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

Ferrari, Mathieu; Mekkaoui, Leila; Ilca, F. Tudor; Akbar, Zulaikha; Bughda, Reyisa; Lamb, Katarina; Ward, Katarzyna; Parekh, Farhaan; Karattil, Rajeev; Allen, Christopher; Wu, Philip; Baldan, Vania; Mattiuzzo, Giada; Bentley, Emma M.; Takeuchi, Yasuhiro; Sillibourne, James; Datta, Preeta; Kinna, Alexander; Pule, Martin; Onuoha, Shimobi C.

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.