FAP: The Next Billion Dollar Nuclear Theranostics Target?

Calais, Jérémie

doi:10.2967/jnumed.119.241232

Cited by 73 publications

(63 citation statements)

References 26 publications

(41 reference statements)

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“…One of those ligands (termed FAPI-04) has shown encouraging results in quantitative biodistribution experiments in tumor-bearing mice and excellent selectivity in PET studies in cancer patients using gallium-68 as a radionuclide (1,20,21,35). More than 30 different tumor types could be efficiently imaged using FAPI-04, which has led to intense industrial developments in the field (1,22).…”

Section: Discussionmentioning

confidence: 99%

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An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

Millul

Bassi

Mock

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177–labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer.

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Section: Discussionmentioning

confidence: 99%

“…types including breast, lung, pancreatic, head and neck, esophagus, and colorectal cancer presented a remarkably high uptake of a FAP-targeted small molecule labeled with gallium-68 (1,20,21). For this reason, FAP has recently been dubbed as "the next billion-dollar target for theranostic products" (22).…”

Section: Significancementioning

confidence: 99%

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

Millul

Bassi

Mock

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…A mAb is better suited for therapeutic development given the higher therapeutic benefit from prolonged exposure to cytotoxic agents. A FAP-targeted peptide, FAP-2286, is also being developed for peptide-targeted radionuclide therapy by Clovis Oncology, but so far, no data have been published (39). Although these studies demonstrate the utility of FAP-targeted imaging, they focus on applications in breast, colorectal, and lung cancers.…”

Section: Discussionmentioning

confidence: 99%

Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography

Hintz

Gallant

Griend

et al. 2020

Clinical Cancer Research

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Purpose: Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, heterogeneous disease with few therapeutic strategies that significantly prolong survival. Innovative therapies for mCRPC are needed; however, the development of new therapies relies on accurate imaging to assess metastasis and monitor response. Standard imaging modalities for prostate cancer require improvement and there remains a need for selective and sensitive imaging probes that can be widely used in patients with mCRPC. Experimental Design: We evaluated the transmembrane protease fibroblast activation protein alpha (FAP) as a targetable cell surface antigen for mCRPC. Genomic and IHC analyses were performed to investigate FAP expression in prostate cancer. Our FAP-targeted antibody imaging probe, [ 89 Zr]Zr-B12 IgG, was evaluated by PET/CT imaging in preclinical prostate cancer models. Results: Analysis of patient data documented FAP overexpression in metastatic disease across tumor subtypes. PET imaging with [ 89 Zr]Zr-B12 IgG demonstrated high tumor uptake and long-term retention of the probe in the preclinical models examined. FAPpositive stroma tumor uptake of [ 89 Zr]Zr-B12 IgG was 5-fold higher than the isotype control with mean %ID/cc of 34.13 AE 1.99 versus 6.12 AE 2.03 (n ¼ 3/group; P ¼ 0.0006) at 72 hours. Ex vivo biodistribution corroborated these results documenting rapid blood clearance by 24 hours and high tumor uptake of [ 89 Zr]Zr-B12 IgG by 72 hours. Conclusions: Our study reveals FAP as a target for imaging the tumor microenvironment of prostate cancer. Validation of [ 89 Zr]Zr-B12 IgG as a selective imaging probe for FAPexpressing tumors presents a new approach for noninvasive PET/CT imaging of mCRPC.

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“…Therefore, it represents a potent biomarker for cancer prognosis. Due to its overexpression in the tumor environment, combined with low expression in most normal tissues, FAP is considered as an important target for diagnostic imaging and anti-cancer therapies in nuclear medicine (Gascard and Tlsty 2016;Lamprecht et al 2018;Lindner et al 2019;Marsh et al 2013;Plava et al 2019;Pure and Lo 2016;Calais 2020).…”

Section: Introductionmentioning

confidence: 99%

18F-labeled tracers targeting fibroblast activation protein

Lindner

Altmann

Giesel

et al. 2021

EJNMMI radiopharm. chem.

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Background Cancer-associated fibroblasts are found in the stroma of epithelial tumors. They are characterized by overexpression of the fibroblast activation protein (FAP), a serine protease which was already proven as attractive target for chelator-based theranostics. Unfortunately, the value of gallium-68 labeled tracers is limited by their batch size and the short nuclide half-life. To overcome this drawback, radiolabeling with aluminum fluoride complexes and 6-fluoronicotinamide derivatives of the longer-lived nuclide fluorine-18 was established. The novel compounds were tested for their FAP-specific binding affinity. Uptake and binding competition were studied in vitro using FAP expressing HT-1080 cells. HEK cells transfected with the closely related dipeptidyl peptidase-4 (HEK-CD26) were used as negative control. Small animal positron emission tomography imaging and biodistribution experiments were performed in HT-1080-FAP xenografted nude mice. [18F]AlF-FAPI-74 was selected for PET/CT imaging in a non-small cell lung cancer (NSCLC) patient. Results In vitro, 18F-labeled FAPI-derivatives demonstrated high affinity (EC50 = < 1 nm to 4.2 nm) and binding of up to 80% to the FAP-expressing HT1080 cells while no binding to HEK-CD26 cells was observed. While small animal PET imaging revealed unfavorable biliary excretion of most of the 18F-labeled compounds, the NOTA bearing compounds [18F]AlF-FAPI-74 and -75 achieved good tumor-to-background ratios, as a result of their preferred renal excretion. These two compounds showed the highest tumor accumulation in PET imaging. The organ distribution values of [18F]AlF-FAPI-74 were in accordance with the small animal PET imaging results. Due to its less complex synthesis, fast clearance and low background values, [18F]AlF-FAPI-74 was chosen for clinical imaging. PET/CT of a patient with metastasized non-small cell lung cancer (NSCLC), enabled visualization of the primary tumor and its metastases at the hepatic portal and in several bones. This was accompanied by a rapid clearance from the blood pool and low background in healthy organs. Conclusion [18F]AlF-labeled FAPI derivatives represent powerful tracers for PET. Owing to an excellent performance in PET imaging, FAPI-74 can be regarded as a promising precursor for [18F]AlF-based FAP-imaging.

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FAP: The Next Billion Dollar Nuclear Theranostics Target?

Cited by 73 publications

References 26 publications

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography

18F-labeled tracers targeting fibroblast activation protein

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