Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Shane Miersch; Zhijie Li; Reza Saberianfar; Mart Ustav; James Brett Case; Levi L. Blazer; Chao Chen; Wei Ye; Alevtina Pavlenco; Maryna Gorelik; Julia Garcia Perez; Suryasree Subramania; Serena Singh; Lynda Ploder; Safder S. Ganaie; Rita E. Chen; Daisy W. Leung; Pier Paolo Pandolfi; Giuseppe Novelli; Giulia Matusali; Francesca Colavita; Maria Rosaria Capobianchi; Suresh Jain; J.B. Gupta; Gaya K. Amarasinghe; Michael Diamond; James M. Rini; Sachdev S. Sidhu

doi:10.1016/j.jmb.2021.167177

Synthetic BiologyJournal of Molecular BiologyJul 28, 2021

Peer-reviewed journal article

Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Shane Miersch iD, Zhijie Li iD, Reza Saberianfar, Mart Ustav iD, James Brett Case iD, Levi L. Blazer iD, Chao Chen iD, Wei Ye iD, Alevtina Pavlenco, Maryna Gorelik, Julia Garcia Perez iD, Suryasree Subramania iD, Serena Singh iD, Lynda Ploder, Safder S. Ganaie iD, Rita E. Chen iD, Daisy W. Leung iD, Pier Paolo Pandolfi iD, Giuseppe Novelli iD, Giulia Matusali iD, Francesca Colavita iD, Maria Rosaria Capobianchi iD, Suresh Jain, J.B. Gupta, Gaya K. Amarasinghe iD, , Sachdev S. Sidhu iD

Abstract

Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development.

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