AUTHOR=Wines Bruce D. , Kurtovic Liriye , Trist Halina M. , Esparon Sandra , Lopez Ester , Chappin Klasina , Chan Li-Jin , Mordant Francesca L. , Lee Wen Shi , Gherardin Nicholas A. , Patel Sheila K. , Hartley Gemma E. , Pymm Phillip , Cooney James P. , Beeson James G. , Godfrey Dale I. , Burrell Louise M. , van Zelm Menno C. , Wheatley Adam K. , Chung Amy W. , Tham Wai-Hong , Subbarao Kanta , Kent Stephen J. , Hogarth P. Mark TITLE=Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2 JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.889372 DOI=10.3389/fimmu.2022.889372 ISSN=1664-3224 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.