A Microdose PET Study of the Safety, Immunogenicity, Biodistribution, and Radiation Dosimetry of¹⁸F-FB-A20FMDV2 for Imaging the Integrin α_vβ₆

Abstract

The αβ integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid αβ-binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image αβ levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of αβ in humans. Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female)received a single microdose of F-FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of F-FB-A20FMDV2 was 8.7 ± 4.4 μg (range, 2.7-13.0 μg). The mean administered activity was 124 ± 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq.F-FB-A20FMDV2 successfully passed toxicology criteria, showed no adverse effects in this first-in-humans study, and has an effective dose that enables multiple scans in a single subject.

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

“…[ 18 F]FB-A20FMDV2 is a potent, selective ligand for integrin αvβ6, as shown by in vitro cell-free and cellular binding assays [18,30,31] and by in vivo animal models of cancer [25,32] and pulmonary fibrosis [33,21]. In addition, it has been tested in a first dose in human study of the safety, tolerability, biodistribution, radio-dosimetry and immunogenicity of [ 18 F]FB-A20FMDV2 [20]. Visual inspection of these PET images from healthy humans suggested that uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, ureters and bladder [20].…”

“…In addition, it has been tested in a first dose in human study of the safety, tolerability, biodistribution, radio-dosimetry and immunogenicity of [ 18 F]FB-A20FMDV2 [20]. Visual inspection of these PET images from healthy humans suggested that uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, ureters and bladder [20]. Immunohistochemistry and SPECT imaging of healthy rodent tissues revealed that αvβ6 is expressed constitutively in the epithelium of the gall bladder, stomach wall, duodenum, ileum, colon, and at lower levels in the lungs and skin [34,35]; largely supporting the observed expression in healthy humans [20].…”

“…A direct immunoassay for A20FMV2 was developed and validated [20]. Serum samples were stored at − 70°C until assayed.…”

“…Following assessment of human dosimetry [20], the dose conversion factor was later revised downwards to 21.7 μSv/ MBq, with correspondingly lower dose estimates of 5.1 mSv for the healthy and 18.8 mSv for the IPF patient group. Furthermore, following review of the quality of the images from healthy and IPF participants, the maximum administered activity for the CTD-ILD participants, was reduced from 180 to 150 MBq, thus lowering the maximum estimated radiation dose to 17.6 mSv.…”

“…Automated GMP-compatible radiochemistry non-clinical radiodosimetry of the A20FMDV2 peptide is described in the accompanying article [19]. [ 1 9 F]FB-labelled A20FMDV2 has an acceptable toxicology profile, showed no adverse effects in healthy subjects and has an effective dose (0.0217 mSv/MBq) that permits multiple scans in a single subject [20]. In the murine bleomycin model, the evolution of pulmonary fibrosis is accompanied by an increased expression of αvβ6 integrins that is reproducibly quantifiable using SPECT assessment of A20FMDV2 binding [21].…”