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Highly efficient inhibition of SARS-CoV-2 entry by a biologically unique ACE2-IgG4-Fc fusion protein with a stabilized hinge region

Hristo L. Svilenov*1, Julia Sacherl*2, Alwin Reiter*5, Lisa Wolff2, Cho-Chin Chen2,4, Marcel Stern3,4, Frank-Peter Wachs5, Nicole Simonavicius5, Susanne Pippig5, Florian Wolschin5, Oliver T. Keppler3,4, Johannes Buchner1, Carsten Brockmeyer5, Ulrike Protzer2

* These authors contributed equally to this work.

1 Department of Chemistry, Technical University of Munich, Garching, Germany; 2 Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany; 3 Max von Pettenkofer Institute & Gene Center, Virology, LMU München, Munich, Germany; 4 German Center for Infection Research, Munich partner site, Munich, Germany; 5 Formycon AG, Martinsried/Planegg, Germany

The novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) enters its host cells after binding to the angiotensin-converting enzyme 2 (ACE2) via its spike glycoprotein. This interaction is critical for virus entry and virus-host membrane fusion. Soluble ACE2 ectodomains bind and neutralize the virus, yet the short in vivo half-live of soluble ACE2 limits its therapeutic use. This limitation can be overcome by fusion of the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of unwanted Fc-receptor activation and antibody-dependent disease enhancement. Here, we describe optimized ACE2-Fc fusion constructs that avoid Fc-receptor binding and unwanted effector function by using the biologically unique IgG4-Fc as fusion partner. The engineered ACE2-IgG4-Fc fusion proteins described herein show broad antiviral activity at single-digit nanomolar concentration and promising pharmaceutical properties while they allow to preserve the beneficial enzymatic activity of ACE2. Taken together, ACE2-IgG4-Fc fusion proteins are promising candidates for the development of a broadly acting coronavirus antiviral.