Bivalent binding of a fully human IgG to the SARS-CoV-2 spike proteins reveals mechanisms of potent neutralization
Daniel E. Asarnow,
Patricia Miang Lon Ng,
Eve Zi Xian Ngoh,
Hwee Ching Tan,
Chia Yin Lee,
Rabiatul Adawiyah Minhat,
Mun Kuen Soh,
Frannie Jiuyi Teo,
Yvonne Yee Chin Yeap,
Shirley Gek Kheng Seah,
Brendon John Hanson,
Charles S. Craik,
Posted 15 Jul 2020
bioRxiv DOI: 10.1101/2020.07.14.203414
Posted 15 Jul 2020
In vitro antibody selection against pathogens from naive combinatorial libraries can yield various classes of antigen-specific binders that are distinct from those evolved from natural infection. Also, rapid neutralizing antibody discovery can be made possible by a strategy that selects for those interfering with pathogen and host interaction. Here we report the discovery of antibodies that neutralize SARS-CoV-2, the virus responsible for the COVID-19 pandemic, from a highly diverse naive human Fab library. Lead antibody 5A6 blocks the receptor binding domain (RBD) of the viral spike from binding to the host receptor angiotensin converting enzyme 2 (ACE2), neutralizes SARS-CoV-2 infection of Vero E6 cells, and reduces viral replication in reconstituted human nasal and bronchial epithelium models. 5A6 has a high occupancy on the viral surface and exerts its neutralization activity via a bivalent binding mode to the tip of two neighbouring RBDs at the ACE2 interaction interface, one in the "up" and the other in the "down" position, explaining its superior neutralization capacity. Furthermore, 5A6 is insensitive to several spike mutations identified in clinical isolates, including the D614G mutant that has become dominant worldwide. Our results suggest that 5A6 could be an effective prophylactic and therapeutic treatment of COVID-19. ### Competing Interest Statement B.W., W.H.L., C.W.H., P.M.L.N., E.Z.X.N., H.C.T., C.Y.L., R.A.M., M.K.S., F.J.T., Y.Y.C.Y., Y.H., and C.I.W. are listed as inventors of a filed patent for all 27 monoclonal antibodies mentioned in this manuscript. The other authors declare that they have no competing interests.
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