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Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers

Vanshylla, Kanika and Fan, Chengcheng and Wunsch, Marie and Poopalasingam, Nareshkumar and Meijers, Matthijs and Kreer, Christoph and Kleipass, Franziska and Ruchnewitz, Denis and Ercanoglu, Meryem S. and Gruell, Henning and Münn, Friederike and Pohl, Kai and Janicki, Hanna and Nolden, Tobias and Bartl, Simone and Stein, Saskia C. and Augustin, Max and Dewald, Felix and Gieselmann, Lutz and Schommers, Philipp and Schulz, Thomas F. and Sander, Leif Erik and Koch, Manuel and Łuksza, Marta and Lässig, Michael and Bjorkman, Pamela J. and Klein, Florian (2022) Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers. Cell Host and Microbe, 30 (1). pp. 69-82. ISSN 1931-3128. PMCID PMC8683262. doi:10.1016/j.chom.2021.12.010.

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A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both “up” and “down” conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Vanshylla, Kanika0000-0003-4552-9170
Fan, Chengcheng0000-0003-4213-5758
Poopalasingam, Nareshkumar0000-0002-4981-6209
Meijers, Matthijs0000-0002-1876-8064
Kreer, Christoph0000-0002-9140-9850
Ruchnewitz, Denis0000-0001-5740-6958
Gruell, Henning0000-0002-0725-7138
Nolden, Tobias0000-0002-8996-5612
Augustin, Max0000-0002-2300-9337
Schommers, Philipp0000-0003-3375-6800
Koch, Manuel0000-0002-2962-7814
Lässig, Michael0000-0002-3575-6719
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2021 Elsevier Inc. Received 28 September 2021, Revised 8 November 2021, Accepted 10 December 2021, Available online 18 December 2021. We would like to thank all members of the Klein lab for helpful discussions; Clara Lehmann for critical review of this manuscript and facilitating our work with the COVID-19 outpatient unit; Petra Meyer, Nicole Riet, and Ricarda Stumpf for technical assistance; Daniela Weiland, Nadine Henn, and Susanne Salomon for project and laboratory management; Knut Elbers for support with SARS-CoV-2 spike escape variants; Ching-Lin Hsieh and Jason S. McLellan for the SARS-CoV-2 HexaPro spike construct; Michael Korenkov and the team at Boehringer Ingelheim for antibody plasmids and antibodies; Pauline Hoffman, Dr. Jost Vielmetter, and the Caltech Beckman Institute Protein Expression Center for protein expression and purification; and Dr. Songye Chen for maintaining the electron microscope. Cryo-EM was performed in the Beckman Institute Resource Center for Transmission Electron Microscope at Caltech. This work was funded by grants to M.K. (DFG FOR2722); to P.J.B. by National Institutes of Health (1P01AI138938-S1); to M. Laessig by German Research Foundation (DFG) (CRC1310); to L.E.S. from COVIM “NaFoUniMedCovid19” (FKZ: 01KX2021); to F. Klein from the German Center for Infection Research (DZIF), the DFG (CRC1279 and CRC1310), European Research Council (ERC) (ERC-StG639961), and COVIM “NaFoUniMedCovid19” (FKZ: 01KX2021). Data and code availability: All data has been included in main figures or supplementary information. SARS-CoV-2 antibody sequences are available at GenBank with accession numbers OL741060 - OL741311. The atomic coordinate and 3D EM reconstruction for SARS-CoV-2 S 6P in complex with R40-1G8 Fab has been deposited in the Protein Data Bank (PDB) with PDB ID 7SC1 and the Electron Microscopy Data Bank (EMDB) with EMDB 25008, respectively. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Author contributions: Conceptualization, F. Klein and K.V.; methodology, F. Klein, K.V., M.M., C.K., D.R., and C.F.; formal analysis, K.V., C.F., M.M., C.K., M.W., N.P., F.M., K.P., and H.G.; investigation, K.V., C.F., M.W., N.P., C.K., F. Kleipass, H.J., M.S.E., D.R., H.G., T.N., S.B., M.K., F.M., and K.P.; phylogenetic analysis, M.M.; sequence analysis, C.K.; resources, S.C.S., M.A., F.D., L.G., P.S., and M. Luksza; writing – original draft, K.V. and F. Klein; writing – reviewing and editing, C.F., M.M., H.G., N.P., C.K., and M.K.; supervision; F. Klein, P.J.B., M. Laessig, T.F.S., and L.E.S.; funding acquisition, F. Klein, L.E.S., M.K., M. Laessig, and P.J.B. Declaration of interests: F. Klein, K.V., and H.G. are listed as inventors on a patent application that covers aspects of this work. F.K., C.K., and H.G. are listed as inventors on a patent application regarding neutralizing antibodies against SARS-related coronaviruses. All other authors declare no competing interests.
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)FOR2722
Deutsche Forschungsgemeinschaft (DFG)CRC1310
Bundesministerium für Bildung und Forschung (BMBF)01KX2021
German Center for Infection Research (DZIF)UNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)CRC1279
Deutsche Forschungsgemeinschaft (DFG)CRC1310
European Research Council (ERC)639961
Subject Keywords:COVID-19; SARS-CoV-2; broadly neutralizing antibodies; cryo-EM; variants of concern; emerging variants; ultrapotent monoclonal antibodies
Issue or Number:1
PubMed Central ID:PMC8683262
Record Number:CaltechAUTHORS:20211220-495801000
Persistent URL:
Official Citation:Kanika Vanshylla, Chengcheng Fan, Marie Wunsch, Nareshkumar Poopalasingam, Matthijs Meijers, Christoph Kreer, Franziska Kleipass, Denis Ruchnewitz, Meryem S. Ercanoglu, Henning Gruell, Friederike Münn, Kai Pohl, Hanna Janicki, Tobias Nolden, Simone Bartl, Saskia C. Stein, Max Augustin, Felix Dewald, Lutz Gieselmann, Philipp Schommers, Thomas F. Schulz, Leif Erik Sander, Manuel Koch, Marta Łuksza, Michael Lässig, Pamela J. Bjorkman, Florian Klein, Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers, Cell Host & Microbe, Volume 30, Issue 1, 2022, Pages 69-82.e10, ISSN 1931-3128,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112568
Deposited By: George Porter
Deposited On:20 Dec 2021 22:43
Last Modified:12 Jan 2022 18:47

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