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Photoimmunotherapy (PIT), carried out using an Ab conjugated to the near infrared dye IRDye700DX, is achieving significant success in target‐specific elimination of cells. Fibroblast activation protein alpha (FAP‐α) is an important target in cancer because of its expression by cancer‐associated fibroblasts (CAFs) as well as by some cancer cells. Cancer‐associated fibroblasts that express FAP‐α have protumorigenic and immune suppressive functions. Using immunohistochemistry of human breast cancer tissue microarrays, we identified an increase of FAP‐α+ CAFs in invasive breast cancer tissue compared to adjacent normal tissue. We found FAP‐α expression increased in fibroblasts cocultured with cancer cells. In proof‐of‐principle studies, we engineered human FAP‐α overexpressing MDA‐MB‐231 and HT‐1080 cancer cells and murine FAP‐α overexpressing NIH‐3T3 fibroblasts to evaluate several anti‐FAP‐α Abs and selected AF3715 based on its high binding affinity with both human and mouse FAP‐α. After conjugation of AF3715 with the phthalocyanine dye IR700, the resultant Ab conjugate, FAP‐α‐IR700, was evaluated in cells and tumors for its specificity and effectiveness in eliminating FAP‐α expressing cell populations with PIT. Fibroblast activation protein‐α‐IR700‐PIT resulted in effective FAP‐α‐specific cell killing in the engineered cancer cells and in two patient‐derived CAFs in a dose‐dependent manner. Following an intravenous injection, FAP‐α‐IR700 retention was three‐fold higher than IgG‐IR700 in FAP‐α overexpressing tumors, and two‐fold higher compared to WT tumors. Fibroblast activation protein‐α‐IR700‐PIT resulted in significant growth inhibition of tumors derived from FAP‐α overexpressing human cancer cells. A reduction of endogenous FAP‐α+ murine CAFs was identified at 7 days after FAP‐α‐IR700‐PIT. Fibroblast activation protein‐α‐targeted near infrared PIT presents a promising strategy to eliminate FAP‐α+ CAFs. In our studies we first demonstrated increased expression of FAP‐α CAFs in human breast cancer tissue microarrays and in human mammary fibroblasts (HMFs) co‐cultured with human breast cancer cells. Next, in proof‐of‐principle studies, we engineered FAP‐α overexpressing human breast cancer MDA‐MB‐231 and human fibrosarcoma HT‐1080 cells to demonstrate successful elimination of FAP‐α expressing cell populations in tumors in vivo with NIR‐PIT. NIR‐PIT resulted in significant and selective growth inhibition of FAP‐α overexpressing tumors, and effective depletion of endogenous FAP‐α murine CAFs. The combination of target‐specific antibody binding with localized NIR exposure of the tumor avoided the off‐target toxicity associated with systemic FAP‐α‐targeted therapies.

Fibroblast activation protein-α (FAP) is a type-II transmembrane serine protease expressed almost exclusively to pathological conditions including fibrosis, arthritis, and cancer. Across most cancer types, elevated FAP is associated with worse clinical outcomes. Despite the clear association between FAP and disease severity, the biological reasons underlying these clinical observations remain unclear. Here we review basic FAP biology and FAP’s role in non-oncologic and oncologic disease. We further explore how FAP may worsen clinical outcomes via its effects on extracellular matrix remodeling, intracellular signaling regulation, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. Lastly, we discuss the potential to exploit FAP biology to improve clinical outcomes.

