A Phase I Study to Evaluate the Safety and Preliminary Signs of Efficacy of [177Lu]Lu-OncoFAP-23 Alone or in Combination with L19-IL2 As a Treatment of Metastatic FAP-positive Solid Tumors

The aim of this study is to assess the safety of [177Lu]Lu-OncoFAP-23 alone or in combination with L19-IL2 for the treatment of advanced/metastatic Fibroblast Activation Protein (FAP)-positive solid tumors and to establish a Recommended Dose (RD).

开始日期2024-12-31

申办/合作机构

Philogen SpA

100 项与 [177Lu]Lu-OncoFAP-23 相关的临床结果

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100 项与 [177Lu]Lu-OncoFAP-23 相关的转化医学

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100 项与 [177Lu]Lu-OncoFAP-23 相关的专利（医药）

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项与 [177Lu]Lu-OncoFAP-23 相关的文献（医药）

2024-10-01·Journal of Nuclear Medicine

Preclinical Evaluation of¹⁷⁷Lu-OncoFAP-23, a Multivalent FAP-Targeted Radiopharmaceutical Therapeutic for Solid Tumors

Article

作者: Ravazza, Domenico ; Neri, Dario ; Gilardoni, Ettore ; Galbiati, Andrea ; Mock, Jacqueline ; Cazzamalli, Samuele ; Bocci, Matilde

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide ¹⁷⁷Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: ¹⁷⁷Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ∼16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of ¹⁷⁷Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and ^natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of ¹⁷⁷Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.

European Journal of Nuclear Medicine and Molecular Imaging

Effect of molar dose on the in vivo tissue biodistribution profile of FAP-targeted radioligand therapeutics

Article

作者: Galbiati, Andrea ; Neri, Dario ; Cazzamalli, Samuele ; Bocci, Matilde

PURPOSE¹⁷⁷Lu-OncoFAP-23 is a novel FAP-targeted radioligand therapeutic (RLT) with high and prolonged tumor residence time and promising preclinical efficacy. In this work, we investigated the correlation between the injected molar dose and the in vivo tumor-to-organ ratios and tumor-targeting performance of ¹⁷⁷Lu-OncoFAP-23.METHODSWe evaluated the quantitative biodistribution profile of ¹⁷⁷Lu-OncoFAP-23 at different molar doses (i.e., 3 to 2250 nmol/kg) in tumor-bearing mice by means of ex vivo gamma counting, we included ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-BiOncoFAP as experimental controls.RESULTSThe biodistribution profile of ¹⁷⁷Lu-OncoFAP-23 strongly depends on the molar dose injected. Molar doses below 30 nmol/kg result in unwanted uptake of the compound in healthy organs, while doses higher than 725 nmol/kg determined a reduced tumor uptake due to receptor saturation. We identified an optimal molar dose ranging from 90 to 250 nmol/kg, characterized by elevated tumor uptake and adequate tumor-to-organ ratios.CONCLUSION¹⁷⁷Lu-OncoFAP-23 presents a favorable in vivo biodistribution profile at molar doses ranging from 90 to 250 nmol/kg in tumor-bearing mice. Our results guide the design of the first-in-human Phase I clinical trial with this novel FAP-targeted radioligand therapeutic.

100 项与 [177Lu]Lu-OncoFAP-23 相关的药物交易

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