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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	726-738.e4
Journal	Cell Chemical Biology
Volume	30
Issue number	7
DOIs	https://doi.org/10.1016/j.chembiol.2023.05.011
State	Published - Jul 20 2023

Keywords

SARS-CoV-2
antigen cleavage
catalytic antibodies
viral neutralization

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2023.05.011

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McConnell, S. A., Sachithanandham, J., Mudrak, N. J., Zhu, X., Farhang, P. A., Cordero, R. J. B., Wear, M. P., Shapiro, J. R., Park, H. S., Klein, S. L., Tobian, A. A. R., Bloch, E. M., Sullivan, D. J., Pekosz, A., & Casadevall, A. (2023). Spike-protein proteolytic antibodies in COVID-19 convalescent plasma contribute to SARS-CoV-2 neutralization. Cell Chemical Biology, 30(7), 726-738.e4. https://doi.org/10.1016/j.chembiol.2023.05.011

McConnell, SA, Sachithanandham, J, Mudrak, NJ, Zhu, X, Farhang, PA, Cordero, RJB , Wear, MP, Shapiro, JR, Park, HS , Klein, SL , Tobian, AAR , Bloch, EM , Sullivan, DJ , Pekosz, A & Casadevall, A 2023, 'Spike-protein proteolytic antibodies in COVID-19 convalescent plasma contribute to SARS-CoV-2 neutralization', Cell Chemical Biology, vol. 30, no. 7, pp. 726-738.e4. https://doi.org/10.1016/j.chembiol.2023.05.011

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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.",

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AU - Farhang, Parsa Alba

AU - Cordero, Radames J.B.

AU - Wear, Maggie P.

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AU - Klein, Sabra L.

AU - Tobian, Aaron A.R.

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N2 - 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.

AB - 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.

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

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Keywords

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