Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2

Bruce D. Wines; Liriye Kurtovic; Halina M. Trist; Sandra Esparon; Ester Lopez; Klasina Chappin; Li Jin Chan; Francesca L. Mordant; Wen Shi Lee; Nicholas A. Gherardin; Sheila K. Patel; Gemma E. Hartley; Phillip Pymm; James P. Cooney; James G. Beeson; Dale I. Godfrey; Louise M. Burrell; Menno C. van Zelm; Adam K. Wheatley; Amy W. Chung; Wai Hong Tham; Kanta Subbarao; Stephen J. Kent; P. Mark Hogarth

doi:10.3389/fimmu.2022.889372

Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2

Bruce D. Wines, Liriye Kurtovic, Halina M. Trist, Sandra Esparon, Ester Lopez, Klasina Chappin, Li Jin Chan, Francesca L. Mordant, Wen Shi Lee, Nicholas A. Gherardin, Sheila K. Patel, Gemma E. Hartley, Phillip Pymm, James P. Cooney, James G. Beeson, Dale I. Godfrey, Louise M. Burrell, Menno C. van Zelm, Adam K. Wheatley, Amy W. ChungWai Hong Tham, Kanta Subbarao, Stephen J. Kent, P. Mark Hogarth^*

^*Corresponding author for this work

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

9 Citations (Scopus)

Abstract

Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.

Original language	English
Article number	889372
Number of pages	15
Journal	Frontiers in Immunology
Volume	13
DOIs	https://doi.org/10.3389/fimmu.2022.889372
Publication status	Published - 28 Jul 2022
Externally published	Yes

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10.3389/fimmu.2022.889372

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Wines, B. D., Kurtovic, L., Trist, H. M., Esparon, S., Lopez, E., Chappin, K., Chan, L. J., Mordant, F. L., Lee, W. S., Gherardin, N. A., Patel, S. K., Hartley, G. E., Pymm, P., Cooney, J. P., Beeson, J. G., Godfrey, D. I., Burrell, L. M., van Zelm, M. C., Wheatley, A. K., ... Hogarth, P. M. (2022). Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2. Frontiers in Immunology, 13, Article 889372. https://doi.org/10.3389/fimmu.2022.889372

@article{07057dfef70b4cb292612037b6af1cff,

title = "Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2",

abstract = "Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.",

keywords = "ACE2-Fc, ADCC, antibody effector function, complement, coronavirus, COVID-19, neutralization, SARS-CoV-2",

author = "Wines, \{Bruce D.\} and Liriye Kurtovic and Trist, \{Halina M.\} and Sandra Esparon and Ester Lopez and Klasina Chappin and Chan, \{Li Jin\} and Mordant, \{Francesca L.\} and Lee, \{Wen Shi\} and Gherardin, \{Nicholas A.\} and Patel, \{Sheila K.\} and Hartley, \{Gemma E.\} and Phillip Pymm and Cooney, \{James P.\} and Beeson, \{James G.\} and Godfrey, \{Dale I.\} and Burrell, \{Louise M.\} and \{van Zelm\}, \{Menno C.\} and Wheatley, \{Adam K.\} and Chung, \{Amy W.\} and Tham, \{Wai Hong\} and Kanta Subbarao and Kent, \{Stephen J.\} and Hogarth, \{P. Mark\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Wines, Kurtovic, Trist, Esparon, Lopez, Chappin, Chan, Mordant, Lee, Gherardin, Patel, Hartley, Pymm, Cooney, Beeson, Godfrey, Burrell, van Zelm, Wheatley, Chung, Tham, Subbarao, Kent and Hogarth.",

year = "2022",

month = jul,

day = "28",

doi = "10.3389/fimmu.2022.889372",

language = "English",

volume = "13",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media SA",

}

Wines, BD, Kurtovic, L, Trist, HM, Esparon, S, Lopez, E, Chappin, K, Chan, LJ, Mordant, FL, Lee, WS, Gherardin, NA, Patel, SK, Hartley, GE, Pymm, P, Cooney, JP, Beeson, JG, Godfrey, DI, Burrell, LM, van Zelm, MC, Wheatley, AK, Chung, AW, Tham, WH, Subbarao, K, Kent, SJ & Hogarth, PM 2022, 'Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2', Frontiers in Immunology, vol. 13, 889372. https://doi.org/10.3389/fimmu.2022.889372

TY - JOUR

T1 - Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2

AU - Wines, Bruce D.

AU - Kurtovic, Liriye

AU - Trist, Halina M.

AU - Esparon, Sandra

AU - Lopez, Ester

AU - Chappin, Klasina

AU - Chan, Li Jin

AU - Mordant, Francesca L.

AU - Lee, Wen Shi

AU - Gherardin, Nicholas A.

AU - Patel, Sheila K.

AU - Hartley, Gemma E.

AU - Pymm, Phillip

AU - Cooney, James P.

AU - Beeson, James G.

AU - Godfrey, Dale I.

AU - Burrell, Louise M.

AU - van Zelm, Menno C.

AU - Wheatley, Adam K.

AU - Chung, Amy W.

AU - Tham, Wai Hong

AU - Subbarao, Kanta

AU - Kent, Stephen J.

AU - Hogarth, P. Mark

N1 - Publisher Copyright: Copyright © 2022 Wines, Kurtovic, Trist, Esparon, Lopez, Chappin, Chan, Mordant, Lee, Gherardin, Patel, Hartley, Pymm, Cooney, Beeson, Godfrey, Burrell, van Zelm, Wheatley, Chung, Tham, Subbarao, Kent and Hogarth.

PY - 2022/7/28

Y1 - 2022/7/28

N2 - Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.

AB - Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.

KW - ACE2-Fc

KW - ADCC

KW - antibody effector function

KW - complement

KW - coronavirus

KW - COVID-19

KW - neutralization

KW - SARS-CoV-2

UR - https://www.scopus.com/pages/publications/85136838345

U2 - 10.3389/fimmu.2022.889372

DO - 10.3389/fimmu.2022.889372

M3 - Article

C2 - 35967361

AN - SCOPUS:85136838345

SN - 1664-3224

VL - 13

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 889372

ER -

Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2

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Corrigendum: Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2: (Front. Immunol., (2022), 13, (889372), 10.3389/fimmu.2022.889372)

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