Characterization of a Novel ACE2-Based Therapeutic with Enhanced Rather than Reduced Activity against SARS-CoV-2 Variants
Mathieu Ferrari, Leila Mekkaoui, F. Tudor Ilca, Zulaikha Akbar, Reyisa Bughda, Katarina Lamb, Katarzyna Ward, Farhaan Parekh, Rajeev Karattil, Christopher Allen, Philip Fei Wu, Vania Baldan, Giada Mattiuzzo, Emma Bentley, Yasuhiro Takeuchi, James Sillibourne, Preeta Datta, Alexander Kinna, Martin Pulé, Shimobi Onuoha
Abstract
Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing 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 (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) 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 neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.