Tumor-Targeted Interleukin 2 Boosts the Anticancer Activity of FAP-Directed Radioligand Therapeutics.

Autor:	Galbiati A; Research and Development Department, Philochem AG, Otelfingen, Switzerland., Dorten P; European Institute for Molecular Imaging, University of Münster, Münster, Germany., Gilardoni E; Research and Development Department, Philochem AG, Otelfingen, Switzerland., Gierse F; European Institute for Molecular Imaging, University of Münster, Münster, Germany., Bocci M; Research and Development Department, Philochem AG, Otelfingen, Switzerland., Zana A; Research and Development Department, Philochem AG, Otelfingen, Switzerland., Mock J; Research and Development Department, Philochem AG, Otelfingen, Switzerland., Claesener M; Department of Nuclear Medicine, University Hospital Münster, Münster, Germany., Cufe J; European Institute for Molecular Imaging, University of Münster, Münster, Germany.; Department of Nuclear Medicine, University Hospital Münster, Münster, Germany., Büther F; Department of Nuclear Medicine, University Hospital Münster, Münster, Germany., Schäfers K; European Institute for Molecular Imaging, University of Münster, Münster, Germany., Hermann S; European Institute for Molecular Imaging, University of Münster, Münster, Germany., Schäfers M; European Institute for Molecular Imaging, University of Münster, Münster, Germany.; Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.; West German Cancer Centre, Münster, Germany., Neri D; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zurich, Switzerland; and.; Philogen S.p.A., Siena, Italy., Cazzamalli S; Research and Development Department, Philochem AG, Otelfingen, Switzerland; samuele.cazzamalli@philochem.ch philipp.backhaus@ukmuenster.de., Backhaus P; European Institute for Molecular Imaging, University of Münster, Münster, Germany; samuele.cazzamalli@philochem.ch philipp.backhaus@ukmuenster.de.; Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.; West German Cancer Centre, Münster, Germany.
Jazyk:	angličtina
Zdroj:	Journal of nuclear medicine : official publication, Society of Nuclear Medicine [J Nucl Med] 2023 Dec 01; Vol. 64 (12), pp. 1934-1940. Date of Electronic Publication: 2023 Dec 01.
DOI:	10.2967/jnumed.123.266007
Abstrakt:	We studied the antitumor efficacy of a combination of 177 Lu-labeled radioligand therapeutics targeting the fibroblast activation protein (FAP) (OncoFAP and BiOncoFAP) with the antibody-cytokine fusion protein L19-interleukin 2 (L19-IL2) providing targeted delivery of interleukin 2 to tumors. Methods: The biodistribution of 177 Lu-OncoFAP and 177 Lu-BiOncoFAP at different molar amounts (3 vs. 250 nmol/kg) of injected ligand was studied via SPECT/CT in mice bearing subcutaneous HT-1080.hFAP tumors, and self-absorbed tumor and organ doses were calculated. The in vivo anticancer effect of 5 MBq of the radiolabeled preparations was evaluated as monotherapy or in combination with L19-IL2 in subcutaneously implanted HT-1080.hFAP and SK-RC-52.hFAP tumors. Tumor samples from animals treated with 177 Lu-BiOncoFAP, L19-IL2, or both were analyzed by mass spectrometry-based proteomics to identify therapeutic signatures on cellular and stromal markers of cancer and on immunomodulatory targets. Results: 177 Lu-BiOncoFAP led to a significantly higher self-absorbed dose in FAP-positive tumors (0.293 ± 0.123 Gy/MBq) than did 177 Lu-OncoFAP (0.157 ± 0.047 Gy/MBq, P = 0.01) and demonstrated favorable tumor-to-organ ratios at high molar amounts of injected ligand. Administration of L19-IL2 or 177 Lu-BiOncoFAP as single agents led to cancer cures in only a limited number of treated animals. In 177 Lu-BiOncoFAP-plus-L19-IL2 combination therapy, complete remissions were observed in all injected mice (7/7 complete remissions for the HT-1080.hFAP model, and 4/4 complete remissions for the SK-RC-52.hFAP model), suggesting therapeutic synergy. Proteomic studies revealed a mechanism of action based on the activation of natural killer cells, with a significant enhancement of the expression of granzymes and perforin 1 in the tumor microenvironment after combination treatment. Conclusion: The combination of OncoFAP-based radioligand therapeutics with concurrent targeting of interleukin 2 shows synergistic anticancer effects in the treatment of FAP-positive tumors. This experimental finding should be corroborated by future clinical studies. (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)
Databáze:	MEDLINE
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