A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients by phage display is binding to the ACE2-RBD interface and is tolerant to most known recently emerging RBD mutations
Author:
Bertoglio FedericoORCID, Fühner Viola, Ruschig Maximilian, Heine Philip Alexander, Abasi Leila, Klünemann Thomas, Rand UlfertORCID, Meier Doris, Langreder Nora, Steinke StephanORCID, Ballmann Rico, Schneider Kai-Thomas, Ralph Roth Kristian Daniel, Kuhn Philipp, Riese Peggy, Schäckermann Dorina, Korn Janin, Koch Allan, Chaudhry M. Zeeshan, Eschke Kathrin, Kim Yeonsu, Zock-Emmenthal Susanne, Becker Marlies, Scholz Margitta, Schmidt Garcia Moreira Gustavo Marçal, Wenzel Esther Veronika, Russo Giulio, Garritsen Hendrikus S.P., Casu Sebastian, Gerstner Andreas, Roth Günter, Adler Julia, Trimpert Jakob, Hermann Andreas, Schirrmann Thomas, Dübel StefanORCID, Frenzel André, Van den Heuvel Joop, Čičin-Šain LukaORCID, Schubert MarenORCID, Hust MichaelORCID
Abstract
AbstractThe novel betacoranavirus SARS-CoV-2 causes a form of severe pneumonia disease, termed COVID-19 (coronavirus disease 2019). Recombinant human antibodies are proven potent neutralizers of viruses and can block the interaction of viral surface proteins with their host receptors. To develop 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 S1 subunit of the viral spike (S) protein were selected by phage display. The selected antibodies were produced in the scFv-Fc format and 30 showed more than 80% inhibition of spike (S1-S2) binding to cells expressing ACE2, assessed by flow cytometry screening assay. The majority of these inhibiting antibodies are derived from the VH3-66 V-gene. The antibody STE90-C11 showed a sub nM IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody was demonstrated in the Syrian hamster and in the hACE2 mice model using a silenced human IgG1 Fc part. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD was solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibtion of STE90-C11 is not blocked by many known RBD mutations including N439K, L452R, E484K or L452R+E484Q (emerging B.1.617). STE90-C11 derived human IgG1 with FcγR silenced Fc (COR-101) is currently undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.In BriefHuman antibodies were selected from convalescent COVID-19 patients using antibody phage display. The antibody STE90-C11 is neutralizing authentic SARS-CoV-2 virus in vitro and in vivo and the crystal structure of STE90-C11 in complex with SARS-CoV-2-RBD revealed that this antibody is binding in the RBD-ACE2 interface. S1 binding of STE90-C11 and inhibition of ACE2 binding is not blocked by many known RBD mutations.
Publisher
Cold Spring Harbor Laboratory
Reference104 articles.
1. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19;ACTIV-3/TICO LY-CoV555 Study Group;N Engl J Med,2021 2. Towards automated crystallographic structure refinement with phenix.refine 3. Phage Display Derived Monoclonal Antibodies: From Bench to Bedside;Frontiers in Immunology,2020 4. Annavajhala, M.K. , Mohri, H. , Zucker, J.E. , Sheng, Z. , Wang, P. , Gomez-Simmonds, A. , Ho, D.D. , and Uhlemann, A.-C. (2021). A Novel SARS-CoV-2 Variant of Concern, B.1.526, Identified in New York. MedRxiv 2021.02.23.21252259. 5. Recombinant human IgG molecules lacking Fcγ receptor I binding and monocyte triggering activities
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|