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

• DOI: 10.1016/j.hlife.2024.12.006
• Publication Date: 2025-01-25T12:08:30Z
• Authors: 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 Fu Gao
• Keywords: 2019-20 coronavirus outbreak; Pandemic

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.