A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations.

Federico Bertoglio,Kathrin Eschke,Maximilian Ruschig,Allan Koch,Maren Schubert,Jakob Trimpert,Günter Roth,Doris Meier,Hendrikus S.P Garritsen,Joop Van Den Heuvel,Rico Ballmann,Andreas Hermann,André Frenzel,Yeonsu Kim,Giulio Russo,Philip Alexander Heine,Janin Korn,Gustavo Marçal Schmidt Garcia Moreira,Stefan Dübel,Michael Hust,Nora Langreder,Leila Abassi,Marlies Becker,Esther Veronika Wenzel,Sebastian Casu,Thomas Klünemann,Kristian Daniel Ralph Roth,Ulfert Rand,Peggy Riese,Dorina Schäckermann,Kai-Thomas Schneider,Stephan Steinke,Viola Fühner,Susanne Zock-Emmenthal,Thomas Schirrmann,M Zeeshan Chaudhry,Julia M Adler ,Philipp Kühn ,Andreas O H Gerstner ,M Scholz ,Luka Čičin‐Šain

doi:10.1016/j.celrep.2021.109433

Abstract

The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcγR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.

Highlights

The severe pneumonia COVID-19 is a disease caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and was described at the end of 2019 in Wuhan, China (Lu et al, 2020; Zhou et al., 2020)
To develop human neutralizing antiSARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments against the receptor-binding domain (RBD) of the spike protein were selected by phage display
The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 mice model

Summary

Introduction

The severe pneumonia COVID-19 (coronavirus disease 2019) is a disease caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and was described at the end of 2019 in Wuhan, China (Lu et al, 2020; Zhou et al., 2020). This new human pathogenic coronavirus is closely related to the bat coronavirus RATG13, indicating an animal-to-human transition (Shang et al, 2020a). Article receptor binding domain (RBD), and the viral membraneanchored C-terminal S2 subunit, which is required for trimerization and fusion of the virus and host membrane for viral entry (Shang et al, 2020b; Starr et al, 2020; Walls et al, 2020; Wang et al, 2020b; Wrapp et al, 2020; Yan et al, 2020). Some of the anti-SARS-CoV antibodies showed cross-reaction and cross-neutralization of SARS-CoV-2 (Huo et al, 2020; Tian et al, 2020; Wang et al, 2020a)

Results

Discussion

Conclusion