PhD Scientific Days 2025

Poster Session III. - K: Theoretical and Translational Medicine

A Novel ACE2 Decoy for Neutralization of SARS-CoV-2 Variants and Elimination of Infected Cells

Name of the presenter

Hajdrik Polett

Institute/workplace of the presenter

Department of Biophysics and Radiation Biology

Authors

Polett Hajdrik¹, Ralf Bergmann², Bernadett Pályi³, Zoltán Kis³, Krisztián Szigeti¹, Domokos Máthé⁴

1: Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
2: Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
3: National Biosafety Laboratory, Division of Microbiological Reference Laboratories, National Public Health Center, Budapest, Hungary
4: Hungarian Centre of Excellence for Molecular Medicine, In Vivo Imaging Advanced Core Facility, Szeged, Hungary

Text of the abstract

Aims:
To develop a dual-function therapeutic agent based on the ACE2 receptor that can both neutralize a broad range of SARS-CoV-2 variants and facilitate the immune-mediated elimination of infected cells, addressing limitations of current monoclonal antibody treatments.

Method:
We engineered a soluble ACE2 decoy fused with an epitope tag to enhance viral spike protein binding and enable antibody-dependent cellular cytotoxicity (ADCC). The decoy's binding affinity to spike proteins of various SARS-CoV-2 variants was measured via ELISA. Neutralization efficacy was assessed using pseudovirus infection assays. ADCC activity was evaluated in co-culture assays with effector cells, and therapeutic efficacy was tested in vivo using a SARS-CoV-2-infected hamster model.

Results:
The ACE2 decoy showed high binding affinity with EC50 values of 0.22 nM (Omicron BA.1), 0.47 nM (Delta), and 0.67 nM (Beta). It effectively neutralized pseudotyped viruses with IC50 values as low as 0.06 μg/mL for BA.1 and 0.11 μg/mL for Delta. In ADCC assays, >80% of spike-expressing target cells were eliminated. In vivo administration of the decoy reduced lung viral RNA levels by approximately 90% compared to untreated controls. Its activity was independent of MHC class I presentation, suggesting resilience against viral immune evasion.

Conclusion:
This novel ACE2 decoy represents a promising broad-spectrum antiviral candidate with dual-action capability—neutralizing diverse SARS-CoV-2 variants and promoting immune clearance of infected cells. Its MHC-independent mechanism provides an advantage in overcoming viral escape pathways. These findings support further preclinical and clinical development.

Funding:
This study was supported by the Saxon State Ministry for Science, Culture and Tourism, the Else Kröner-Fresenius-Stiftung (Viroprotect), the Helmholtz Initiative (MHELTHERA), 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). Additional support was provided by the University of Pécs and the Saxony-Anhalt State Ministry.