The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody

Conrad E.Z. Chan, Shirley G.K. Seah, De Hoe Chye, Shane Massey, Maricela Torres, Angeline P.C. Lim, Steven K.K. Wong, Jacklyn J.Y. Neo, Pui San Wong, Jie Hui Lim, Gary S.L. Loh, Dongling Wang, Jerome D. Boyd-Kirkup, Siyu Guan, Dipti Thakkar, Guo Hui Teo, Kiren Purushotorman, Paul E. Hutchinson, Barnaby E. Young, Jenny G. LowPaul A. MacAry, Hannes Hentze, Venkateshan S. Prativadibhayankara, Kantharaj Ethirajulu, Jason E. Comer, Chien Te K. Tseng, Alan D.T. Barrett, Piers J. Ingram, Trevor Brasel, Brendon John Hanson

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID- 19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated proinflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2- infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.

Original languageEnglish (US)
Article numbere0253487
JournalPloS one
Volume16
Issue number6 June
DOIs
StatePublished - Jun 2021

ASJC Scopus subject areas

  • General

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