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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

06.09.2024 | Original Article

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

verfasst von: 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

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 2/2025

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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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Funeh CN, Bridoux J, Ertveldt T, De Groof TWM, Chigoho DM, Asiabi P, et al. Optimizing the Safety and Efficacy of Bio-radiopharmaceuticals for Cancer Therapy. Pharmaceutics. 2023;15. https://doi.org/10.3390/pharmaceutics15051378.

Rondon A, Rouanet J, Degoul F. Radioimmunotherapy in Oncology: overview of the last decade clinical trials. Cancers (Basel). 2021;13. https://doi.org/10.3390/CANCERS13215570.

Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hammers C, Songa EB, et al. Naturally occurring antibodies devoid of light chains. Nature. 1993;363:446–8. https://doi.org/10.1038/363446A0.CrossRefPubMed

Awad RM, Meeus F, Ceuppens H, Ertveldt T, Hanssens H, Lecocq Q, et al. Emerging applications of nanobodies in cancer therapy. Int Rev Cell Mol Biol. 2022;369:143–99. https://doi.org/10.1016/bs.ircmb.2022.03.010.CrossRefPubMed

D’Huyvetter M, De Vos J, Caveliers V, Vaneycken I, Heemskerk J, Duhoux FP, et al. Phase I trial of 131I-GMIB-Anti-HER2-VHH1, a New Promising candidate for HER2-Targeted Radionuclide Therapy in breast Cancer patients. J Nucl Med. 2021;62:1097–105. https://doi.org/10.2967/JNUMED.120.255679.CrossRefPubMed

Dekempeneer Y, Caveliers V, Ooms M, Maertens D, Gysemans M, Lahoutte T, et al. Therapeutic efficacy of 213Bi-labeled sdAbs in a preclinical model of Ovarian Cancer. Mol Pharm. 2020;17:3553–66. https://doi.org/10.1021/ACS.MOLPHARMACEUT.0C00580.CrossRefPubMed

Ertveldt T, De Beck L, De Ridder K, Locy H, de Mey W, Goyvaerts C, et al. Targeted Radionuclide Therapy with Low and High-Dose Lutetium-177-Labeled single domain antibodies induces distinct Immune signatures in a mouse Melanoma Model. Mol Cancer Ther. 2022;21:1136–48. https://doi.org/10.1158/1535-7163.MCT-21-0791.CrossRefPubMedPubMedCentral

Ertveldt T, Krasniqi A, Ceuppens H, Puttemans J, Dekempeneer Y, Jonghe K, De, et al. Targeted α-Therapy using 225Ac radiolabeled single-domain antibodies induces Antigen-Specific Immune responses and instills Immunomodulation both systemically and at the Tumor Microenvironment. J Nucl Med. 2023;64:751–8. https://doi.org/10.2967/jnumed.122.264752.CrossRefPubMed

Puttemans J, Dekempeneer Y, Eersels JL, Hanssens H, Debie P, Keyaerts M, et al. Preclinical Targeted α- and β--Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies. Cancers (Basel). 2020;12. https://doi.org/10.3390/cancers12041017.

10.

Puttemans J, Stijlemans B, Keyaerts M, Meeren S, Vander, Renmans W, Fostier K, et al. The Road to Personalized Myeloma Medicine: patient-specific single-domain antibodies for anti-idiotypic Radionuclide Therapy. Mol Cancer Ther. 2022;21:159–69. https://doi.org/10.1158/1535-7163.MCT-21-0220.CrossRefPubMed

11.

Liu Y, Watabe T, Kaneda-Nakashima K, Shirakami Y, Naka S, Ooe K, et al. Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model. Eur J Nucl Med Mol Imaging. 2022;49:871–80. https://doi.org/10.1007/S00259-021-05554-2.CrossRefPubMed

12.

Dekempeneer Y, Massa S, Santens F, Navarro L, Berdal M, Lucero MM, et al. Preclinical evaluation of a Radiotheranostic single-domain antibody against fibroblast activation protein α. J Nucl Med. 2023;64:1941–8. https://doi.org/10.2967/jnumed.123.266381.CrossRefPubMed

13.

Puré E, Blomberg R. Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene. 2018;37:4343–57. https://doi.org/10.1038/S41388-018-0275-3.CrossRefPubMedPubMedCentral

14.

