A pair of noncompeting neutralizing human monoclonal antibodies protecting from disease in a SARS-CoV-2 infection model

  • TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.

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Author:Antonia Sophia Peter, Edith Roth, Sebastian R. Schulz, Kirsten Fraedrich, Tobit Steinmetz, Dominik Damm, Manuela Hauke, Elie Richel, Sandra Müller-Schmucker, Katharina Habenicht, Valentina Eberlein, Leila Issmail, Nadja Uhlig, Simon Dolles, Eva Grüner, David Peterhoff, Sandra CiesekORCiDGND, Markus Hoffmann, Stefan Pöhlmann, Paul F. McKay, Robin J. Shattock, Roman Wölfel, Eileen Socher, Ralf Wagner, Jutta Eichler, Heinrich Sticht, Wolfgang Schuh, Frank Neipel, Armin Ensser, Dirk Alexander Mielenz, Matthias Tenbusch, Thomas H. Winkler, Thomas Grunwald, Klaus Thomas Überla, Hans-Martin Jäck
Parent Title (English):European journal of immunology
Place of publication:Weinheim
Document Type:Article
Date of Publication (online):2021/08/06
Date of first Publication:2021/08/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/02/14
Tag:COVID-19; SARS-CoV-2; neutralizing antibodies; spike protein; variants of concern
Issue:online version before inclusion in an issue
Page Number:14
First Page:1
Last Page:14
Early View: Online Version before inclusion in an issue
The peer review history for this article is available at https://publons.com/publon/10.1002/eji.202149374
This work was supported by a Grant (01KI2043) from the Bundesministerium für Bildung und Forschung (BMBF) and funds from the Bavarian State Ministry for Science and the Arts to K.Ü., H-M J., and T.H.W. Further support was provided by B-FAST and COVIM, two BMBF-funded projects of the Netzwerk Universitätsmedizin (NaFoUniMedCovid19; FKZ: 01KX2021) and funds from the Deutsche Forschungsgemeinschaft (DFG) through the research training groups RTG 2504 and RTG1660 and the DFG-funded TRR130 (to HMJ and TW).
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0