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

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posted on 06.06.2021, 17:20 by Qihong Yan, Ping He, Xiaohan Huang, Kun Luo, Yudi Zhang, Haisu Yi, Qian Wang, Feng Li, Ruitian Hou, Xiaodi Fan, Pingchao Li, Xinglong Liu, Huan Liang, Yijun Deng, Zhaoming Chen, Yunfei Chen, Xiaoneng Mo, Liqiang Feng, Xiaoli Xiong, Song Li, Jian Han, Linbing Qu, Xuefeng Niu, Ling Chen

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.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 82041014, 82061138006 81661148056, and 61971187], the Chinese Academy of Sciences Pilot Strategic Science and Technology Projects [grant number XDB29050701]. Hunan Urgency Project [grant number 2020SK3005]; Zhongnanshan Medical Foundation of Guangdong Province [grant number ZNSA-2020001].

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