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 Show all
CELL REPORTS | CELL PRESS | Published : 2021
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. Assessi..View full abstract
Awarded by Medical Research Future Fund (MRFF)
Awarded by Howard Hughes Medical Institute Wellcome Trust
We thank the generous participation of the trial subjects for providing samples. SARS-CoV-2 RBD expression plasmids were kindly provided by Florian Krammer, Mt Sinai School of Medicine, NY, USA. Human ACE2 expression plasmids were kindly provided by Merlin Thomas, Monash University, Australia. OC43 spike expression constructs were kindly provided by Dr. Barney Graham, NIAID. SARS1 RBD, and human ACE2 protein was kindly provided by Nicholas Gherardin and Dale Godfrey, University of Melbourne. We thank Damian Purcell for provision of the hCoV-19/Australia/VIC2089/2020 virus for mouse challenge studies. We thank the Melbourne Cytometry Platform (Melbourne Brain Centre node) for provision of flow cytometry services. We thank staff at CSL, including Matthew Hardy, Catherine Owczarek, James Munro, Lok Soon Law, Glenn Powers, and Ping Xu, for expression, purification, and analysis of antibodies scaled-up for use in animalmodels; AdamQuek for provision of theRBDprotein; and Chao-Guang Chen for provision of IgG expression vectors. We thank Janet Newman from CSIRO Collaborative Crystallisation Centre for assistance with setting up the crystallization screens and the MX beamline staff Rachel Williamson and Alan Riboldi-Tunnicliffe at the Australian Synchrotron for their assistance during data collection. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO and made use of the Australian Cancer Research Foundation (ACRF) detector. The authors acknowledge use of Monash Ramaciotti Cryo-EM platform facilities and the Bio21 Advanced Microscopy Facility. This work was supported by computational resources provided by the Australian Government through MASSIVE HPC facility (https://www.massive.org.au) under the National Computational Merit Allocation Scheme. This study was supported by the Victorian Government, the Medical Research Future Fund (MRFF) GNT2002073 (W.-H.T., A.W.C., S.J.K., and A.K.W.) and generous donations from the Paul Ramsay Foundation (A.K.W., A.W.C., and S.J.K.), and Hengyi Pacific to support COVID-19 research (W.-H.T.). W.-H.T. is a Howard Hughes Medical Institute Wellcome Trust International research scholar (208693/Z/17/Z). A.G. is a CSL Centenary Fellow. W.-H.T., S.J.K., D.C., M.P.D., M.P., J.A.J., A.W.C., K.S., and A.K.W. are supported byNHMRCfellowships. The MelbourneWHOCollaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. The authors acknowledge the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.