Journal Article

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

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

2021

Overview

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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Animal models / Animals / Antibodies, Monoclonal / Antibodies, Neutralizing - genetics / Antibodies, Neutralizing - pharmacology / Antibodies, Neutralizing - therapeutic use / Antigens / Coronaviruses / COVID-19 / COVID-19 - immunology / COVID-19 - physiopathology / COVID-19 Drug Treatment / Cricetinae / Cross Reactions / Disease transmission / Epitopes / Fatalities / Humans / Immune clearance / Immunity, Innate - drug effects / Immunity, Innate - immunology / Immunoglobulin Fc Fragments - genetics / Immunoglobulin G / Immunoglobulin G - genetics / Immunoglobulin G - pharmacology / Immunoglobulin G - therapeutic use / Immunology / Infections / Mesocricetus / Mice / Middle East respiratory syndrome / Middle East Respiratory Syndrome Coronavirus - drug effects / Middle East Respiratory Syndrome Coronavirus - immunology / Monoclonal antibodies / Pathogens / Protein Engineering / Proteins / Receptors, Fc - immunology / Respiratory diseases / SARS-CoV-2 - drug effects / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / Severe acute respiratory syndrome-related coronavirus - drug effects / Severe acute respiratory syndrome-related coronavirus - immunology / Severity of Illness Index / Spike Glycoprotein, Coronavirus - immunology / Standard deviation / THP-1 Cells / Viral Load - drug effects / Virus Replication - drug effects / Viruses / Weight Loss - drug effects