Clinical quantification of the integrin αvβ6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study)

Abstract

Purpose The RGD-integrin, αvβ6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFβ). This study sought to quantify expression of αvβ6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvβ6-selective [ 18 F]FB-A20FMDV2 PET ligand. Methods [ 18 F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (V T) were used to quantify αvβ6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvβ6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. Results A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. V T and SUV of [ 18 F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean V T (95% CI) was 0.88 (0.60, 1.29) mL/cm 3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm 3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy V T ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [ 18 F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [ 18 F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [ 18 F]FB-A20FMDV2 was safe and well tolerated. Conclusions Lung uptake of [ 18 F]FB-A20FMDV2, a measure of expression of the integrin αvβ6, was markedly increased in subjects with PF compared with healthy subjects.

​Quantitative Evaluation of Hepatic Integrin Αvβ3 Expression by Positron-emission Tomography Imaging Using 18F-FPP-RGD2 in Rats With Non-alcoholic Steatohepatitis

“…The strengths of these correlations were similar to those between SUV 60-90 min and hepatic integrin α v (r s = 0.680) or β 3 (r s = 0.776) protein expression. Indeed, the clinical usefulness of V T has recently been reported for pulmonary brosis related to other causes than cancer [33]. Our data suggest that hepatic V T , obtained non-invasively using kinetic modelling, might be useful as a predictor of brosis and for determining the e cacy of new drugs in pre-clinical and clinical studies.…”

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

“…In a study of 15 participants (6 healthy, 9 with pulmonary fibrosis), lung uptake of [ 18 F]FB-A20FMDV2 measured by lung volume of distribution (V T ), a partition co-efficient that acts as a marker of expression of the integrin αvβ6, was successfully quantified. This demonstrated increased expression in IPF compared with healthy participants [10]. Additionally, [ 18 F]FB-A20FMDV2 was well-tolerated and the PET measures were reproducible over a two-week period.…”

“…1) It was lower than the maximum 3000 mcg dose used in healthy volunteers, which would enable significant safety margins in the event that systemic exposure was higher in IPF patients than healthy volunteers. 2) PK from the study in healthy participants [10], demonstrated peak systemic unbound concentrations at 1000 mcg that were significantly in excess of the in vitro dissociation constant (Kd). As lung tissue exposures are likely to be at least as high as the systemic exposure, it was expected that αvβ6 would demonstrate significant engagement at this dose.…”

“…Dynamic [ 18 F]FB-A20FMDV2PET scans were acquired using a Siemens PET/CT system Biograph 6 TruePoint with TrueV or a Hi-Rez Biograph 6 (Siemens Healthcare, Erlangen, Germany). Full details of the methodology for image acquisition and analysis have been detailed elsewhere [10]. In brief, for each PET scan, [ 18 F]FB-A20FMDV2 was injected into a cubital or forearm vein through an intravenous cannula and emission data were acquired for up to 90 min.…”

“…Positron emission tomography (PET) imaging using the αvβ6-selective [ 18 F]FB-A20FMDV2 PET ligand provides a non-invasive method for measuring αvβ6 expression and a potential model for assessing target engagement of inhaled therapies in the lung [9,10]. In a study of 15 participants (6 healthy, 9 with pulmonary fibrosis), lung uptake of [ 18 F]FB-A20FMDV2 measured by lung volume of distribution (V T ), a partition co-efficient that acts as a marker of expression of the integrin αvβ6, was successfully quantified.…”