Structure and function analysis of a potent human neutralizing antibody CA521(FALA) against SARS-CoV-2

Song, Deyong; Wang, Wenbo; Dong, Chuangchuang; Ning, Zhenfei; Liu, Xiu; Liu, Chuan; Du, Guangying; Sha, Chunjie; Wang, Kailin; Lu, Jun; Sun, Baiping; Zhao, Yanyan; Wang, Qiaoping; Xu, Hongguang; Li, Ying; Shen, Zhenduo; Jiao, Jie; Wang, Ruiying; Tian, Jingwei; Liu, Wanhui; Wang, Lan; Deng, Yong-Qiang; Dou, Changlin

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic, which has resulted in more than two million deaths at 2021 February . There is currently no approved therapeutics for treating COVID-19. The SARS-CoV-2 Spike protein is considered a key therapeutic target by many researchers. Here we describe the identification of several monoclonal antibodies that target SARS-CoV-2 Spike protein. One human antibody, CA521(FALA), demonstrated neutralization potential by immunizing human antibody transgenic mice. CA521(FALA) showed potent SARS-CoV-2-specific neutralization activity against SARS-CoV-2 pseudovirus and authentic SARS-CoV-2 infection in vitro. CA521(FALA) also demonstrated having a long half-life of 9.5 days in mice and 9.3 days in rhesus monkeys. CA521(FALA) inhibited SARS-CoV-2 infection in SARS-CoV-2 susceptible mice at a therapeutic setting with virus titer of the lung reduced by 4.5 logs. Structural analysis by cryo-EM revealed that CA521(FALA) recognizes an epitope overlapping with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 RBD in the Spike protein. CA521(FALA) blocks the interaction by binding all three RBDs of one SARS-CoV-2 spike trimer simultaneously. These results demonstrate the importance for antibody-based therapeutic interventions against COVID-19 and identifies CA521(FALA) a promising antibody that reacts with SARS-CoV-2 Spike protein to strongly neutralize its activity.