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

doi:10.1172/jci.insight.143129

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

JCI Insight. 2021 Jan 11;6(1):e143129. doi: 10.1172/jci.insight.143129.

Authors

Caroline Atyeo^{1

2}, Matthew D Slein¹, Stephanie Fischinger^{1

3}, John Burke¹, Alexandra Schäfer⁴, Sarah R Leist⁴, Natalia A Kuzmina^{5

6}, Chad Mire^{5

6}, Anna Honko^{7

8}, Rebecca Johnson^{7

8}, Nadia Storm^{7

8}, Matthew Bernett⁹, Pei Tong¹⁰, Teng Zuo¹⁰, Junrui Lin¹⁰, Adam Zuiani¹⁰, Caitlyn Linde¹¹, Todd Suscovich¹¹, Duane R Wesemann¹⁰, Anthony Griffiths^{7

8}, John R Desjarlais⁹, Boris D Juelg¹, Jaap Goudsmit¹², Alexander Bukreyev^{5

6

13}, Ralph Baric^{4

14

15}, Galit Alter¹

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
² Program in Virology, Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA.
³ Program in Immunology and Virology, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁵ Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
⁶ Galveston National Laboratory, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA.
⁷ Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
⁸ National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA.
⁹ Xencor, Monrovia, California, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital; Division of Allergy and Clinical Immunology; and Division of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ SeromYx Systems, Cambridge, Massachusetts, USA.
¹² Departments of Epidemiology and Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹³ Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
¹⁴ Departments of Microbiology and Immunology and Genetics, School of Medicine, and.
¹⁵ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

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.

Keywords: Antigen; COVID-19; Epidemiology; Immunology.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antibodies, Monoclonal
Antibodies, Neutralizing / genetics
Antibodies, Neutralizing / pharmacology*
Antibodies, Neutralizing / therapeutic use
COVID-19 / immunology*
COVID-19 / physiopathology
COVID-19 Drug Treatment
Cricetinae
Cross Reactions
Epitopes
Humans
Immunity, Innate / drug effects*
Immunity, Innate / immunology
Immunoglobulin Fc Fragments / genetics*
Immunoglobulin G / genetics
Immunoglobulin G / pharmacology*
Immunoglobulin G / therapeutic use
Mesocricetus
Mice
Middle East Respiratory Syndrome Coronavirus / drug effects
Middle East Respiratory Syndrome Coronavirus / immunology
Protein Engineering
Receptors, Fc / immunology
SARS-CoV-2 / drug effects*
SARS-CoV-2 / immunology
Severe acute respiratory syndrome-related coronavirus / drug effects
Severe acute respiratory syndrome-related coronavirus / immunology
Severity of Illness Index
Spike Glycoprotein, Coronavirus / immunology
THP-1 Cells
Viral Load / drug effects
Virus Replication / drug effects*
Weight Loss / drug effects

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Epitopes
Immunoglobulin Fc Fragments
Immunoglobulin G
Receptors, Fc
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding