Efficient α and β- radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model

Hannelore Ceuppens; Ana Rita Pombo Antunes; Laurent Navarro; Thomas Ertveldt; Marion Berdal; Surasa Nagachinta; Kirsten De Ridder; Tony Lahoutte; Marleen Keyaerts; Nick Devoogdt; Cleo Goyvaerts; Matthias D'Huyvetter; Karine Breckpot

doi:10.1007/s00259-024-06914-4

Efficient α and β^- radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model

Eur J Nucl Med Mol Imaging. 2024 Sep 6. doi: 10.1007/s00259-024-06914-4. Online ahead of print.

Authors

Affiliations

¹ Vrije Universiteit Brussel, Department of Biomedical Sciences, Translational Oncology Research Center, Laboratory for Molecular and Cellular Therapy, Laarbeeklaan 103. Building E, Brussels, 1090, Belgium. Hannelore.Ceuppens@vub.be.
² Precirix NV/SA, Burg. Etienne Demunterlaan 3, Brussels, B-1090, Belgium.
³ Vrije Universiteit Brussel, Molecular Imaging and Therapy Research Group, Laarbeeklaan 103/K, Brussels, 1090, Belgium.
⁴ Vrije Universiteit Brussel, Department of Biomedical Sciences, Translational Oncology Research Center, Laboratory for Molecular and Cellular Therapy, Laarbeeklaan 103. Building E, Brussels, 1090, Belgium.
⁵ Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel (UZ Brussel), Nuclear Medicine Department, Laarbeeklaan 101, Brussels, 1090, Belgium.
⁶ Precirix NV/SA, Burg. Etienne Demunterlaan 3, Brussels, B-1090, Belgium. Matthias.Dhuyvetter@precirix.com.
⁷ Vrije Universiteit Brussel, Molecular Imaging and Therapy Research Group, Laarbeeklaan 103/K, Brussels, 1090, Belgium. Matthias.Dhuyvetter@precirix.com.
⁸ Vrije Universiteit Brussel, Department of Biomedical Sciences, Translational Oncology Research Center, Laboratory for Molecular and Cellular Therapy, Laarbeeklaan 103. Building E, Brussels, 1090, Belgium. Karine.Breckpot@vub.be.

^# Contributed equally.

PMID: 39237746
DOI: 10.1007/s00259-024-06914-4

Abstract

Purpose: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with ²²⁵Ac or ¹³¹I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB).

Methods: We studied the biodistribution and tumour uptake of [¹³¹I]I-GMIB-4AH29 and [²²⁵Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [¹³¹I]I-GMIB-4AH29 and [²²⁵Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [²²⁵Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [²²⁵Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB.

Results: The biodistribution showed high tumour uptake of [¹³¹I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [²²⁵Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [¹³¹I]I-GMIB-4AH29 or [²²⁵Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [²²⁵Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [²²⁵Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy.

Conclusion: [²²⁵Ac]Ac-DOTA-4AH29 and [¹³¹I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [²²⁵Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.

Keywords: Fibroblast activation protein-α; Programmed death-ligand 1; Single domain antibodies; Targeted radionuclide therapy.

Abstract

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