Li Xiaoman, Pan Yongbing, Yin Qiangling, Wang Zejun, Shan Sisi, Zhang Laixing, Yu Jinfang, Qu Yuanyuan, Sun Lina, Gui Fang, Lu Jia, Jing Zhaofei, Wu Wei, Huang Tao, Shi Xuanling, Li Jiandong, Li Xinguo, Li Dexin, Wang Shiwen, Yang Maojun, Zhang Linqi, Duan Kai, Liang Mifang, Yang Xiaoming, Wang Xinquan
The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China.
National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co. Ltd., Wuhan, Hubei, China.
Cell Discov. 2022 Sep 8;8(1):87. doi: 10.1038/s41421-022-00449-4.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), especially the latest Omicron, have exhibited severe antibody evasion. Broadly neutralizing antibodies with high potency against Omicron are urgently needed for understanding the working mechanisms and developing therapeutic agents. In this study, we characterized the previously reported F61, which was isolated from convalescent patients infected with prototype SARS-CoV-2, as a broadly neutralizing antibody against all VOCs including Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4 sublineages by utilizing antigen binding and cell infection assays. We also identified and characterized another broadly neutralizing antibody D2 with epitope distinct from that of F61. More importantly, we showed that a combination of F61 with D2 exhibited synergy in neutralization and protecting mice from SARS-CoV-2 Delta and Omicron BA.1 variants. Cryo-Electron Microscopy (Cryo-EM) structures of the spike-F61 and spike-D2 binary complexes revealed the distinct epitopes of F61 and D2 at atomic level and the structural basis for neutralization. Cryo-EM structure of the Omicron-spike-F61-D2 ternary complex provides further structural insights into the synergy between F61 and D2. These results collectively indicated F61 and F61-D2 cocktail as promising therapeutic antibodies for combating SARS-CoV-2 variants including diverse Omicron sublineages.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的关注变异株（VOCs），尤其是最新的奥密克戎变异株，已表现出严重的抗体逃逸现象。迫切需要高效的广谱中和抗体来对抗奥密克戎变异株，以了解其作用机制并开发治疗药物。在本研究中，我们通过抗原结合和细胞感染试验，将先前报道的从感染原型SARS-CoV-2的康复患者中分离出的F61鉴定为一种针对包括奥密克戎BA.1、BA.1.1、BA.2、BA.3和BA.4亚谱系在内的所有VOCs的广谱中和抗体。我们还鉴定并表征了另一种表位与F61不同的广谱中和抗体D2。更重要的是，我们发现F61与D2联合使用在中和作用以及保护小鼠免受SARS-CoV-2德尔塔和奥密克戎BA.1变异株感染方面具有协同作用。刺突蛋白-F61和刺突蛋白-D2二元复合物的冷冻电镜（Cryo-EM）结构在原子水平上揭示了F61和D2的不同表位以及中和作用的结构基础。奥密克戎-刺突蛋白-F61-D2三元复合物的冷冻电镜结构为F61和D2之间的协同作用提供了进一步的结构见解。这些结果共同表明，F61和F61-D2组合作为对抗包括多种奥密克戎亚谱系在内的SARS-CoV-2变异株的有前景的治疗性抗体。
