Landscape of human antibody recognition of the SARS-CoV-2 receptor binding domain

Adam K Wheatley; Phillip Pymm; Robyn Esterbauer; Melanie H Dietrich; Wen Shi Lee; Damien Drew; Hannah G Kelly; Li-Jin Chan; Francesca L Mordant; Katrina A Black; Amy Adair; Hyon-Xhi Tan; Jennifer A Juno; Kathleen M Wragg; Thakshila Amarasena; Ester Lopez; Kevin J Selva; Ebene R Haycroft; James P Cooney; Hariprasad Venugopal; Li Lynn Tan; Matthew T O Neill; Cody C Allison; Deborah Cromer; Miles P Davenport; Richard A Bowen; Amy W Chung; Marc Pellegrini; Mark T Liddament; Alisa Glukhova; Kanta Subbarao; Stephen J Kent; Wai-Hong Tham

doi:10.1016/j.celrep.2021.109822

Landscape of human antibody recognition of the SARS-CoV-2 receptor binding domain

Cell Rep. 2021 Oct 12;37(2):109822. doi: 10.1016/j.celrep.2021.109822. Epub 2021 Sep 25.

Authors

Adam K Wheatley¹, Phillip Pymm², Robyn Esterbauer³, Melanie H Dietrich², Wen Shi Lee³, Damien Drew², Hannah G Kelly³, Li-Jin Chan², Francesca L Mordant³, Katrina A Black², Amy Adair⁴, Hyon-Xhi Tan³, Jennifer A Juno³, Kathleen M Wragg³, Thakshila Amarasena³, Ester Lopez³, Kevin J Selva³, Ebene R Haycroft³, James P Cooney², Hariprasad Venugopal⁵, Li Lynn Tan⁴, Matthew T O Neill⁴, Cody C Allison², Deborah Cromer⁶, Miles P Davenport⁶, Richard A Bowen⁷, Amy W Chung³, Marc Pellegrini², Mark T Liddament⁸, Alisa Glukhova⁹, Kanta Subbarao¹⁰, Stephen J Kent¹¹, Wai-Hong Tham¹²

Affiliations

¹ Department of Microbiology and Immunology, University of Melbourne, the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Australian Research Council Centre for Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC 3010, Australia.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
³ Department of Microbiology and Immunology, University of Melbourne, the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁵ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
⁶ Kirby Institute, University of New South Wales, Kensington, NSW 2052, Australia.
⁷ Laboratory of Animal Reproduction and Biotechnology, Colorado State University, Fort Collins, CO 80523, USA.
⁸ CSL Limited, Parkville, VIC 3052, Australia.
⁹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia; Drug Discovery Biology, Monash Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁰ Department of Microbiology and Immunology, University of Melbourne, the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.
¹¹ Department of Microbiology and Immunology, University of Melbourne, the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Australian Research Council Centre for Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC 3010, Australia; Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC 3004, Australia. Electronic address: [email protected].
¹² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: [email protected].

Abstract

Potent neutralizing monoclonal antibodies are one of the few agents currently available to treat COVID-19. SARS-CoV-2 variants of concern (VOCs) that carry multiple mutations in the viral spike protein can exhibit neutralization resistance, potentially affecting the effectiveness of some antibody-based therapeutics. Here, the generation of a diverse panel of 91 human, neutralizing monoclonal antibodies provides an in-depth structural and phenotypic definition of receptor binding domain (RBD) antigenic sites on the viral spike. These RBD antibodies ameliorate SARS-CoV-2 infection in mice and hamster models in a dose-dependent manner and in proportion to in vitro, neutralizing potency. Assessing the effect of mutations in the spike protein on antibody recognition and neutralization highlights both potent single antibodies and stereotypic classes of antibodies that are unaffected by currently circulating VOCs, such as B.1.351 and P.1. These neutralizing monoclonal antibodies and others that bind analogous epitopes represent potentially useful future anti-SARS-CoV-2 therapeutics.

Keywords: SARS-CoV-2; anti-viral therapeutics; cryo-EM; crystallography; human antibodies; mAb.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2 / immunology*
Angiotensin-Converting Enzyme 2 / metabolism
Angiotensin-Converting Enzyme 2 / ultrastructure
Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / therapeutic use
Antibodies, Neutralizing / ultrastructure
Antibodies, Viral / immunology
COVID-19 / immunology
Cricetinae
Cryoelectron Microscopy / methods
Epitopes / immunology
Female
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
Neutralization Tests
Protein Binding / physiology
Receptors, Virus / metabolism
SARS-CoV-2 / immunology*
SARS-CoV-2 / pathogenicity
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Receptors, Virus
Spike Glycoprotein, Coronavirus
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Grants and funding

WT_/Wellcome Trust/United Kingdom