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

Front Immunol. 2022 Jul 28:13:889372. doi: 10.3389/fimmu.2022.889372. eCollection 2022.

Authors

Bruce D Wines^{1

2

3

4}, Liriye Kurtovic^{2

3}, Halina M Trist¹, Sandra Esparon¹, Ester Lopez⁵, Klasina Chappin¹, Li-Jin Chan^{6

7}, Francesca L Mordant⁵, Wen Shi Lee⁵, Nicholas A Gherardin⁵, Sheila K Patel⁸, Gemma E Hartley³, Phillip Pymm^{6

7}, James P Cooney^{6

7}, James G Beeson^{2

3

9

10}, Dale I Godfrey⁵, Louise M Burrell⁸, Menno C van Zelm^{3

11}, Adam K Wheatley^{5

12}, Amy W Chung⁵, Wai-Hong Tham^{6

7}, Kanta Subbarao^{5

13}, Stephen J Kent^{5

12

14}, P Mark Hogarth^{1

2

3}

Affiliations

¹ Immune therapies Laboratory, Burnet Institute, Melbourne, VIC, Australia.
² Life Sciences, Burnet Institute, Melbourne, VIC, Australia.
³ Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
⁴ Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia.
⁵ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
⁶ Infectious Diseases and Immune Defence Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
⁷ Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
⁸ Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
⁹ Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
¹⁰ Department of Microbiology, Monash University, Clayton VIC, Australia.
¹¹ Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Alfred Hospital, Melbourne, VIC, Australia.
¹² Australian Research Council Centre for Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Melbourne, VIC, Australia.
¹³ World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC, Australia.

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; COVID-19; SARS-CoV-2; antibody effector function; complement; coronavirus; neutralization.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2*
COVID-19*
Humans
Peptidyl-Dipeptidase A / metabolism
RNA, Viral
SARS-CoV-2

Substances

RNA, Viral
Peptidyl-Dipeptidase A
Angiotensin-Converting Enzyme 2

Grants and funding

WT_/Wellcome Trust/United Kingdom