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 Griffiths, John R. Desjarlais, Boris D. Juelg, Jaap Goudsmit, Alexander Bukreyev, Ralph Baric, Galit Alter
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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Research Article COVID-19 Immunology

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

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 3

CR3022 can be enhanced through Fc engineering.

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CR3022 can be enhanced through Fc engineering. (A) Each CR3022 variant w...
(A) Each CR3022 variant was analyzed for its ability to bind the human FcγR2a, FcγR2b, FcγR3a, and FcγR3b or the mouse FcγR2b, FcγR3, and FcγR4 by Luminex. Each bar represents the average MFI and error bars show standard deviation. (B) The CR3022 variants were analyzed for their ability to drive NK activation, as measured by MIP-1b activity. The bar graphs represent the average of 3 donors, and the error bars represent the standard deviation. For AUC, significance was determined by an ordinary 1-way ANOVA followed by Tukey’s multiple-comparison test. *P < 0.05. (C–E) The CR3022 variants were evaluated for their ADCP (C), ADNP (D), and ADCD (E) activity. The dots on the line graph represent the average of 2 replicates. The bar graphs represent the average AUC of 8 serial dilutions run as replicates, and the error bars represent the standard deviation. For AUC, significance was determined by an ordinary 1-way ANOVA followed by Tukey’s multiple-comparison test. *P < 0.05. (F and G) BALB/c mice (5 per group) were treated with a CR3022 variant or control therapeutically. Lung viral titers were determined 2 days postinfection (dpi) (F), and weight was monitored daily (G). For viral titer (F), significance was determined by an ordinary 1-way ANOVA followed by Tukey’s multiple-comparison test. *P < 0.05. For weight (G), significance was determined by an ordinary 1-way ANOVA followed by Tukey’s multiple-comparison test. *P < 0.05, **P < 0.01, between the respective antibody, indicated by the color of the asterisk, and the CR3022 WT. For weight (G), each dot represents a mouse, and the error bars represent the standard deviation.