Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Li, Tingting; Han, Xiaojian; Gu, Chenjian; Guo, Hangtian; Zhang, Huajun; Wang, Yingming; Hu, Chao; Wang, Kai; Liu, Fengjiang; Luo, Feiyang; Zhang, Yanan; Hu, Jie; Wang, Wang; Li, Shenglong; Hao, Yanan; Shen, Meiying; Huang, Jingjing; Long, Yingyi; Song, Shuyi; Wu, Ruixin; Mu, Song; Chen, Qian; Gao, Fengxia; Wang, Jianwei; Long, Shunhua; Li, Luo; Wu, Yang; Gao, Yan; Xu, Wei; Cai, Xia; Qu, Di; Zhang, Zherui; Zhang, Hongqing; Li, Na; Gao, Qingzhu; Zhang, Guiji; He, Changlong; Wang, Wei; Ji, Xiaoyun; Tang, Ni; Yuan, Zhenghong; Xie, Youhua; Yang, Haitao; Zhang, Bo; Huang, Ailong; Jin, Aishun

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.