De Veirman K, Puttemans J, Krasniqi A, Ertveldt T, Hanssens H, Romao E, et al. CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8 + T cells and PD-L1 expression in multiple myeloma. Oncoimmunology. 2021;10. https://doi.org/10.1080/2162402X.2021.2000699.

15.

Novruzov E, Mori Y, Alavi A, Giesel FL. The impact of FAP imaging in lung cancer and beyond: a new chapter. Eur Radiol. 2024;34:1946–7. https://doi.org/10.1007/S00330-023-10398-5.CrossRefPubMed

16.

Lepareur N, Ramée B, Mougin-Degraef M, Bourgeois M. Clinical advances and perspectives in targeted Radionuclide Therapy. Pharmaceutics. 2023;15. https://doi.org/10.3390/PHARMACEUTICS15061733.

17.

Kerr CP, Grudzinski JJ, Nguyen TP, Hernandez R, Weichert JP, Morris ZS. Developments in combining targeted Radionuclide therapies and immunotherapies for Cancer Treatment. Pharmaceutics. 2022;15. https://doi.org/10.3390/PHARMACEUTICS15010128.

18.

Tanaka T, Delong PA, Amin K, Henry A, Kruklitis R, Kapoor V, et al. Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib: potential value as adjuvant therapy after surgery. Ann Surg. 2005;241:168–78. https://doi.org/10.1097/01.SLA.0000149427.84712.D9.CrossRefPubMedPubMedCentral

19.

De Ridder K, Tung N, Werle J-T, Karpf L, Awad RM, Bernier A, et al. Novel 3D lung tumor spheroids for Oncoimmunological assays. Adv Nanobiomed Res. 2022;2. https://doi.org/10.1002/anbr.202100124.

20.

D’Huyvetter M, Xavier C, Caveliers V, Lahoutte T, Muyldermans S, Devoogdt N. Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer. Expert Opin Drug Deliv. 2014;11:1939–54. https://doi.org/10.1517/17425247.2014.941803.CrossRefPubMedPubMedCentral

21.

Breckpot K, Dullaers M, Bonehill A, Van Meirvenne S, Heirman C, De Greef C, et al. Lentivirally transduced dendritic cells as a tool for cancer immunotherapy. J Gene Med. 2003;5:654–67. https://doi.org/10.1002/jgm.400.CrossRefPubMed

22.

Loening AM, Gambhir SS. AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging. 2003;2:153535002003031. https://doi.org/10.1162/15353500200303133.CrossRef

23.

D’Huyvetter M, De Vos J, Xavier C, Pruszynski M, Sterckx YGJ, Massa S, et al. 131I-labeled Anti-HER2 camelid sdAb as a Theranostic Tool in Cancer Treatment. Clin Cancer Res. 2017;23:6616–28. https://doi.org/10.1158/1078-0432.CCR-17-0310.CrossRefPubMedPubMedCentral

24.

Rodak M, Dekempeneer Y, Wojewodzka M, Caveliers V, Covens P, Miller BW, et al. Preclinical evaluation of 225Ac-Labeled single-domain antibody for the treatment of HER2pos Cancer. Mol Cancer Ther. 2022;21:1835–45. https://doi.org/10.1158/1535-7163.MCT-21-1021.CrossRefPubMedPubMedCentral

25.

Lemaire M, D’Huyvetter M, Lahoutte T, Van Valckenborgh E, Menu E, De Bruyne E, et al. Imaging and radioimmunotherapy of multiple myeloma with anti-idiotypic nanobodies. Leukemia. 2014;28:444–7. https://doi.org/10.1038/LEU.2013.292.CrossRefPubMed

26.

Kratochwil C, Bruchertseifer F, Giesel F, Apostolidis C, Haberkorn U, Morgenstern A. Ac-225-DOTATOC – an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors. J Nucl Med. 2015;56(S3):1232.

27.

Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, et al. Targeted α-Therapy of metastatic castration-resistant prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding. J Nucl Med. 2017;58:1624–31. https://doi.org/10.2967/JNUMED.117.191395.CrossRefPubMed

28.

Zboralski D, Hoehne A, Bredenbeck A, Schumann A, Nguyen M, Schneider E, et al. Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy. Eur J Nucl Med Mol Imaging. 2022;49:3651–67. https://doi.org/10.1007/S00259-022-05842-5.CrossRefPubMedPubMedCentral

29.

Privé BM, Boussihmad MA, Timmermans B, van Gemert WA, Peters SMB, Derks YHW, et al. Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies. Eur J Nucl Med Mol Imaging. 2023;50:1906–18. https://doi.org/10.1007/S00259-023-06144-0.CrossRefPubMedPubMedCentral

30.

Ferdinandus J, Costa PF, Kessler L, Weber M, Hirmas N, Kostbade K, et al. Initial clinical experience with 90Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid tumors: a Case Series of 9 patients. J Nucl Med. 2022;63:727–34. https://doi.org/10.2967/JNUMED.121.262468.CrossRefPubMedPubMedCentral

31.

Kuyumcu S, Kovan B, Sanli Y, Buyukkaya F, Has Simsek D, Özkan ZG, et al. Safety of fibroblast activation protein-targeted Radionuclide Therapy by a low-dose Dosimetric Approach using 177Lu-FAPI04. Clin Nucl Med. 2021;46:641–6. https://doi.org/10.1097/RLU.0000000000003667.CrossRefPubMed

32.

Rao Z, Zhang Y, Liu L, Wang M, Zhang C. [177Lu]Lu-FAP-2286 therapy in a case of right lung squamous cell carcinoma with systemic metastases. Eur J Nucl Med Mol Imaging. 2023;50:1266–7. https://doi.org/10.1007/S00259-022-06048-5.CrossRefPubMed

33.

Olson B, Li Y, Lin Y, Liu ET, Patnaik A. Mouse models for cancer immunotherapy research. Cancer Discov. 2018;8:1358–65. https://doi.org/10.1158/2159-8290.CD-18-0044.CrossRefPubMedPubMedCentral

34.

Potluri HK, Ferreira CA, Grudzinski J, Massey C, Aluicio-Sarduy E, Engle JW, et al. Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors. J Immunother Cancer. 2022;10. https://doi.org/10.1136/JITC-2022-005060.

35.

Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology. 2018;7. https://doi.org/10.1080/2162402X.2017.1364828.

36.

Lecocq Q, Keyaerts M, Devoogdt N, Breckpot K. The Next-Generation Immune Checkpoint LAG-3 and its therapeutic potential in Oncology: Third Time’s a Charm. Int J Mol Sci. 2021;22:1–17. https://doi.org/10.3390/IJMS22010075.CrossRef

37.

Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020;11. https://doi.org/10.1038/S41467-020-18570-X.

38.

Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. PD-L1 interacts specifically with B7-1 to inhibit T cell proliferation. Immunity. 2007;27:111. https://doi.org/10.1016/J.IMMUNI.2007.05.016.CrossRefPubMedPubMedCentral

39.

Lee EJ, Jang GY, Lee SE, Lee Jwon, Han HD, Park YM, et al. A novel form of immunotherapy using antigen peptides conjugated on PD-L1 antibody. Immunol Lett. 2021;240:137–48. https://doi.org/10.1016/j.imlet.2021.10.006.CrossRefPubMed

40.

Awad RM, Breckpot K. Novel technologies for applying immune checkpoint blockers. Int Rev Cell Mol Biol. 2024;382:1–101. https://doi.org/10.1016/BS.IRCMB.2023.03.003.CrossRefPubMed

41.

Konen JM, Wu H, Gibbons DL. Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities. Trends Pharmacol Sci. 2024;45:520–36. https://doi.org/10.1016/J.TIPS.2024.04.006.CrossRefPubMed

42.

Poty S, Ordas L, Dekempeneer Y, Parach AA, Navarro L, Santens F, et al. Optimizing the therapeutic index of sdab-based radiopharmaceuticals using pretargeting. Annual Congress of the European Association of Nuclear Medicine October 15–19, 2022 Barcelona, Spain. Eur J Nucl Med Mol Imaging. 2022;49(Suppl 1):1–751. https://doi.org/10.1007/s00259-022-05924-4.CrossRef

Titel: Efficient α and β− radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model
verfasst von: 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
Publikationsdatum: 06.09.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 2/2025
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-024-06914-4

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

Abstract

Purpose

Methods

Results

Conclusion

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Characterization of a gonadal vein Capillary Hemangioma by [68Ga]FAPI-46 and [18 F]FDG PET and immunohistochemistry: a potential pitfall of FAPI PET signal

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