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Efficient inhibition of SARS-CoV-2 strains by a novel ACE2-IgG4-Fc fusion protein with a stabilized hinge region

Hristo L. Svilenov, Julia Sacherl, Alwin Reiter, Lisa Wolff, Cho-Chin Chen, Marcel Stern, Frank-Peter Wachs, Nicole Simonavicius, Susanne Pippig, Florian Wolschin, Johannes Buchner, Carsten Brockmeyer, Ulrike Protzer
doi: https://doi.org/10.1101/2020.12.06.413443
Hristo L. Svilenov
1Department of Chemistry, Technical University of Munich, Garching, Germany
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Julia Sacherl
2Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany
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Alwin Reiter
5Formycon AG, Martinsried/Planegg, Germany
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Lisa Wolff
2Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany
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Cho-Chin Chen
2Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany
4German Center for Infection Research, Munich partner site, Munich, Germany
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Marcel Stern
3Max von Pettenkofer Institute & Gene Center, Virology, LMU München, Munich, Germany
4German Center for Infection Research, Munich partner site, Munich, Germany
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Frank-Peter Wachs
5Formycon AG, Martinsried/Planegg, Germany
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Nicole Simonavicius
5Formycon AG, Martinsried/Planegg, Germany
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Susanne Pippig
5Formycon AG, Martinsried/Planegg, Germany
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Florian Wolschin
5Formycon AG, Martinsried/Planegg, Germany
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Johannes Buchner
1Department of Chemistry, Technical University of Munich, Garching, Germany
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Carsten Brockmeyer
5Formycon AG, Martinsried/Planegg, Germany
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  • For correspondence: carsten.brockmeyer@formycon.com protzer@tum.de
Ulrike Protzer
2Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany
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  • For correspondence: carsten.brockmeyer@formycon.com protzer@tum.de
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Abstract

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 but the short in vivo half-lives of soluble ACE2 limits its therapeutic use. Fusion of the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain can prolong the in vivo half-life but 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 by using IgG4-Fc as a fusion partner. The engineered ACE2-IgG4-Fc fusion proteins described herein exhibit promising pharmaceutical properties and a broad antiviral activity at single-digit nanomolar concentration. In addition, they allow to maintain the beneficial enzymatic activity of ACE2 and thus are very promising candidate antivirals broadly acting against coronaviruses.

Competing Interest Statement

The authors have declared no competing interest.

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Posted December 11, 2020.
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Efficient inhibition of SARS-CoV-2 strains by a novel ACE2-IgG4-Fc fusion protein with a stabilized hinge region
Hristo L. Svilenov, Julia Sacherl, Alwin Reiter, Lisa Wolff, Cho-Chin Chen, Marcel Stern, Frank-Peter Wachs, Nicole Simonavicius, Susanne Pippig, Florian Wolschin, Johannes Buchner, Carsten Brockmeyer, Ulrike Protzer
bioRxiv 2020.12.06.413443; doi: https://doi.org/10.1101/2020.12.06.413443
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Efficient inhibition of SARS-CoV-2 strains by a novel ACE2-IgG4-Fc fusion protein with a stabilized hinge region
Hristo L. Svilenov, Julia Sacherl, Alwin Reiter, Lisa Wolff, Cho-Chin Chen, Marcel Stern, Frank-Peter Wachs, Nicole Simonavicius, Susanne Pippig, Florian Wolschin, Johannes Buchner, Carsten Brockmeyer, Ulrike Protzer
bioRxiv 2020.12.06.413443; doi: https://doi.org/10.1101/2020.12.06.413443

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