Dissecting strategies to tune the therapeutic potential of SARS-CoV-2–specific monoclonal antibody CR3022

Caroline Atyeo, Matthew D. Slein, Stephanie Fischinger, John Burke, Alexandra Schäfer, Sarah R. Leist, Natalia A. Kuzmina, Chad Mire, Anna Honko, Rebecca Johnson, Nadia Storm, Matthew Bernett, Pei Tong, Teng Zuo, Junrui Lin, Adam Zuiani, Caitlyn Linde, Todd Suscovich, Duane R. Wesemann, Anthony GriffithsJohn R. Desjarlais, Boris D. Juelg, Jaap Goudsmit, Alexander Bukreyev, Ralph Baric, Galit Alter

Research output: Contribution to journalArticlepeer-review

Abstract

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross–SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection.

Original languageEnglish (US)
Article numbere143129
JournalJCI insight
Volume6
Issue number1
DOIs
StatePublished - Jan 11 2021

ASJC Scopus subject areas

  • Medicine(all)

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