A First Time in Human , Microdose , Positron Emission Tomography Study of the Safety , Immunogenicity , Biodistribution and Radiation Dosimetry of [ 18 F ] FBA 20 FMDV 2 for Imaging the Integrin αvβ 6

Background The αvβ6 integrin is involved in the pathogenesis of cancer and fibrosis. Levels of αvβ6 expression measured by immunohistochemistry have been shown to provide clinically relevant prognostic and potentially theranostic information. A radio-labelled 20-amino acid αvβ6-binding peptide, derived from the foot and mouth virus (A20FMDV2), has been developed to image αvβ6 levels pre-clinically. Aim To translate pre-clinical findings into a clinical PET imaging protocol to measure the expression of αvβ6 in humans. Methods A first time in human study was conducted in healthy subjects to measure the safety, tolerability, immunogenicity, biodistribution and radiation dosimetry of [F]FB-A20FMDV2. Prior to the clinical study, pre-clinical toxicology was undertaken using FB-A20FMDV2 and a direct immunoassay was developed and validated to detect antibodies to A20FMDV2. Four healthy subjects (two males and two females) were enrolled in the study and received a single microdose of [F]FB-A20FMDV2. Subjects underwent a multibed positron emission tomography (PET) scan of the whole body (vertex to mid-thigh) over 3+ hours. Results There were no findings in the pre-clinical toxicology assessments of FB-A20FMDV2. The PET ligand was well tolerated in humans with no peptide-related clinically significant adverse events. No antiA20FMDV2 antibodies were detected before or after dosing with the PET ligand. On visual inspection of PET images, uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, ureters and bladder. Time-activity curves from the regions of interest indicated that the highest activity was observed 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 Organ Level INternal Dosimetry Assessment/EXponential Modelling software (OLINDA/EXM), the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave a standard deviation of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq. Conclusion [F]FB-A20FMDV2 caused no adverse effects in healthy subjects and has an effective dose that enables multiple scans in a single subject.