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ImmunoPET imaging–based pharmacokinetic profiles of an antibody and its Fab targeting endothelin A receptors on glioblastoma stem cells in a preclinical orthotopic model

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Abstract

Background

The resistance of glioblastoma stem cells (GSCs) to treatment is one of the causes of glioblastoma (GBM) recurrence. Endothelin A receptor (ETA) overexpression in GSCs constitutes an attractive biomarker for targeting this cell subpopulation, as illustrated by several clinical trials evaluating the therapeutic efficacy of endothelin receptor antagonists against GBM. In this context, we have designed an immunoPET radioligand combining the chimeric antibody targeting ETA, chimeric-Rendomab A63 (xiRA63), with 89Zr isotope and evaluated the abilities of xiRA63 and its Fab (ThioFab-xiRA63) to detect ETA+ tumors in a mouse model xenografted orthotopically with patient-derived Gli7 GSCs.

Results

Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [89Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [89Zr]Zr-ThioFab-xiRA63.

Conclusions

This study shows the high potential of [89Zr]Zr-xiRA63 in specifically targeting ETA+ tumors, thus raising the possibility of detecting and treating ETA+ GSCs, which could improve the management of GBM patients.

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Data Availability

Data generated and analyzed by the authors during the study are available in supplementary information. Complementary information are available from the corresponding author by request.

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Acknowledgements

We thank Céline Chevaleyre for her expertise on the pharmacokinetic model with Patlak and Benoit Jego for his support on ex vivo processing.

Funding

This work was funded by the ANR (ANR-19-CE18-0013, DualMab) and performed at an imaging platform supported by the France Life Imaging network (ANR-11-INBS-0006).

Author information

Authors and Affiliations

  1. Université Paris-Saclay, CEA, DMTS, SPI, 91191, Gif-Sur-Yvette, France

    Marie Hautiere, Amaury Herbet, Narciso Costa & Didier Boquet

  2. Université Paris-Saclay, CEA, CNRS, Inserm, BioMaps, 91401, Orsay, France

    Marie Hautiere, Caroline Denis, Dimitri Kereselidze & Charles Truillet

  3. Université de Bourgogne, ICMUB UMR CNRS 6302, Dijon, France

    Delphine Vivier, Victor Goncalves & Franck Denat

  4. Université de Montpellier, IGF, INSERM U 1191 - CNRS UMR 5203, 34094, Montpellier, France

    Donovan Pineau & Jean Philippe Hugnot

  5. Université Paris-Saclay, CEA, CNRS, NeuroSpin/BAOBAB, Gif-Sur-Yvette, France

    Erwan Selingue & Benoit Larrat

Authors
  1. Marie Hautiere
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Corresponding authors

Correspondence to Didier Boquet or Charles Truillet.

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Ethical approval

All animal experiments were performed according to the European Directive 2010/63/EU and to its transposition into the French law (Decree No. 2013–118). This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

DB and AH are scientific cofounders and hold equity in Skymab Biotherapeutics.

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Didier Boquet (Endothelin A receptor and antibodies) and Charles Truillet (ImmunoPET imaging and Pharmacokinetic)  are joint last authors.

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Hautiere, M., Vivier, D., Pineau, D. et al. ImmunoPET imaging–based pharmacokinetic profiles of an antibody and its Fab targeting endothelin A receptors on glioblastoma stem cells in a preclinical orthotopic model. Eur J Nucl Med Mol Imaging 50, 3192–3201 (2023). https://doi.org/10.1007/s00259-023-06268-3

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