A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Guillaume Beaudoin-Bussières; Yaozong Chen; Irfan Ullah; Jérémie Prévost; William D. Tolbert; Kelly Symmes; Shilei Ding; Mehdi Benlarbi; Shang Yu Gong; Alexandra Tauzin; Romain Gasser; Debashree Chatterjee; Dani Vézina; Guillaume Goyette; Jonathan Richard; Fei Zhou; Leonidas Stamatatos; Andrew T. McGuire; Hughes Charest; Michel Roger; Edwin Pozharski; Priti Kumar; Walther Mothes; Pradeep D. Uchil; Marzena Pazgier; Andrés Finzi

doi:10.1016/j.celrep.2022.110368

A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Guillaume Beaudoin-Bussières, Yaozong Chen, Irfan Ullah, Jérémie Prévost, William D. Tolbert, Kelly Symmes, Shilei Ding, Mehdi Benlarbi, Shang Yu Gong, Alexandra Tauzin, Romain Gasser, Debashree Chatterjee, Dani Vézina, Guillaume Goyette, Jonathan Richard, Fei Zhou, Leonidas Stamatatos, Andrew T. McGuire, Hughes Charest, Michel RogerEdwin Pozharski, Priti Kumar, Walther Mothes, Pradeep D. Uchil^*, Marzena Pazgier^*, Andrés Finzi^*

^*Corresponding author for this work

Medicine

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

96 Scopus citations

Abstract

Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.

Original language	English
Article number	110368
Pages (from-to)	110368
Journal	Cell Reports
Volume	38
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2022.110368
State	Published - 15 Feb 2022

Keywords

Animals
Antibodies, Neutralizing/therapeutic use
Antibodies, Viral/chemistry
Antibody-Dependent Cell Cytotoxicity
COVID-19 Serotherapy
COVID-19/mortality
Disease Models, Animal
Epitopes
Humans
Immunization, Passive/mortality
Immunoglobulin Fab Fragments/chemistry
Immunoglobulin Fc Fragments/genetics
Mice
Protein Binding
Protein Conformation
SARS-CoV-2/immunology
Spike Glycoprotein, Coronavirus/chemistry

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10.1016/j.celrep.2022.110368

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Beaudoin-Bussières, G., Chen, Y., Ullah, I., Prévost, J., Tolbert, W. D., Symmes, K., Ding, S., Benlarbi, M., Gong, S. Y., Tauzin, A., Gasser, R., Chatterjee, D., Vézina, D., Goyette, G., Richard, J., Zhou, F., Stamatatos, L., McGuire, A. T., Charest, H., ... Finzi, A. (2022). A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection. Cell Reports, 38(7), 110368. Article 110368. https://doi.org/10.1016/j.celrep.2022.110368

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title = "A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection",

abstract = "Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.",

keywords = "Animals, Antibodies, Neutralizing/therapeutic use, Antibodies, Viral/chemistry, Antibody-Dependent Cell Cytotoxicity, COVID-19 Serotherapy, COVID-19/mortality, Disease Models, Animal, Epitopes, Humans, Immunization, Passive/mortality, Immunoglobulin Fab Fragments/chemistry, Immunoglobulin Fc Fragments/genetics, Mice, Protein Binding, Protein Conformation, SARS-CoV-2/immunology, Spike Glycoprotein, Coronavirus/chemistry",

author = "Guillaume Beaudoin-Bussi{\`e}res and Yaozong Chen and Irfan Ullah and J{\'e}r{\'e}mie Pr{\'e}vost and Tolbert, \{William D.\} and Kelly Symmes and Shilei Ding and Mehdi Benlarbi and Gong, \{Shang Yu\} and Alexandra Tauzin and Romain Gasser and Debashree Chatterjee and Dani V{\'e}zina and Guillaume Goyette and Jonathan Richard and Fei Zhou and Leonidas Stamatatos and McGuire, \{Andrew T.\} and Hughes Charest and Michel Roger and Edwin Pozharski and Priti Kumar and Walther Mothes and Uchil, \{Pradeep D.\} and Marzena Pazgier and Andr{\'e}s Finzi",

