Germline IGHV3-53-encoded RBD-targeting neutralizing antibodies are commonly present in the antibody repertoires of COVID-19 patients

• Published in: Emerging microbes & infections Vol. 10; no. 1; pp. 1097 - 1111
• Main Authors: Yan, Qihong, He, Ping, Huang, Xiaohan, Luo, Kun, Zhang, Yudi, Yi, Haisu, Wang, Qian, Li, Feng, Hou, Ruitian, Fan, Xiaodi, Li, Pingchao, Liu, Xinglong, Liang, Huan, Deng, Yijun, Chen, Zhaoming, Chen, Yunfei, Mo, Xiaoneng, Feng, Liqiang, Xiong, Xiaoli, Li, Song, Han, Jian, Qu, Linbing, Niu, Xuefeng, Chen, Ling
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2021; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Antibodies; antibody repertoire sequencing; COVID-19; IGHV3-53; receptor-binding domain; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; shared clonotype
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1080/22221751.2021.1925594

Monoclonal antibodies (mAbs) encoded by IGHV3-53 (VH3-53) targeting the spike receptor-binding domain (RBD) have been isolated from different COVID-19 patients. However, the existence and prevalence of shared VH3-53-encoded antibodies in the antibody repertoires is not clear. Using antibody repertoire sequencing, we found that the usage of VH3-53 increased after SARS-CoV-2 infection. A highly shared VH3-53-J6 clonotype was identified in 9 out of 13 COVID-19 patients. This clonotype was derived from convergent gene rearrangements with few somatic hypermutations and was evolutionary conserved. We synthesized 34 repertoire-deduced novel VH3-53-J6 heavy chains and paired with a common IGKV1-9 light chain to produce recombinant mAbs. Most of these recombinant mAbs (23/34) possess RBD binding and virus-neutralizing activities, and recognize ACE2 binding site via the same molecular interface. Our computational analysis, validated by laboratory experiments, revealed that VH3-53 antibodies targeting RBD are commonly present in COVID-19 patients' antibody repertoires, indicating many people have germline-like precursor sequences to rapidly generate SARS-CoV-2 neutralizing antibodies. Moreover, antigen-specific mAbs can be digitally obtained through antibody repertoire sequencing and computational analysis.