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Dissecting strategies to tune the therapeutic potential of SARS-CoV-2–specific monoclonal antibody CR3022
Caroline Atyeo, … , Ralph Baric, Galit Alter
Caroline Atyeo, … , Ralph Baric, Galit Alter
Published January 11, 2021
Citation Information: JCI Insight. 2021;6(1):e143129. https://doi.org/10.1172/jci.insight.143129.
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Research Article COVID-19 Immunology

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

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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.

Authors

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 Griffiths, John R. Desjarlais, Boris D. Juelg, Jaap Goudsmit, Alexander Bukreyev, Ralph Baric, Galit Alter

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Figure 4

Increased Fc function causes enhancement of disease in vivo.

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Increased Fc function causes enhancement of disease in vivo.
Hamsters (5...
Hamsters (5 per group) were challenged with SARS-CoV-2 and treated with a CR3022 variant or control antibody 1 dpi. Lung viral titers were determined 3 dpi (A), and weight was monitored daily (B). For viral titers (A), significance was determined by an ordinary 1-way ANOVA followed by Tukey’s multiple-comparison test. **P < 0.01, ***P < 0.001. For weight (B), significance was determined by 2-way ANOVA test followed by Tukey’s multiple-comparison test. *P < 0.05 between the respective antibody and the CR3022 WT. For weight (B), each dot represents the average of 5 hamsters, and the error bars represent the standard deviation.

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