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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 24-05-2022 | Sarcoma | Original Article

Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy

Authors: Dirk Zboralski, Aileen Hoehne, Anne Bredenbeck, Anne Schumann, Minh Nguyen, Eberhard Schneider, Jan Ungewiss, Matthias Paschke, Christian Haase, Jan L. von Hacht, Tanya Kwan, Kevin K. Lin, Jan Lenore, Thomas C. Harding, Jim Xiao, Andrew D. Simmons, Ajay-Mohan Mohan, Nicola Beindorff, Ulrich Reineke, Christiane Smerling, Frank Osterkamp

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 11/2022

Abstract

Purpose

Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies.

Methods

FAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in in vivo imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule–based FAP-targeting agent.

Results

Immunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of ⁶⁸Ga-FAP-2286, ¹¹¹In-FAP-2286, and ¹⁷⁷Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. ¹⁷⁷Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46.

Conclusion

In preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of ⁶⁸Ga-FAP-2286 for imaging and ¹⁷⁷Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.

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Title: Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy
Authors: Dirk Zboralski
Aileen Hoehne
Anne Bredenbeck
Anne Schumann
Minh Nguyen
Eberhard Schneider
Jan Ungewiss
Matthias Paschke
Christian Haase
Jan L. von Hacht
Tanya Kwan
Kevin K. Lin
Jan Lenore
Thomas C. Harding
Jim Xiao
Andrew D. Simmons
Ajay-Mohan Mohan
Nicola Beindorff
Ulrich Reineke
Christiane Smerling
Frank Osterkamp
Publication date: 24-05-2022
Publisher: Springer Berlin Heidelberg
Keyword: Sarcoma
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 11/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05842-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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