Enhancing fibroblast activation protein (FAP)-targeted radionuclide therapy with albumin binding, and beyond

Younis, Muhsin H.; Malih, Sara; Lan, Xiaoli; Rasaee, Mohammad Javad; Cai, Weibo

doi:10.1007/s00259-022-05766-0

Cited by 11 publications

(7 citation statements)

References 25 publications

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“…The therapeutic value of FAP-targeting radioligands is harmed mainly due to their short tumor residence time [7,11,24]. Three different strategies have been proposed for prolonging tumor residence time: (a) multimerization of the FAP-binding moiety [15,16,25], (b) conjugation of an albumin binder [17,18,[26][27][28], and (c) peptide-based structures as an alternative to small molecules [19,20]. Nevertheless, a direct comparison among them is still missing.…”

Section: Discussionmentioning

confidence: 99%

Head-to-head comparison of different classes of FAP radioligands designed to increase tumor residence time: monomer, dimer, albumin binders, and small molecules vs peptides

Millul

Koepke

Haridas

et al. 2023

Eur J Nucl Med Mol Imaging

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Purpose Fibroblast activation protein-α (FAP)-targeting radioligands have recently demonstrated high diagnostic potential. However, their therapeutic value is impaired by the short tumor residence time. Several strategies have been tested to overcome this limitation, but a head-to-head comparison has never been done. With the aim to identify strengths and limitations of the suggested strategies, we compared the monomer FAPI-46 versus (a) its dimer (FAPI-46-F1D), (b) two albumin binders conjugates (FAPI-46-Ibu (ibuprofen) and FAPI-46-EB (Evans Blue)), and (c) cyclic peptide FAP-2286. Methods 177Lu-labeled ligands were evaluated in vitro in cell lines with low (HT-1080.hFAP) and high (HEK-293.hFAP) humanFAP expression. SPECT/CT imaging and biodistribution studies were conducted in HT-1080.hFAP and HEK-293.hFAP xenografts. The areas under the curve (AUC) of the tumor uptake and tumor-to-critical-organs ratios and the absorbed doses were estimated. Results Radioligands showed IC50 in the picomolar range. Striking differences were observed in vivo regarding tumor uptake, residence, specificity, and total body distribution. All [177Lu]Lu-FAPI-46-based radioligands showed similar uptake between the two tumor models. [177Lu]Lu-FAP-2286 showed higher uptake in HEK-293.hFAP and the least background. The AUC of the tumor uptake and absorbed dose was higher for [177Lu]Lu-FAPI-46-F1D and the two albumin binder conjugates, [177Lu]Lu-FAPI-46-Ibu and [177Lu]Lu-FAPI-46-EB, in HT1080.hFAP xenografts and for [177Lu]Lu-FAPI-46-EB and [177Lu]Lu-FAP-2286 in HEK293.hFAP xenografts. The tumor-to-critical-organs AUC values and the absorbed doses were in favor of [177Lu]Lu-FAP-2286, but tumor-to-kidneys. Conclusion The study indicated dimerization and cyclic peptide structures as promising strategies for prolonging tumor residence time, sparing healthy tissues. Albumin binding strategy outcome depended on the albumin binding moiety. The peptide showed advantages in terms of tumor-to-background ratios, besides tumor-to-kidneys, but its tumor uptake was FAP expression–dependent.

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Section: Discussionmentioning

confidence: 99%

Head-to-head comparison of different classes of FAP radioligands designed to increase tumor residence time: monomer, dimer, albumin binders, and small molecules vs peptides

Millul

Koepke

Haridas

et al. 2023

Eur J Nucl Med Mol Imaging

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“…(S)-44- 7,10,13,16,19,22,25,28,31,34,. Compound 37 (45 mg, 81 μmol) was reacted with H 2 N-PEG12-COOH following General Procedure B.…”

Section: (S)-20-((4-((2-(2-cyano-44-difluoropyrrolidin-1-yl)-2-oxoeth...mentioning

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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“…Reducing 𝜅 𝑃𝐾 is likely to prolong radioligand retention in healthy tissue, which is generally undesirable. Notwithstanding, strategies aimed at prolonging retention in the blood compartment can improve efficacy, as recently shown using radioligands equipped with an additional albumin binding moiety [6][7][8][9].…”

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Simple and Versatile Pharmacokinetic Model for Radioligand Therapy

Zounek,

Zounek

2024

Preprint

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In recent years radioligand therapy has emerged as an effective treatment modality for various solid malignancies, with pharmacokinetic modeling being routinely used for absorbed dose calculation and patient-specific therapy planning. Exemplary time-activity curves of FAP-targeted radioligands in a mouse model are accurately fitted by a sum of right skew biexponential distributions with four adjustable parameters in total. This type of modeling function is versatile and also suitable for conventional drugs. For further insight, an auxiliary equation is derived that relates tumor clearance to FAP expression and the radioligand dissociation constant.

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Enhancing fibroblast activation protein (FAP)-targeted radionuclide therapy with albumin binding, and beyond

Abstract: Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cited by 11 publications

References 25 publications

Head-to-head comparison of different classes of FAP radioligands designed to increase tumor residence time: monomer, dimer, albumin binders, and small molecules vs peptides

Head-to-head comparison of different classes of FAP radioligands designed to increase tumor residence time: monomer, dimer, albumin binders, and small molecules vs peptides

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

Simple and Versatile Pharmacokinetic Model for Radioligand Therapy

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