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Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 10, pp 2025–2038 | Cite as

Novel PSCA targeting scFv-fusion proteins for diagnosis and immunotherapy of prostate cancer

  • Claudia Kessler
  • Alessa Pardo
  • Mehmet K. Tur
  • Stefan Gattenlöhner
  • Rainer Fischer
  • Katharina Kolberg
  • Stefan BarthEmail author
Original Article – Cancer Research

Abstract

Purpose

Despite great progress in the diagnosis and treatment of localized prostate cancer (PCa), there remains a need for new diagnostic markers that can accurately distinguish indolent and aggressive variants. One promising approach is the antibody-based targeting of prostate stem cell antigen (PSCA), which is frequently overexpressed in PCa. Here, we show the construction of a molecular imaging probe comprising a humanized scFv fragment recognizing PSCA genetically fused to an engineered version of the human DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT), the SNAP-tag, enabling specific covalent coupling to various fluorophores for diagnosis of PCa. Furthermore, the recombinant immunotoxin (IT) PSCA(scFv)-ETA′ comprising the PSCA(scFv) and a truncated version of Pseudomonas exotoxin A (PE, ETA′) was generated.

Methods

We analyzed the specific binding and internalization behavior of the molecular imaging probe PSCA(scFv)-SNAP in vitro by flow cytometry and live cell imaging, compared to the corresponding IT PSCA(scFv)-ETA′. The cytotoxic activity of PSCA(scFv)-ETA′ was tested using cell viability assays. Specific binding was confirmed on formalin-fixed paraffin-embedded tissue specimen of early and advanced PCa.

Results

Alexa Fluor® 647 labeling of PSCA(scFv)-SNAP confirmed selective binding to PSCA, leading to rapid internalization into the target cells. The recombinant IT PSCA(scFv)-ETA′ showed selective binding leading to internalization and efficient elimination of target cells.

Conclusions

Our data demonstrate, for the first time, the specific binding, internalization, and cytotoxicity of a scFv-based fusion protein targeting PSCA. Immunohistochemical staining confirmed the specific ex vivo binding to primary PCa material.

Keywords

Prostate cancer Prostate stem cell antigen (PSCA) Immunotoxin (IT) Single-chain fragment variable (scFv) Pseudomonas exotoxin A (ETA′) SNAP-tag 

Notes

Acknowledgements

This work was funded by the ForSaTum project, sponsored within the NRW-EU Ziel 2-Programm “Regionale Wettbewerbsfähigkeit und Beschäftigung 2007–2013” (ERFE). We would like to thank Radoslav Mladenov and Nina Berges (Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany) for their help with immunohistochemistry and confocal microscopy. We also thank Dr. Richard M. Twyman for support in preparation of the manuscript draft.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical standard

In accordance with the Helsinki Declaration of 1975, primary tissue samples were obtained during routine clinical practice at the University Hospital Giessen approved by the appropriate ethics committee.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Fraunhofer Institute for Molecular Biology and Applied Ecology IMEAachenGermany
  2. 2.Institute of Applied Medical EngineeringUniversity Hospital RWTH AachenAachenGermany
  3. 3.Institute for PathologyJustus-Liebig UniversityGiessenGermany
  4. 4.Institute of Molecular Biotechnology (Biology VII)RWTH Aachen UniversityAachenGermany
  5. 5.South African Research Chair in Cancer Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM)University of Cape TownObservatorySouth Africa

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