A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells

Alexandra Kegler; Laura Drewitz; Claudia Arndt; Cansu Daglar; Liliana Rodrigues Loureiro; Nicola Mitwasi; Christin Neuber; Karla Elizabeth González Soto; Tabea Bartsch; Larysa Baraban; Holger Ziehr; Markus Heine; Annabel Nieter; Andres Moreira-Soto; Arne Kühne; Jan Felix Drexler; Barbara Seliger; Markus Laube; Domokos Máthé; Bernadett Pályi; Polett Hajdrik; László Forgách; Zoltán Kis; Krisztián Szigeti; Ralf Bergmann; Anja Feldmann; Michael Bachmann

doi:10.3389/fimmu.2023.1204543

A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells

Front Immunol. 2023 Jun 13:14:1204543. doi: 10.3389/fimmu.2023.1204543. eCollection 2023.

Authors

Alexandra Kegler¹, Laura Drewitz¹, Claudia Arndt^{1

2}, Cansu Daglar¹, Liliana Rodrigues Loureiro¹, Nicola Mitwasi¹, Christin Neuber¹, Karla Elizabeth González Soto¹, Tabea Bartsch¹, Larysa Baraban¹, Holger Ziehr³, Markus Heine³, Annabel Nieter³, Andres Moreira-Soto⁴, Arne Kühne⁴, Jan Felix Drexler⁴, Barbara Seliger^{5

6}, Markus Laube⁷, Domokos Máthé^{8

9

10}, Bernadett Pályi¹¹, Polett Hajdrik⁸, László Forgách¹², Zoltán Kis¹¹, Krisztián Szigeti⁸, Ralf Bergmann^{1

8}, Anja Feldmann^{1

13

14}, Michael Bachmann^{1

13

14}

Affiliations

¹ Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
² Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
³ Department of Pharmaceutical Biotechnology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Braunschweig, Germany.
⁴ Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁵ Medical Faculty, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
⁶ Institute of Translational Immunology, Medical High School, Brandenburg an der Havel, Germany.
⁷ Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
⁸ Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
⁹ Hungarian Centre of Excellence for Molecular Medicine, In Vivo Imaging Advanced Core Facility, Szeged, Hungary.
¹⁰ CROmed Translational Research Ltd., Budapest, Hungary.
¹¹ National Biosafety Laboratory, Division of Microbiological Reference Laboratories, National Public Health Center, Budapest, Hungary.
¹² Semmelweis University School of Pharmacy, Semmelweis University, Budapest, Hungary.
¹³ National Center for Tumor Diseases Dresden (NCT), German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
¹⁴ German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to millions of infections and deaths worldwide. As this virus evolves rapidly, there is a high need for treatment options that can win the race against new emerging variants of concern. Here, we describe a novel immunotherapeutic drug based on the SARS-CoV-2 entry receptor ACE2 and provide experimental evidence that it cannot only be used for (i) neutralization of SARS-CoV-2 in vitro and in SARS-CoV-2-infected animal models but also for (ii) clearance of virus-infected cells. For the latter purpose, we equipped the ACE2 decoy with an epitope tag. Thereby, we converted it to an adapter molecule, which we successfully applied in the modular platforms UniMAB and UniCAR for retargeting of either unmodified or universal chimeric antigen receptor-modified immune effector cells. Our results pave the way for a clinical application of this novel ACE2 decoy, which will clearly improve COVID-19 treatment.

Keywords: ACE2 decoy; COVID-19; SARS–CoV–2; T-cell based immunotherapy; adapter CAR platform; bispecific antibody.

Copyright © 2023 Kegler, Drewitz, Arndt, Daglar, Rodrigues Loureiro, Mitwasi, Neuber, González Soto, Bartsch, Baraban, Ziehr, Heine, Nieter, Moreira-Soto, Kühne, Drexler, Seliger, Laube, Máthé, Pályi, Hajdrik, Forgách, Kis, Szigeti, Bergmann, Feldmann and Bachmann.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2
Animals
COVID-19 Drug Treatment
COVID-19*
Humans
SARS-CoV-2*

Substances

Angiotensin-Converting Enzyme 2

Supplementary concepts

SARS-CoV-2 variants

Grants and funding

This study was funded by the Saxon State Ministry for Science, Culture and Tourism (“Diese Maßnahme wird mitfinanziert mit Steuermitteln auf Grundlage des vom Sächsischen Landtag beschlossenen Haushaltes,” application-ID: 100526737), the Else Kröner-Fresenius-Stiftung (Viroprotect, project ID: 7244119004), and the Helmholtz Initiative and Networking Fund (Radio-Immunotheranostics (MHELTHERA), project ID: InterLabs-0031), all granted to MB. This work was further supported by the Higher Education Institutional Excellence Program of the Ministry of Innovation and Technology (TKP2021-EGA, Therapeutic Development of Semmelweis University, TKP-Bioimaging-2020-4.1.1-TKP2020, and the Investment to the Future grant 2020.1.16-jövő-2021-00013), the European Union’s Horizon 2020-EU.4.a. program, grant agreement No. 739593: HCEMM. This work was supported by the European Union’s Horizon 2020 OPEN FET RIA (NEURAM, No, 712821), the Higher Education Institutional Excellence Program of the Ministry for Innovation and Technology in Hungary, within the framework of the “Innovation for the sustainable life and environment” thematic program of the University of Pécs. In addition, the work was supported by a grant from the Saxony-Anhalt State Ministry for Science (BS) and from the DAAD “GLACIER” (BS, JD, AM-S).