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

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

doi:10.1016/j.celrep.2021.109822

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.

Highlights

The global spread of SARS-CoV-2 has sparked intense global research efforts to combat the significant health and economic effects of the pandemic
Neutralizing epitopes have been mapped across the viral spike, including the receptor binding domain (RBD) (Barnes et al, 2020b; Dejnirattisai et al, 2021), N-terminal domain (NTD) (Cerutti et al, 2021; McCallum et al, 2021), and S2 domain (Wang et al, 2021a), with the most potent neutralizing activity associated with Monoclonal antibodies (mAbs) that directly block RBD interaction with the human receptor angiotensin-converting enzyme 2
Recovery of potent human neutralizing mAbs against SARS-CoV-2 spike We previously described a cohort of individuals recovered from COVID-19 (Juno et al, 2020b) who developed serological binding and neutralizing antibodies against SARS-CoV-2 spike after recovery

Summary

Introduction

The global spread of SARS-CoV-2 has sparked intense global research efforts to combat the significant health and economic effects of the pandemic. The rapid clinical development of SARS-CoV-2 antibodybased therapeutics (reviewed in Taylor et al [2021]) has seen rapid progression of candidate mAbs through clinical trials, with two human mAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one monotherapy (bamlanivimab) conditionally approved for treatment of high-risk, ambulatory patients. Some of these first-generation treatments suffer significant losses of neutralization potency in the face of ongoing viral evolution, with near-complete loss of activity against B.1.351 and P.1. This should allow the selection of antibody cocktails for maximized protection against VOCs and inform rational improvements to the generation of COVID-19 vaccines

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Discussion

Conclusion