Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA

Backhaus, Philipp; Gierse, F.; Burg, Matthias C.; Büther, Florian; Asmus, Inga; Dorten, P.; Cufe, J.; Roll, Wolfgang; Neri, Dario; Cazzamalli, Samuele; Millul, Jacopo; Mock, Jacqueline; Galbiati, Andrea; Zana, Aureliano; Schäfers, KP; Hermann, Sven; Weckesser, Matthias; Tio, Joke; Wagner, Stefan; Breyholz, Hans-Jörg; Schäfers, Michael

doi:10.1007/s00259-021-05653-0

Cited by 56 publications

(54 citation statements)

References 22 publications

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“…FAP-targeted radiopharmaceuticals may revolutionize the field of radioligand imaging of cancer, because of their applicability to many types of malignancies and for the excellent tumour selectivity which has already been proven at the clinical level. ( 12,13,19 ) Other SMRC products, 177 Lu-PSMA-617 and Lutathera®, are limited to certain specific cancer indications and may be taken up by certain normal organ structures. ( 31,32 ) FAP is mainly expressed in the stroma of solid malignancies, thus adding a new element of differentiation compared to previously established targeting platforms, based on SSTR-2 and PSMA as cellular antigens.…”

Section: Discussionmentioning

confidence: 99%

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A novel dimeric FAP-targeting small molecule-radio conjugate with high and prolonged tumour uptake

Galbiati

Zana

Bocci

et al. 2022

Preprint

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Imaging procedures based on small molecule-radio conjugates (SMRCs) targeting fibroblast activation protein (FAP) have recently emerged as a powerful tool for the diagnosis of a wide variety of tumours. However, the therapeutic potential of radiolabeled FAP-targeting agents is limited by their short residence time in neoplastic lesions. In this work, we present the development and in vivo characterization of BiOncoFAP, a new dimeric FAP-binding motif with extended tumour residence time and favorable tumour-to-organ ratio. Methods: The binding properties of BiOncoFAP and its monovalent OncoFAP analogue were assayed against recombinant hFAP. Preclinical experiments with [177Lu]Lu-OncoFAP-DOTAGA (177Lu-OncoFAP) and [177Lu]Lu-BiOncoFAP-DOTAGA (177Lu-BiOncoFAP) were performed in mice bearing FAP-positive HT-1080 tumours. OncoFAP and BiOncoFAP displayed comparable sub-nanomolar dissociation constants towards hFAP in solution, but the bivalent BiOncoFAP bound more avidly to the target immobilized on solid supports. In a comparative biodistribution study, 177Lu-BiOncoFAP exhibited a more stable and prolonged tumour uptake than 177Lu-OncoFAP (~20% ID/g vs ~4% ID/g, at 24h p.i., respectively). Notably, 177Lu-BiOncoFAP showed favorable tumour-to-organ ratios with low kidney uptake. Both 177Lu-OncoFAP and 177Lu-BiOncoFAP displayed potent anti-tumour efficacy when administered at therapeutic doses in tumour bearing mice. 177Lu-BiOncoFAP is a promising candidate for radioligand therapy of cancer, with favorable in vivo tumour-to-organ ratio, long tumour residence time and potent anti-cancer efficacy.

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Section: Discussionmentioning

confidence: 99%

“…( 18 ) Proof-of-concept targeting studies with [ 68 Ga]Ga-OncoFAP-DOTAGA ( 68 Ga-OncoFAP), a PET tracer based on OncoFAP, have confirmed excellent biodistribution in patients with different primary and metastatic solid malignancies. ( 19 )…”

Section: Introductionmentioning

confidence: 99%

A novel dimeric FAP-targeting small molecule-radio conjugate with high and prolonged tumour uptake

Galbiati

Zana

Bocci

et al. 2022

Preprint

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“…Encouraged by these results, we further applied our methodology for the assessment of the biodistributions of [ nat Ga]Ga-OncoFAP-DOTAGA and [ nat Ga]Ga-BiOncoFAP-DOTAGA, cold molecular counterparts of two novel diagnostic radiotracers (i.e., [ 68 Ga]Ga-OncoFAP-DOTAGA and [ 68 Ga]Ga-BiOncoFAP-DOTAGA) 6 ( Figure 4, table S5 ). Similarly to Lutetium derivatives, both compounds showed a consistent tumor uptake and no significant uptake in healthy organs, with favorable tumor-to-organ ratios.…”

Section: Resultsmentioning

confidence: 99%

“…OncoFAP and BiOncoFAP, as well as their metal chelator conjugates and "cold"-labeled derivatives were synthesized through established protocols 6,10,11 .…”

Section: Chemical Synthesismentioning

confidence: 99%

“…In the recent years, clinical success of Lutathera® 2 and of PSMA-617 3 for the treatment of patients with neuroendocrine tumors and metastatic castration resistant prostate cancer has demonstrated the potential of this class of theragnostic. Many novel SMRC drug candidates are being developed and studied in clinical trials for diagnostic and therapeutic applications of patients with cancer and other types of chronic malignancies 4,5 , Among several new tumor-targeting radiopharmaceuticals, SMRCs targeting fibroblast activation protein (FAP) are promising pan-tumoral compounds which accumulate to tumors with exquisite selectivity against normal tissues 4,6,7 . FAP is a membrane-bound serine protease abundantly expressed on the stroma of most epithelial cancers 8 .…”

Section: Introductionmentioning

confidence: 99%

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A mass spectrometry-based method for the determination ofin vivobiodistribution of tumor targeting small molecule-metal conjugates

Gilardoni

Zana

Galbiati

et al. 2022

Preprint

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Nuclear medicine plays a key role in modern diagnosis and cancer therapy. The development of tumor targeting radionuclide conjugates (also named Small Molecule-Radio Conjugates - SMRCs) represents a significant improvement over the clinical use of metabolic radiotracers (e.g., [18F]-Fluorodeoxyglucose) for imaging and over the application of biocidal external beam radiations for therapy. During the discovery of SMRCs, molecular candidates must be carefully evaluated typically by performing biodistribution assays in preclinical tumor models. Quantification methodologies based on radioactive counts are typically demanding due to safety concerns, availability of radioactive material, and infrastructures. In this article, we report the development of a mass spectrometry (MS)-based method for the detection and quantification of small molecule-metal conjugates (SMMCs) as cold surrogates of SMRCs. We applied this methodology for the evaluation of the biodistribution of a particular class of tumor-targeting drug candidates based on natLu, natGa, natF and directed against Fibroblast Activation Protein (FAP). The reliability of the LC-MS analysis was validated by direct comparison of MS-based and radioactivity-based biodistribution data. Results show that MS biodistribution of stable isotope metal conjugates is an orthogonal tool for the preclinical characterization of different classes of radiopharmaceuticals.

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

Zboralski¹,

Hoehne²,

Bredenbeck³

et al. 2022

Eur J Nucl Med Mol Imaging

105

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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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Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA

Cited by 56 publications

References 22 publications

A novel dimeric FAP-targeting small molecule-radio conjugate with high and prolonged tumour uptake

A novel dimeric FAP-targeting small molecule-radio conjugate with high and prolonged tumour uptake

A mass spectrometry-based method for the determination ofin vivobiodistribution of tumor targeting small molecule-metal conjugates

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

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