TY - JOUR
T1 - Dissecting strategies to tune the therapeutic potential of SARS-CoV-2–specific monoclonal antibody CR3022
AU - Atyeo, Caroline
AU - Slein, Matthew D.
AU - Fischinger, Stephanie
AU - Burke, John
AU - Schäfer, Alexandra
AU - Leist, Sarah R.
AU - Kuzmina, Natalia A.
AU - Mire, Chad
AU - Honko, Anna
AU - Johnson, Rebecca
AU - Storm, Nadia
AU - Bernett, Matthew
AU - Tong, Pei
AU - Zuo, Teng
AU - Lin, Junrui
AU - Zuiani, Adam
AU - Linde, Caitlyn
AU - Suscovich, Todd
AU - Wesemann, Duane R.
AU - Griffiths, Anthony
AU - Desjarlais, John R.
AU - Juelg, Boris D.
AU - Goudsmit, Jaap
AU - Bukreyev, Alexander
AU - Baric, Ralph
AU - Alter, Galit
N1 - Funding Information:
We thank Nancy Zimmerman, Bruce Walker, Mark and Lisa Schwartz, and Terry and Susan Ragon for their support. We would also like to thank Bing Chen, Kizzmekia Corbett, Aaron Schmidt, Jared Feldman, Blake Hauser, and Tim Caradonna for protein production efforts and Sierra Downs for technical support. The following reagent was obtained through BEI Resources, NIAID, NIH: VERO C1008 (E6), Kidney (African green monkey), Working Cell Bank, NR-596. The SARS-CoV-2 starting material was provided by the World Reference Center for Emerging Viruses and Arboviruses, with Natalie Thornburg (nax3@cdc.gov) as the CDC principal investigator. Avicel RC-591 was provided by DuPont Nutrition & Health. We would like to thank Deborah Gakpo, Jillian Bensko, Sudeshna Fisch, Meghan Travers, Shaghayaegh Habibi, Yuezhou Chen, Adam Zuiani, and Felipe N. Lelis for organizing and collecting human samples used for the cloning of monoclonal antibodies. We would also like to thank Massachusetts Consortium on Pathogen Readiness, the Samana Cay MGH Scholar program, and an anonymous donor for financial support. This work was supported by the NIH (3R37AI080289-11S1) and the NIAID, NIH (1U01CA260476-01, U19 AI135995, NIH AI121394, AI139538).
Funding Information:
We thank Nancy Zimmerman, Bruce Walker, Mark and Lisa Schwartz, and Terry and Susan Ragon for their support. We would also like to thank Bing Chen, Kizzmekia Corbett, Aaron Schmidt, Jared Feld-man, Blake Hauser, and Tim Caradonna for protein production efforts and Sierra Downs for technical support. The following reagent was obtained through BEI Resources, NIAID, NIH: VERO C1008 (E6), Kidney (African green monkey), Working Cell Bank, NR-596. The SARS-CoV-2 starting material was provided by the World Reference Center for Emerging Viruses and Arboviruses, with Natalie Thornburg (nax3@cdc.gov) as the CDC principal investigator. Avicel RC-591 was provided by DuPont Nutrition & Health. We would like to thank Deborah Gakpo, Jillian Bensko, Sudeshna Fisch, Meghan Travers, Shaghayaegh Habibi, Yuezhou Chen, Adam Zuiani, and Felipe N. Lelis for organizing and collecting human samples used for the cloning of monoclonal antibodies. We would also like to thank Massachusetts Consortium on Pathogen Readiness, the Samana Cay MGH Scholar program, and an anonymous donor for financial support. This work was supported by the NIH (3R37AI080289-11S1) and the NIAID, NIH (1U01CA260476-01, U19 AI135995, NIH AI121394, AI139538).
Publisher Copyright:
© 2021, Atyeo et al.
PY - 2021/1/11
Y1 - 2021/1/11
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.143129
DO - 10.1172/jci.insight.143129
M3 - Article
C2 - 33427208
AN - SCOPUS:85099293162
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 1
M1 - e143129
ER -