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SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties

View ORCID ProfileCraig Fenwick, Priscilla Turelli, Dongchun Ni, Laurent Perez, Kelvin Lau, Erica Lana, Céline Pellaton, Charlène Raclot, Line Esteves-Leuenberger, Jérémy Campos, Alex Farina, Flurin Fiscalini, Cécile Herate, Romain Marlin, View ORCID ProfileRana Abdelnabi, Caroline S. Foo, Johan Neyts, Pieter Leyssen, Roger LeGrand, Yves Lévy, Florence Pojer, View ORCID ProfileHenning Stahlberg, Didier Trono, Giuseppe Pantaleo
doi: https://doi.org/10.1101/2022.03.18.484873
Craig Fenwick
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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  • ORCID record for Craig Fenwick
Priscilla Turelli
2School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Dongchun Ni
3School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne and Faculty of Biology and Medicine, UNIL, Lausanne, Switzerland
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Laurent Perez
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Kelvin Lau
2School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Erica Lana
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Céline Pellaton
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Charlène Raclot
2School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Line Esteves-Leuenberger
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Jérémy Campos
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Alex Farina
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Flurin Fiscalini
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Cécile Herate
5CEA, Université Paris Sud 11, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
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Romain Marlin
5CEA, Université Paris Sud 11, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
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Rana Abdelnabi
4KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Caroline S. Foo
4KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Johan Neyts
4KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Pieter Leyssen
4KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Roger LeGrand
5CEA, Université Paris Sud 11, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
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Yves Lévy
6VRI, Université Paris-Est Créteil, Faculté de Médicine, INSERM U955, 94010 Créteil, France
7Inserm U955, Equipe 16, Créteil, France
8AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d’Immunologie Clinique et Maladies Infectieuses, Créteil, France
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Florence Pojer
2School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Henning Stahlberg
3School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne and Faculty of Biology and Medicine, UNIL, Lausanne, Switzerland
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Didier Trono
2School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • For correspondence: giuseppe.pantaleo@chuv.ch didier.trono@epfl.ch
Giuseppe Pantaleo
1Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
9Swiss Vaccine Research Institute, Lausanne University Hospital and University of Lausanne, Switzerland
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  • For correspondence: giuseppe.pantaleo@chuv.ch didier.trono@epfl.ch
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Abstract

The SARS-CoV-2 Omicron variant exhibits very high levels of transmission, pronounced resistance to authorized therapeutic human monoclonal antibodies and reduced sensitivity to vaccine-induced immunity. Here we describe P2G3, a human monoclonal antibody (mAb) isolated from a previously infected and vaccinated donor, which displays picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other current variants, and is thus markedly more potent than all authorized or clinically advanced anti-SARS-CoV-2 mAbs. Structural characterization of P2G3 Fab in complex with the Omicron Spike demonstrates unique binding properties to both down and up spike trimer conformations at an epitope that partially overlaps with the receptor-binding domain (RBD), yet is distinct from those bound by all other characterized mAbs. This distinct epitope and angle of attack allows P2G3 to overcome all the Omicron mutations abolishing or impairing neutralization by other anti-SARS-COV-2 mAbs, and P2G3 accordingly confers complete prophylactic protection in the SARS-CoV-2 Omicron monkey challenge model. Finally, although we could isolate in vitro SARS-CoV2 mutants escaping neutralization by P2G3 or by P5C3, a previously described broadly active Class 1 mAb, we found these viruses to be lowly infectious and their key mutations extremely rare in the wild, and we could demonstrate that P2G3/P5C3 efficiently cross-neutralized one another’s escapees. We conclude that this combination of mAbs has great prospects in both the prophylactic and therapeutic settings to protect from Omicron and other VOCs.

Competing Interest Statement

C.F., G.P., P.T. and D.T. are co-inventors on a patent application that encompasses the antibodies and data described in this manuscript (EP 22153464.7 and PCT/IB2022/050731). DT and GP are amongst the founders of and own equity in Aerium Therapeutics, which has rights to and is pursuing the development of the antibodies described in the publication, and has Sponsored Research Agreements with the Lausanne University Hospital (CHUV) and the Ecole Polytechnique Fédérale de Lausanne (EPFL).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 18, 2022.
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SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties
Craig Fenwick, Priscilla Turelli, Dongchun Ni, Laurent Perez, Kelvin Lau, Erica Lana, Céline Pellaton, Charlène Raclot, Line Esteves-Leuenberger, Jérémy Campos, Alex Farina, Flurin Fiscalini, Cécile Herate, Romain Marlin, Rana Abdelnabi, Caroline S. Foo, Johan Neyts, Pieter Leyssen, Roger LeGrand, Yves Lévy, Florence Pojer, Henning Stahlberg, Didier Trono, Giuseppe Pantaleo
bioRxiv 2022.03.18.484873; doi: https://doi.org/10.1101/2022.03.18.484873
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SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties
Craig Fenwick, Priscilla Turelli, Dongchun Ni, Laurent Perez, Kelvin Lau, Erica Lana, Céline Pellaton, Charlène Raclot, Line Esteves-Leuenberger, Jérémy Campos, Alex Farina, Flurin Fiscalini, Cécile Herate, Romain Marlin, Rana Abdelnabi, Caroline S. Foo, Johan Neyts, Pieter Leyssen, Roger LeGrand, Yves Lévy, Florence Pojer, Henning Stahlberg, Didier Trono, Giuseppe Pantaleo
bioRxiv 2022.03.18.484873; doi: https://doi.org/10.1101/2022.03.18.484873

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