Journal
EMBO MOLECULAR MEDICINE
Volume 13, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202114544
Keywords
COVID-19; cross-active neutralizing antibody; destruction of spike; receptor-binding domain; variants of concern
Categories
Funding
- Strategic Priority Research Program of CAS [XDB37020204, XDB29010102]
- Key Program of CAS Frontier Science [QYZDB-SSW-SMC037]
- CAS Facility-based Open Research Program (2017)
- National Natural Science Foundation of China (NSFC) [31870726, 31870153, 31970880]
- Ministry of Science and Technology of China [2020YFC0845900, 2017YFA0506700]
- CAS President's International Fellowship Initiative [2020VBA0023]
- Key R & D Program of Jiangsu Province (Social Development) [BE2019625]
- Science and Technology Commission of Shanghai Municipality (STCSM) [20ZR1466700, 20490760200]
- Shanghai Municipal Science and Technology Major Project [20431900402]
- Innovation Capacity Building Project of Jiangsu province Nanjing Unicorn Academy of innovation [BM2020019]
- ERINHA-Advance project (European Union's Horizon 2020 Research & Innovation program) [824061]
- Science and Technology Commission of Hangzhou Municipality [202013A02]
- RECOVER European Union's Horizon 2020 research and innovation program [101003589]
- NSFC [31822055]
- Youth Innovation Promotion Association of the Chinese Academy of Sciences (Youth Innovation Promotion Association CAS) [2017122]
- CAS [JCTD-2020-17]
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The non-RBM-targeting monoclonal antibody FD20 isolated from convalescent patients neutralizes SARS-CoV-2, including Variants of Concern. It engages the RBD at a distal epitope, coinciding with a predicted vulnerability site. The antibody's mechanism of neutralization involves destructing the Spike protein, showing potential for antiviral drug development.
An essential step for SARS-CoV-2 infection is the attachment to the host cell receptor by its Spike receptor-binding domain (RBD). Most of the existing RBD-targeting neutralizing antibodies block the receptor-binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non-RBM-targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a K-D of 5.6 nM, neutralizes SARS-CoV-2 including the current Variants of Concern such as B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta), displays modest cross-reactivity against SARS-CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted ideal vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20-binding but confers little or no resistance to neutralization. Finally, in vitro mode-of-action characterization and negative-stain electron microscopy suggest a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS-CoV-2 Spike for the development of potential antiviral drugs.
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