First-In-Human Results On The Biodistribution, Pharmacokinetics, And Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in Patients with Various End-stage Cancers

Ballal, Sanjana; Yadav, Madhav P.; Moon, Euy Sung; Kramer, Vasko; Roesch, Frank; Kumari, Samta; Bal, Chandrasekhar

doi:10.21203/rs.3.rs-786088/v1

Cited by 18 publications

(1 citation statement)

References 10 publications

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“…One of the most advanced compounds, 177 Lu-DOTAGA. (SA.FAPi) 2 , was offered as a compassionate treatment to patients with various cancers, including metastatic breast cancer, 47 medullary thyroid cancer, 44 radioiodine-refractory differentiated thyroid cancer (RR-DTC), 50 and radioiodine resistant follicular cell-derived thyroid cancer, 46 at doses of ∼5.5. GBq/cycle.…”

Section: ■ Introductionmentioning

confidence: 99%

Molecular Evolution of Multivalent OncoFAP Derivatives with Enhanced Tumor Uptake and Prolonged Tumor Retention

Galbiati,

Bocci,

Gervasoni

et al. 2024

J. Med. Chem.

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Fibroblast activation protein (FAP) is a protein biomarker widely expressed in most solid human malignancies of epithelial origin. In recent years, a number of FAP-targeted small organic radioligands, including OncoFAP, have been utilized in the clinic for the detection and diagnosis of cancer. Despite their selective accumulation, conventional FAP ligands present a relatively short half-life in tumors, corresponding to a few hours after systemic administration. In order to maximize their efficacy, FAP-targeted radioligand therapeutics must possess prolonged tumor retention, thus irradiating tumor cells for days. In this work, we describe the development of compact OncoFAP multimers with improved FAP affinity (low picomolar IC 50 s), aimed at increasing tumor-residence time for therapeutic applications. An in silico analysis of the interaction of the multimers with FAP revealed a wide and deep pocket and six additional secondary binding sites. TriOncoFAP-DOTAGA emerged for its favorable in vitro profile and superior in vivo biodistribution performance in tumor-bearing mice.

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Section: ■ Introductionmentioning

confidence: 99%

Molecular Evolution of Multivalent OncoFAP Derivatives with Enhanced Tumor Uptake and Prolonged Tumor Retention

Galbiati,

Bocci,

Gervasoni

et al. 2024

J. Med. Chem.

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Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies

Privé

Boussihmad

Timmermans

et al. 2023

Eur J Nucl Med Mol Imaging

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Introduction Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. Methods A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15th of July 2022) to search for prospective trials on FAP TRT. Results In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD. Conclusion To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [177Lu]Lu-FAPI-04, [90Y]Y-FAPI-46, [177Lu]Lu-FAP-2286, [177Lu]Lu-DOTA.SA.FAPI and [177Lu]Lu-DOTAGA.(SA.FAPi)2. In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.

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Fibroblast activation protein inhibitors: New frontier of molecular imaging and therapy

Rangarajan

Choudhury

Agrawal

et al. 2022

Nuclear Medicine and Molecular Imaging

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First-In-Human Results On The Biodistribution, Pharmacokinetics, And Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in Patients with Various End-stage Cancers

Cited by 18 publications

References 10 publications

Molecular Evolution of Multivalent OncoFAP Derivatives with Enhanced Tumor Uptake and Prolonged Tumor Retention

Molecular Evolution of Multivalent OncoFAP Derivatives with Enhanced Tumor Uptake and Prolonged Tumor Retention

Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies

Fibroblast activation protein inhibitors: New frontier of molecular imaging and therapy

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