Background Fibroblast activation protein (FAP) is a pan-cancer target. Its selective expression on the majority of solid tumors with minimal to absent expression in healthy tissues positions FAP as a promising target for radiotheranostic applications. Nanobodies (Nbs) have unique characteristics, including small size, high affinity, stability, and ease of modification, making them ideal candidates for cancer diagnostics and targeted radiotherapeutics. Llama-derived Nbs were generated and screened against full-length FAP, with three unique candidates selected from the library for further characterization. The lead candidate Nb159 was engineered for site-specific radiolabeling with 89 Zr for PET imaging and with 177 Lu coupled with PEG for therapeutic evaluation in mice bearing FAP-positive U87 tumor xenografts. Results Nb159 exhibited exceptional picomolar binding affinity to FAP with stable interaction and slow dissociation. PET imaging with [ 89 Zr]Zr-Nb159 demonstrated specific tumor uptake, peaking at 1 h post-injection, with rapid renal clearance and minimal uptake in non-target organs. A competitive binding study confirmed its specificity to FAP on U87 tumors, as pre-injection with a tenfold molar excess of unlabeled Nb159 reduced tumor uptake by ~ 55% (3.78 ± 0.50 to 1.67 ± 0.26%ID/g). PEGylation of Nb159 improved its pharmacokinetic profile, yielding prolonged tumor accumulation and significantly reduced renal retention when co-injected with lysine. PET imaging further demonstrated target-specific uptake in FAP-positive U87 xenografts, which exhibited higher signal than FAP-negative HCT116 tumors, with SUV mean at 48 h of 0.45 ± 0.04 versus 0.09 ± 0.01 ( P  < 0.0001). In the therapeutic study, [ 177 Lu]Lu-PEG-Nb159 demonstrated significant tumor growth inhibition with no observable toxicity. Mice treated with a single dose of [ 177 Lu]Lu-PEG-Nb159 survived significantly longer compared to either [ 177 Lu]Lu-DOTA (23 days, P  < 0.001, HR: 0.06107) or vehicle (21 days, P  < 0.0001, HR: 0.04017). Conclusions The lead candidate Nb159 holds promise as a versatile platform for FAP-targeted radiotheranostics, with [ 89 Zr]Zr-Nb159 serving as an effective companion diagnostic and [ 177 Lu]Lu-PEG-Nb159 demonstrating promising therapeutic potential. These findings support further development of Nb159-based radiopharmaceuticals for treatment of FAP positive tumors.

Background Fibroblast activation protein (FAP)-targeting radioligands have gained attention for the ability to image multiple tumor types. Current FAP-targeting radioligands are labeled with 68 Ga and 18 F, but their short half-lives limit distribution range after production and later time-point imaging. This study describes the development Kalios, a novel class of NODAGA-conjugated FAP-targeting radioligands labeled with the cyclotron-produced Copper-61 (t 1/2  = 3.33 h), for greater temporal range for FAP-targeted imaging. Results Four Kalios ligands were synthesized and radiolabeled with [ 61 Cu]CuCl 2 in high yield and radiochemical purity within 5 min at room temperature. All radioligands demonstrated high hydrophilicity and strong affinity for FAP, and were primarily internalized after incubation with FAP-positive cells. PET/CT images obtained at 0–1 h and 4 h post-injection (p.i.) illustrated accumulation of all radioligands in FAP-positive tumors. Biodistribution studies of [ 61 Cu]Cu-Kalios-02 demonstrated stable tumor uptake between 1 and 4 h p.i., with washout from normal tissues at 4 h, resulting in improved tumor-to-background ratios. Conclusions Kalios ligands represent a new class of FAP-targeting 61 Cu-labeled radioligands. The half-life of 61 Cu allowed delayed 4-h imaging with improved tumor-to-background ratios. The improved delayed imaging and greater distribution range of these 61 Cu-labeled FAP-targeting radioligands demonstrates their clear potential for clinical translation, while combination with the therapeutic twin 67 Cu allows for truly paired Kalios theranostics.

Fibroblast activation protein (FAP) is a type II membrane-bound glycoprotein which is overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Since the first clinical application of quinoline-based FAP ligands in 2018, FAP inhibitor (FAPI)-based PET imaging and radiotherapy have been investigated for a wide variety of diseases, both cancerous and non-cancerous. As a consequence, promising strides have been made in particular to improve the understanding of FAPI-based PET imaging and the potential value of FAPI-based tumor radiotherapy. Herein, we present a comprehensive review of radiolabeled FAPI, including their clinical translation, in order to clarify the current and potential future role of this class of molecules in nuclear medicine. In particular, this review underlines the value of FAPI radiopharmaceuticals in the diagnosis or therapy of tumors or benign conditions. However, limitations in present studies have hampered a precise evaluation of FAPI radiopharmaceuticals. Despite this, it will likely be worthwhile to further explore the clinical value of FAPI in diagnosis and therapy through better-designed and larger-population clinical trials in the future.

IntroductionFibroblast activation protein-α (FAPα) is overexpressed on cancer-associated fibroblasts in approximately 90% of epithelial neoplasms, representing an appealing target for therapeutic and molecular imaging applications. [68 Ga]Ga-labelled radiopharmaceuticals—FAP-inhibitors (FAPI)—have been developed for PET. We systematically reviewed and meta-analysed published literature to provide an overview of its clinical role.Materials and methodsThe search, limited to January 1st, 2018–March 31st, 2021, was performed on MedLine and Embase databases using all the possible combinations of terms “FAP”, “FAPI”, “PET/CT”, “positron emission tomography”, “fibroblast”, “cancer-associated fibroblasts”, “CAF”, “molecular imaging”, and “fibroblast imaging”. Study quality was assessed using the QUADAS-2 criteria. Patient-based and lesion-based pooled sensitivities/specificities of FAPI PET were computed using a random-effects model directly from the STATA “metaprop” command. Between-study statistical heterogeneity was tested (I2-statistics).ResultsTwenty-three studies were selected for systematic review. Investigations on staging or restaging head and neck cancer (n = 2, 29 patients), abdominal malignancies (n = 6, 171 patients), various cancers (n = 2, 143 patients), and radiation treatment planning (n = 4, 56 patients) were included in the meta-analysis. On patient-based analysis, pooled sensitivity was 0.99 (95% CI 0.97–1.00) with negligible heterogeneity; pooled specificity was 0.87 (95% CI 0.62–1.00), with negligible heterogeneity. On lesion-based analysis, sensitivity and specificity had high heterogeneity (I2 = 88.56% and I2 = 97.20%, respectively). Pooled sensitivity for the primary tumour was 1.00 (95% CI 0.98–1.00) with negligible heterogeneity. Pooled sensitivity/specificity of nodal metastases had high heterogeneity (I2 = 89.18% and I2 = 95.74%, respectively). Pooled sensitivity in distant metastases was good (0.93 with 95% CI 0.88–0.97) with negligible heterogeneity.ConclusionsFAPI-PET appears promising, especially in imaging cancers unsuitable for [18F]FDG imaging, particularly primary lesions and distant metastases. However, high-level evidence is needed to define its role, specifically to identify cancer types, non-oncological diseases, and clinical settings for its applications.

PurposeThis study aimed to evaluate the potential utility of [68Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [18F]-FDG PET/CT.MethodsWe performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [68Ga]Ga-FAPI-04 and [18F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis.ResultsAmong the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [68Ga]Ga-FAPI-04, and [18F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively. Regarding the diagnosis of all intrahepatic lesions, the per-lesion detection rate of [68Ga]Ga-FAPI-04 PET/CT was slightly lower than that of MRI (85% vs. 100%, P = 0.34) and significantly higher than that of [18F]-FDG PET/CT (85% vs. 52%, P < 0.001). Regarding the diagnosis of all malignant lesions (including extrahepatic disease), the tumor detection rate of [68Ga]Ga-FAPI-04 PET/CT was 87.4%, which was significantly higher than that of [18F]-FDG PET/CT (65.0%, P < 0.001).ConclusionsOur findings indicate that the sensitivity of [68Ga]Ga-FAPI-04 PET/CT to correctly identify primary liver tumors and metastatic lesions is equivalent to that of CE-CT and liver MRI. Moreover, [68Ga]Ga-FAPI-04 PET/CT is better at identifying liver lesions than [18F]-FDG PET/CT, and its use may improve tumor staging, recurrence detection, and implementation of necessary treatment modifications.

