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
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.
Subject
Immunology,Immunology and Allergy