) in the "down" conformation through interactions with adjacent Fabs and RBDs, and cross-linking Spike trimers into di-trimers. In vivo studies conducted in a JN.1-infected hamster model validated the protective efficacy of CYFN1006-1. These findings suggest that antibodies with cross-neutralization activities can be identified from individuals with exclusively ancestral virus exposure.
多种新冠病毒变异株的出现给抗体疗法带来了挑战，这凸显了对更有效且具有广泛中和作用的抗体的需求。在此，我们采用了一种无偏向性的筛选方法，成功从仅接触过原始新冠病毒的个体中分离出两种抗体。其中一种抗体CYFN1006-1对一系列新冠病毒变异株，包括最新的KP.2、KP.3和XEC，表现出强大的交叉中和作用，其IC值稳定在约1至5 ng/mL之间。它还对严重急性呼吸综合征冠状病毒（SARS-CoV）及相关的沙贝病毒表现出广泛的中和活性。结构分析表明，这些抗体靶向共同的热点但抗突变的表位，其Fab片段通过与相邻的Fab片段和受体结合域（RBD）相互作用，将RBD锁定在“向下”构象，并将刺突三聚体交联成二聚体。在感染JN.1的仓鼠模型中进行的体内研究验证了CYFN1006-1的保护效果。这些发现表明，可从仅接触过原始病毒的个体中鉴定出具有交叉中和活性的抗体。
