Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV2 variants

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 and B.1.351 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.

A tetrameric ACE2 protein broadly neutralizes SARS-CoV-2 spike variants of concern with elevated potency

“…This setup effectively disregards the valency of the ACE2 constructs and measures the intrinsic 1:1 affinity of interaction between the spike paratope and ACE2 epitope for each construct. As previously reported for the bivalent ACE2-Fc ( Ferrari et al, 2021 ), the affinity of the B.1.1.7 spike for the ACE2 proteins was greater than that of the Wuhan or D614G spikes ( Fig. 1 A & B, Table 1 ), as might be expected given their greater transmissibility.…”

“…The soluble ACE2 receptor alone is not suitable for therapeutic use against SARS-CoV-2 due to short systemic half-life ( Haschke et al, 2013 ) and low affinity of the monovalent receptor ( Linsky et al, 2020 ). Both of these properties have been improved by generating ACE2 fusion to human immunoglobulin crystallizable fragment (Fc) domain ( Ferrari et al, 2021 ; Lei et al, 2020 ). An alternative approach to the problem of short serum half-life is to avoid systemic administration altogether.…”

Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection

“…However the emergence of multiple variants of the virus from B.1.1.7 (Alpha strain), B.1.351 (Beta strain), B.1.617.2 (Delta strain) to P.1 and B.1.1.529 (Gamma and Omicron strains) [15], calls for the development of alternative therapeutic strategies. Among the proposals for new Covid19 therapies, approaches to neutralize the virus has been explored amongst which drugs targeting the SARS-CoV2 entry receptor, ACE2 (angiotensin converting enzyme II receptor) has gained paramount importance [4,[15][16][17][18][19][20].…”

“…Such an approach has tremendous potential for preventing infection and spread of virus from person to person at early stages [17,18]. While ACE2 receptor facilitates entry of the virus into the host system, a soluble human recombinant ACE2 receptor molecule is known to inhibit SARS-CoV2 infection by presenting as a decoy receptor [19]. Potency of soluble ACE2 receptor as a therapeutic against SARS-CoV2 infection has been demonstrated in human organoid culture [24] and also in clinical trials [25].…”

“…Usage of exogenous ACE2 receptor analogue to neutralize the viral infection is not vulnerable to mutations in the virus as long as it can bind to the ACE2 receptor. In case the virus mutates to decrease the binding affinity to the ACE2 receptor, then it would ultimately result in diminished infectivity [17,19]. However, soluble ACE2 has been reported to have a shorter circulating half-life, and multiple studies have reported modification of this receptor by expressing it as a fusion protein with human IgG-Fc [15][16][17][18]20,26], either by retaining or abrogating the catalytic activity of the ACE2 protein.…”