note = "Copyright {\textcopyright} 2022. Published by Elsevier Inc.",

year = "2022",

month = feb,

day = "15",

doi = "10.1016/j.celrep.2022.110368",

language = "English",

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Beaudoin-Bussières, G, Chen, Y, Ullah, I, Prévost, J, Tolbert, WD, Symmes, K, Ding, S, Benlarbi, M, Gong, SY, Tauzin, A, Gasser, R, Chatterjee, D, Vézina, D, Goyette, G, Richard, J, Zhou, F, Stamatatos, L, McGuire, AT, Charest, H, Roger, M, Pozharski, E, Kumar, P, Mothes, W, Uchil, PD, Pazgier, M & Finzi, A 2022, 'A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection', Cell Reports, vol. 38, no. 7, 110368, pp. 110368. https://doi.org/10.1016/j.celrep.2022.110368

TY - JOUR

T1 - A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

AU - Beaudoin-Bussières, Guillaume

AU - Chen, Yaozong

AU - Ullah, Irfan

AU - Prévost, Jérémie

AU - Tolbert, William D.

AU - Symmes, Kelly

AU - Ding, Shilei

AU - Benlarbi, Mehdi

AU - Gong, Shang Yu

AU - Tauzin, Alexandra

AU - Gasser, Romain

AU - Chatterjee, Debashree

AU - Vézina, Dani

AU - Goyette, Guillaume

AU - Richard, Jonathan

AU - Zhou, Fei

AU - Stamatatos, Leonidas

AU - McGuire, Andrew T.

AU - Charest, Hughes

AU - Roger, Michel

AU - Pozharski, Edwin

AU - Kumar, Priti

AU - Mothes, Walther

AU - Uchil, Pradeep D.

AU - Pazgier, Marzena

AU - Finzi, Andrés

PY - 2022/2/15

Y1 - 2022/2/15

N2 - Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.

AB - Emerging evidence indicates that both neutralizing and Fc-mediated effector functions of antibodies contribute to protection against SARS-CoV-2. It is unclear whether Fc-effector functions alone can protect against SARS-CoV-2. Here, we isolated CV3-13, a non-neutralizing antibody, from a convalescent individual with potent Fc-mediated effector functions. The cryoelectron microscopy structure of CV3-13 in complex with the SARS-CoV-2 spike reveals that the antibody binds from a distinct angle of approach to an N-terminal domain (NTD) epitope that only partially overlaps with the NTD supersite recognized by neutralizing antibodies. CV3-13 does not alter the replication dynamics of SARS-CoV-2 in K18-hACE2 mice, but its Fc-enhanced version significantly delays virus spread, neuroinvasion, and death in prophylactic settings. Interestingly, the combination of Fc-enhanced non-neutralizing CV3-13 with Fc-compromised neutralizing CV3-25 completely protects mice from lethal SARS-CoV-2 infection. Altogether, our data demonstrate that efficient Fc-mediated effector functions can potently contribute to the in vivo efficacy of anti-SARS-CoV-2 antibodies.

KW - Animals

KW - Antibodies, Neutralizing/therapeutic use

KW - Antibodies, Viral/chemistry

KW - Antibody-Dependent Cell Cytotoxicity

KW - COVID-19 Serotherapy

KW - COVID-19/mortality

KW - Disease Models, Animal

KW - Epitopes

KW - Humans

KW - Immunization, Passive/mortality

KW - Immunoglobulin Fab Fragments/chemistry

KW - Immunoglobulin Fc Fragments/genetics

KW - Mice

KW - Protein Binding

KW - Protein Conformation

KW - SARS-CoV-2/immunology

KW - Spike Glycoprotein, Coronavirus/chemistry

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DO - 10.1016/j.celrep.2022.110368

M3 - Article

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AN - SCOPUS:85124153861

SN - 2211-1247

VL - 38

SP - 110368

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 110368

ER -

A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Abstract

Keywords

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