A SARS-CoV-2 antibody curbs viral nucleocapsid protein-induced complement hyperactivation

Kang, Sisi; Yang, Mei; He, Suhua; Wang, Yueming; Chen, Xiaoxue; Chen, Yao-Qing; Hong, Zhongsi; Liu, Jing; Jiang, Guanmin; Chen, Qiuyue; Zhou, Ziliang; Zhou, Zhechong; Huang, Zhaoxia; Huang, Xi; He, Huanhuan; Zheng, Weihong; Liao, Hua-Xin; Xiao, Fei; Shan, Hong; Chen, Shoudeng

Although human antibodies elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-reactive antibodies. Herein, we isolate and profile a panel of 32 N protein-specific monoclonal antibodies (mAbs) from a quick recovery coronavirus disease-19 (COVID-19) convalescent patient who has dominant antibody responses to the SARS-CoV-2 N protein rather than to the SARS-CoV-2 spike (S) protein. The complex structure of the N protein RNA binding domain with the highest binding affinity mAb (nCoV396) reveals changes in the epitopes and antigen’s allosteric regulation. Functionally, a virus-free complement hyperactivation analysis demonstrates that nCoV396 specifically compromises the N protein-induced complement hyperactivation, which is a risk factor for the morbidity and mortality of COVID-19 patients, thus laying the foundation for the identification of functional anti-N protein mAbs.