Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein

Svilenov, Hristo L.; Sacherl, Julia; Reiter, Alwin; Wolff, Lisa S.; Cheng, Cho-Chin; Stern, Marcel; Grass, Vincent; Feuerherd, Martin; Wachs, Frank-Peter; Simonavicius, Nicole; Pippig, Susanne; Wolschin, Florian; Keppler, Oliver T.; Buchner, Johannes; Brockmeyer, Carsten and Protzer, Ulrike (2021): Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein. In: Antiviral Research, Vol. 196, 105197

Abstract

SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibodydependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fcreceptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate antiantivirals to combat the current and future pandemics.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0166-3542
• Language: English