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European Journal of Nuclear Medicine and Molecular Imaging

06-09-2024 | Radionuclide Therapy | Original Article

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

Authors: 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

Published in: European Journal of Nuclear Medicine and Molecular Imaging

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.

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Title: Efficient α and β− radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model
Authors: 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
Publication date: 06-09-2024
Publisher: Springer Berlin Heidelberg
Keyword: Radionuclide Therapy
Published in: European Journal of Nuclear Medicine and Molecular Imaging
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-024-06914-4

Keynote webinar | Spotlight on modern management of frailty

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on modern management of frailty

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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