Enabling the immune escaped etesevimab fully-armed against SARS-CoV-2 Omicron subvariants including KP.2

作者：Chao Su, Juanhua He, Yufeng Xie, Yu Hu, Xin Li, Shitong Qiao, Peipei Liu, Min Huang, Rong Zhang, Liang Wang, Zhen Chang, Wenqiao Sun, Ke Xu, Jing Zhang, Longxing Cao, Pengcheng Han, Xin Zhao, Jianxun Qi, Qihui Wang, Mengsu Yang, George F. Gao · 发表于：hLife · 年份：2025 · DOI：10.1016/j.hlife.2024.12.006 · 被引用次数：11 · 研究领域：SARS-CoV-2 and COVID-19 Research、COVID-19 Clinical Research Studies、vaccines and immunoinformatics approaches

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously evolving since 2019. Some monoclonal antibodies (mAbs) have been developed and widely used, such as etesevimab (CB6) developed by Eli-Lilly/Junshi. However, the mAb escaped from the variant of concern (VOC) ever since the emergence of Beta VOC, with a complete loss of efficacy against the Omicron subvariants. Here, we developed a broad-spectrum and affinity-mature antibody design (BAADesign) procedure to design CB6, enabling it to bind to the receptor-binding domains (RBDs) of multiple important Omicron subvariants, including the recent variant KP.2. Structural analysis confirmed the desired CB6-RBD interactions. Additionally, identical mutations in the complementarity determining regions (CDR)1 and CDR2 of the CB6 mutants also restored neutralizing potency for some RBD-1 group antibodies. Overall, the enhanced CB6 neutralizing capacity makes it a promising candidate against SARS-CoV-2 infection, and the BAADesign method has implications for the design of other antibodies.