A highly potent antibody effective against SARS-CoV-2 variants of concern
Fenwick, Craig; Turelli, Priscilla; Perez, Laurent; Pellaton, Céline; Esteves-Leuenberger, Line; Farina, Alex; Campos, Jérémy; Lana, Erica; Fiscalini, Flurin; Raclot, Charlène; Pojer, Florence; Lau, Kelvin; Demurtas, Davide; Descatoire, Marc; Joo, Victor S; Foglierini, Mathilde; Noto, Alessandra; Abdelnabi, Rana; Foo, Caroline S; Vangeel, Laura; Neyts, Johan; Du, Wenjuan; Bosch, Berend-Jan; Veldman, Geertruida; Leyssen, Pieter; Thiel, Volker; LeGrand, Roger; Lévy, Yves; Trono, Didier; Pantaleo, Giuseppe
(2021) Cell Reports, volume 37, issue 2
(Article)
Abstract
Control of the ongoing SARS-CoV-2 pandemic is endangered by the emergence of viral variants with increased transmission efficiency, resistance to marketed therapeutic antibodies, and reduced sensitivity to vaccine-induced immunity. Here, we screen B cells from COVID-19 donors and identify P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar
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neutralizing activity against all SARS-CoV-2 variants of concern (VOCs) identified to date. Structural characterization of P5C3 Fab in complex with the spike demonstrates a neutralizing activity defined by a large buried surface area, highly overlapping with the receptor-binding domain (RBD) surface necessary for ACE2 interaction. We further demonstrate that P5C3 shows complete prophylactic protection in the SARS-CoV-2-infected hamster challenge model. These results indicate that P5C3 opens exciting perspectives either as a prophylactic agent in immunocompromised individuals with poor response to vaccination or as combination therapy in SARS-CoV-2-infected individuals.
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Keywords: SARS-CoV-2, neutralizing antibodies, variants of concern, General Biochemistry,Genetics and Molecular Biology
ISSN: 2211-1247
Publisher: Elsevier Saunders
Note: Funding Information: We thank the Service of Immunology and Allergy at the Lausanne University Hospital for contributions in analysis of subject serum samples for levels of anti-Spike protein IgG antibodies, Michael Moulin for establishing the SEC-HPLC protocol for antibody characterization, Antonio Mancarella for initial help with the mAb cloning, Laurence Durrer and Soraya Quinche from PTPSP-EPFL for mammalian cell culture, and Micha?l Fran?ois from PTPSP-EPFL for helping in purification of the Spike trimer proteins. We would like to thank the Trono laboratory, Caroline Tapparel for help to start the SARS-CoV-2-related work, I. Eckerle for providing a SARS-CoV-2 isolate, and Valeria Cagno for providing the initial stocks of titrated SARS-CoV-2 virus; Dr. Chami from C-CINA, Biozentrum, Uni Basel for FEI Titan Krios images acquisition; Christel Genoud at the EPFL for initial EM studies; and Ni Dongchun at the EPFL for precious advice on cryo-EM. We would also like to thank David Wyatt and members of the CARE-IMI work package 4 team for helpful discussions. G.P. received a grant from the Corona Accelerated R&D in Europe (CARE) project funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 101005077. The JU receives support from the European Union's Horizon 2020 research and innovation program, the European Federation of Pharmaceutical Industries Associations (EFPIA), the Bill & Melinda Gates Foundation, the Global Health Drug Discovery Institute, and the University of Dundee. The content of this publication reflects only the authors? views, and the JU is not responsible for any use that may be made of the information it contains. Furthermore, funding was also provided through the Lausanne University Hospital (to G.P.), the Swiss Vaccine Research Institute (to G.P.), Swiss National Science Foundation grants (to G.P.), and through the EPFL COVID fund (to D.T.). C.F. designed the strategy for isolating and profiling anti-Spike antibodies, coordinated all of the research activities, analyzed the data, wrote the initial draft of the manuscript, and contributed to the editing of the manuscript. P.T. established and performed the live SARS-CoV-2 virus cytopathic effect neutralization assay, designed the Spike protein mutations and cloning, analyzed the results, and contributed to the editing of the manuscript. L.P. coordinated the cryo-EM analysis, analyzed the structural data, wrote the manuscript structural section, and contributed to the editing of the manuscript. L.E.-L. performed the B cell sorting, immortalization, and binding studies; A.F. and E.L. performed VH and HL mAb cloning; J.C. performed binding studies and pseudoviral assays; C.P. performed mAb quantitation from in vivo studies and other binding studies; V.S.J. performed Fab preparation; F.F. performed mAb purification, mAb characterization, and molecular biology; M.D. performed the hFcRn PK studies; A.N. helped with antigen-specific B cell staining; M.F. performed antibody sequence analysis; B.-J.B. and W.D. provided proteins, PV vectors, and external testing of mAbs; C.R. performed site-directed mutagenesis of the Spike constructs; Y.L. and R.L. provided in vivo study designs; F.P. K.L. and the Protein Production and Structure Core Facility at the EPFL produced and purified the trimer S proteins; D.D. set up cryo-EM conditions for automated acquisition; R.A. P.L. C.S.F. L.V. G.V. and J.N. performed hamster studies; and G.P. and D.T. conceived the study design, analyzed the results, and wrote the manuscript. C.F. P.T. G.P. and D.T declare that they are co-inventors on a patent application titled ?Neutralizing antibodies and use thereof in the treatment of SARS-CoV-2 infection? with filing number PCT/IB2021/050621 that covers newly identified antibodies described in this manuscript. The remaining authors declare no competing interests. We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: We thank the Service of Immunology and Allergy at the Lausanne University Hospital for contributions in analysis of subject serum samples for levels of anti-Spike protein IgG antibodies, Michael Moulin for establishing the SEC-HPLC protocol for antibody characterization, Antonio Mancarella for initial help with the mAb cloning, Laurence Durrer and Soraya Quinche from PTPSP-EPFL for mammalian cell culture, and Michaël François from PTPSP-EPFL for helping in purification of the Spike trimer proteins. We would like to thank the Trono laboratory, Caroline Tapparel for help to start the SARS-CoV-2-related work, I. Eckerle for providing a SARS-CoV-2 isolate, and Valeria Cagno for providing the initial stocks of titrated SARS-CoV-2 virus; Dr. Chami from C-CINA, Biozentrum, Uni Basel for FEI Titan Krios images acquisition; Christel Genoud at the EPFL for initial EM studies; and Ni Dongchun at the EPFL for precious advice on cryo-EM. We would also like to thank David Wyatt and members of the CARE-IMI work package 4 team for helpful discussions. G.P. received a grant from the Corona Accelerated R&D in Europe (CARE) project funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 101005077 . The JU receives support from the European Union’s Horizon 2020 research and innovation program , the European Federation of Pharmaceutical Industries Associations (EFPIA), the Bill & Melinda Gates Foundation , the Global Health Drug Discovery Institute , and the University of Dundee . The content of this publication reflects only the authors’ views, and the JU is not responsible for any use that may be made of the information it contains. Furthermore, funding was also provided through the Lausanne University Hospital (to G.P.), the Swiss Vaccine Research Institute (to G.P.), Swiss National Science Foundation grants (to G.P.), and through the EPFL COVID fund (to D.T.). Publisher Copyright: © 2021 The Author(s)
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