Spike-protein proteolytic antibodies in COVID-19 convalescent plasma contribute to SARS-CoV-2 neutralization

Scott A McConnell; Jaiprasath Sachithanandham; Nathan J Mudrak; Xianming Zhu; Parsa Alba Farhang; Radames J B Cordero; Maggie P Wear; Janna R Shapiro; Han-Sol Park; Sabra L Klein; Aaron A R Tobian; Evan M Bloch; David J Sullivan; Andrew Pekosz; Arturo Casadevall

doi:10.1016/j.chembiol.2023.05.011

Spike-protein proteolytic antibodies in COVID-19 convalescent plasma contribute to SARS-CoV-2 neutralization

Cell Chem Biol. 2023 Jul 20;30(7):726-738.e4. doi: 10.1016/j.chembiol.2023.05.011. Epub 2023 Jun 23.

Authors

Affiliations

¹ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
² Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
³ Department of International Health, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
⁴ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of International Health, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
⁵ W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address: acascade1@jhu.edu.

Abstract

Understanding the mechanisms of antibody-mediated neutralization of SARS-CoV-2 is critical in combating the COVID-19 pandemic. Based on previous reports of antibody catalysis, we investigated the proteolysis of spike (S) by antibodies in COVID-19 convalescent plasma (CCP) and its contribution to viral neutralization. Quenched fluorescent peptides were designed based on S epitopes to sensitively detect antibody-mediated proteolysis. We observed epitope cleavage by CCP from different donors which persisted when plasma was heat-treated or when IgG was isolated from plasma. Further, purified CCP antibodies proteolyzed recombinant S domains, as well as authentic viral S. Cleavage of S variants suggests CCP antibody-mediated proteolysis is a durable phenomenon despite antigenic drift. We differentiated viral neutralization occurring via direct interference with receptor binding from that occurring by antibody-mediated proteolysis, demonstrating that antibody catalysis enhanced neutralization. These results suggest that antibody-catalyzed damage of S is an immunologically relevant function of neutralizing antibodies against SARS-CoV-2.

Keywords: SARS-CoV-2; antigen cleavage; catalytic antibodies; viral neutralization.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antibodies, Neutralizing
Antibodies, Viral
COVID-19 Serotherapy
COVID-19* / therapy
Epitopes
Humans
Pandemics
Peptide Hydrolases
Proteolysis
SARS-CoV-2*
Spike Glycoprotein, Coronavirus

Substances

spike protein, SARS-CoV-2
Spike Glycoprotein, Coronavirus
Peptide Hydrolases
Antibodies, Neutralizing
Epitopes
Antibodies, Viral

Abstract

Publication types

MeSH terms

Substances

Grants and funding