Purpose The aim of this study was to explore the correlation of 18 F-labeled fibroblast activation protein inhibitor (FAPI) and cardiovascular magnetic resonance (CMR) parameters in ST-elevation myocardial infarction (STEMI) patients with successful primary percutaneous coronary intervention (PPCI) and to investigate the value of FAPI imaging in predicting cardiac functional recovery, as well as the correlation between FAPI activity and circulating fibroblast activation protein (FAP) and inflammatory biomarkers. Methods Fourteen first-time STEMI patients (11 men, mean age: 62 ± 11 years) after PPCI and 14 gender-matched healthy volunteers (10 men, mean age: 50 ± 14 years) who had completed FAPI imaging and blood sample collection were prospectively recruited. All patients underwent baseline FAPI imaging (6 ± 2 days post-MI) and CMR (8 ± 2 days post-MI). Ten patients had follow-up CMR (84 ± 4 days post-MI). Myocardial FAPI activity was analyzed for extent (the percentage of FAPI uptake volume over the left ventricular volume, FAPI%), intensity (target-to-background uptake ratio, TBRmax), and amount (FAPI% × TBRmax). Late gadolinium enhancement (LGE), T2-weighted imaging (T2WI), extracellular volume (ECV), microvascular obstruction (MVO), and cardiac function from CMR imaging were analyzed. Blood samples obtained on the day of FAPI imaging were used to assess circulating FAP, TGF-β1, TNF-α, IL-6, and hsCRP in STEMI patients and controls. Results Localized but inhomogeneous FAPI uptake was observed in STEMI patients, which was larger than the edematous and infarcted myocardium, whereas no uptake was detected in controls. The MVO area showed lower FAPI uptake compared with the surrounding myocardium. FAPI activity was associated with the myocardial injury biomarkers T2WI, LGE, and ECV at both per-patient and per-segment levels (all p  < 0.05), but was not associated with circulating FAP, TGF-β1, TNF-α, IL-6, or hsCRP. Among the CMR parameters, T2WI had the greatest correlation coefficient with both FAPI% and FAPI% × TBRmax. Baseline TBRmax was inversely correlated with the follow-up left ventricular ejection fraction (LVEF) ( r  =  − 0.73, p  = 0.02). Conclusion FAPI imaging detects more involved myocardium than CMR in reperfused STEMI, and is associated with myocardial damage and follow-up LVEF.

PurposeThis study aimed to explore the clinical utility of [68Ga]Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) relative to [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT and magnetic resonance imaging (MRI) for primary staging and recurrence detection in nasopharyngeal carcinoma (NPC).MethodsThis retrospective analysis utilized a sub-cohort of patients from a previously acquired database. Patients with NPC who underwent [18F]FDG and [68Ga]Ga-FAPI PET/CT between October 2019 and November 2020 were included. The radiotracer uptake and clinical staging/restaging performances of [18F]FDG and [68Ga]Ga-FAPI PET/CT were compared.ResultsForty-five participants (39 for initial assessment, 6 for recurrence detection) were included. In treatment-naïve participants, [68Ga]Ga-FAPI PET/CT showed higher radiotracer uptake than [18F]FDG PET/CT in primary tumors (16.18 vs. 10.11, P < 0.001), regional lymph nodes (11.42 vs. 7.37, P < 0.001), and bone and visceral metastases (6.94 vs. 3.11, P < 0.001). Compared with the [18F]FDG-based TNM stage, the [68Ga]Ga-FAPI-based TNM stage was upgraded in ten patients (26%), resulting in management changes in seven patients (18%). Compared with MRI, [68Ga]Ga-FAPI PET/CT upgraded and underestimated the T stage in four and two patients, respectively. In post-treatment patients, [68Ga]Ga-FAPI PET/CT yielded more true-positive findings than [18F]FDG PET/CT in detecting local recurrence.Conclusion[68Ga]Ga-FAPI PET/CT is a promising imaging modality for the diagnosis of primary and metastatic NPC. The exact tumor geographic imaging obtained through [68Ga]Ga-FAPI PET/CT may be a supplement to MRI for T staging and radiotherapy planning.

PurposeFibroblast 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.Methods177Lu-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.ResultsRadioligands 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.ConclusionThe 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.