UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV-2 variants

Ferrari, M; Mekkaoui, L; Ilca, FT; Akbar, Z; Bughda, R; Lamb, K; Ward, K; ... Onuoha, SC; + view all (2021) Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV-2 variants. Journal of Virology , 95 (19) , Article e00685-21. 10.1128/JVI.00685-21. Green open access

[thumbnail of JVI.00685-21.pdf]
Preview
Text
JVI.00685-21.pdf - Accepted Version

Download (5MB) | Preview

Abstract

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351 and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralising antibody approaches. Furthermore, we report a pre-clinical characterisation package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralisation capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralised four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilising soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: While previous ACE2-based therapeutics have been described, ours has novel features including (1) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system; (2) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection and reduced risk of hyperinflammation, and (3) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralisation potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic mAb.

Type: Article
Title: Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV-2 variants
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1128/JVI.00685-21
Publisher version: http://dx.doi.org/10.1128/JVI.00685-21
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10132051
Downloads since deposit
83Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item