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Targeted interleukin-2 enhances the in vivo anti-cancer activity of Pluvicto™

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Pluvicto™ ([177Lu]Lu-PSMA-617), a radioligand therapeutic targeting prostate-specific membrane antigen (PSMA), has been recently approved for the treatment of metastatic castration-resistant prostate cancer (mCRPR). The drug suffers from salivary gland and kidney uptake that prevents its dose escalation to potentially curative doses. In this work, we sought to potentiate the in vivo anti-cancer activity of Pluvicto™ by combining it with L19-IL2, a clinical-stage investigational medicinal product based on tumor-targeted interleukin-2.

Methods

We established a new PSMA-expressing model (HT-1080.hPSMA) and validated it using a fluoresceine analogue of PSMA-617 (compound 1). The HT-1080.hPSMA model was used to study the saturation and tumor retention of Pluvicto™ (compound 2) and to run combination therapy studies with L19-IL2. To complement our understanding of the mechanism of action of this novel combination, we conducted proteomics experiments on tumor samples after therapy with Pluvicto™ alone or in combination with the immunocytokine.

Results

High, selective, and long-lived tumor uptake was observed for Pluvicto™ (2) in the novel HT-1080.hPSMA model. Therapy studies in HT-1080.hPSMA tumor-bearing mice revealed that the combination of Pluvicto™ (2) plus L19-IL2 mediated curative and durable responses in all animals. Potent in vivo anti-cancer activity was observed solely for the combination modality, at doses that were well tolerated by treated animals. Proteomics studies indicated that L19-IL2 boosts the activation of the immune system in animals pre-treated with Pluvicto™.

Conclusion

The therapeutic efficacy of Pluvicto™ at low radioactive doses can be effectively enhanced by the combination with L19-IL2. Our findings warrant further clinical exploration of this novel combination modality.

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Data availability

Data are available free of charge as PDF file in the supplementary information section.

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Acknowledgements

The authors thank Dr. Christian Pellegrino, Claudia Comacchio, and Laura Lucaroni for their support with the generation of the hPSMA-positive tumor cell line.

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Authors and Affiliations

  1. R&D Department, Philochem AG, Libernstrasse 3, CH-8112, Otelfingen, ZH, Switzerland

    Tony Georgiev, Lucrezia Principi, Andrea Galbiati, Ettore Gilardoni & Samuele Cazzamalli

  2. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, CH-8093, Zurich, Switzerland

    Dario Neri

  3. Philogen S.p.A., I-53100, Siena, Italy

    Dario Neri

Authors
  1. Tony Georgiev
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  2. Lucrezia Principi
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  3. Andrea Galbiati
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  4. Ettore Gilardoni
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  5. Dario Neri
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  6. Samuele Cazzamalli
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Contributions

All the authors have contributed to manuscript preparation and revision. Tony Georgiev (TG), Dario Neri (DN), and Samuele Cazzamalli (SC) conceived the experiments. TG performed synthesis of all compounds and ran in vitro (flow cytometry) and in vivo (biodistributions, therapy) studies. Andrea Galbiati (AG) assisted with the in vivo therapy experiment. Lucrezia Principi (LP) performed sample preparation and ran MS measurements for proteomics study. LP and Ettore Gilardoni (EG) interpreted proteomics data. LP and EG performed high-resolution mass spectrometry analysis of synthesized compounds.

Corresponding authors

Correspondence to Dario Neri or Samuele Cazzamalli.

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Competing interests

DN is co-founder, CEO, CSO, and President of the Scientific Advisory Board of Philogen. TG, LP, AG, EG, and SC are employed by Philochem AG, the research and development unit of the Philogen group.

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Georgiev, T., Principi, L., Galbiati, A. et al. Targeted interleukin-2 enhances the in vivo anti-cancer activity of Pluvicto™. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06705-x

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  • DOI: https://doi.org/10.1007/s00259-024-06705-x

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