tetano
Editor, Senior Moderator
Front Immunol
. 2022 Jul 28;13:889372.
doi: 10.3389/fimmu.2022.889372. eCollection 2022.
Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2
Bruce D Wines[SUP] 1 2 3 4 [/SUP], Liriye Kurtovic[SUP] 2 3 [/SUP], Halina M Trist[SUP] 1 [/SUP], Sandra Esparon[SUP] 1 [/SUP], Ester Lopez[SUP] 5 [/SUP], Klasina Chappin[SUP] 1 [/SUP], Li-Jin Chan[SUP] 6 7 [/SUP], Francesca L Mordant[SUP] 5 [/SUP], Wen Shi Lee[SUP] 5 [/SUP], Nicholas A Gherardin[SUP] 5 [/SUP], Sheila K Patel[SUP] 8 [/SUP], Gemma E Hartley[SUP] 3 [/SUP], Phillip Pymm[SUP] 6 7 [/SUP], James P Cooney[SUP] 6 7 [/SUP], James G Beeson[SUP] 2 3 9 10 [/SUP], Dale I Godfrey[SUP] 5 [/SUP], Louise M Burrell[SUP] 8 [/SUP], Menno C van Zelm[SUP] 3 11 [/SUP], Adam K Wheatley[SUP] 5 12 [/SUP], Amy W Chung[SUP] 5 [/SUP], Wai-Hong Tham[SUP] 6 7 [/SUP], Kanta Subbarao[SUP] 5 13 [/SUP], Stephen J Kent[SUP] 5 12 14 [/SUP], P Mark Hogarth[SUP] 1 2 3 [/SUP]
Affiliations
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.
. 2022 Jul 28;13:889372.
doi: 10.3389/fimmu.2022.889372. eCollection 2022.
Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2
Bruce D Wines[SUP] 1 2 3 4 [/SUP], Liriye Kurtovic[SUP] 2 3 [/SUP], Halina M Trist[SUP] 1 [/SUP], Sandra Esparon[SUP] 1 [/SUP], Ester Lopez[SUP] 5 [/SUP], Klasina Chappin[SUP] 1 [/SUP], Li-Jin Chan[SUP] 6 7 [/SUP], Francesca L Mordant[SUP] 5 [/SUP], Wen Shi Lee[SUP] 5 [/SUP], Nicholas A Gherardin[SUP] 5 [/SUP], Sheila K Patel[SUP] 8 [/SUP], Gemma E Hartley[SUP] 3 [/SUP], Phillip Pymm[SUP] 6 7 [/SUP], James P Cooney[SUP] 6 7 [/SUP], James G Beeson[SUP] 2 3 9 10 [/SUP], Dale I Godfrey[SUP] 5 [/SUP], Louise M Burrell[SUP] 8 [/SUP], Menno C van Zelm[SUP] 3 11 [/SUP], Adam K Wheatley[SUP] 5 12 [/SUP], Amy W Chung[SUP] 5 [/SUP], Wai-Hong Tham[SUP] 6 7 [/SUP], Kanta Subbarao[SUP] 5 13 [/SUP], Stephen J Kent[SUP] 5 12 14 [/SUP], P Mark Hogarth[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 35967361
- PMCID: PMC9369017
- DOI: 10.3389/fimmu.2022.889372
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.