ABSTRACT
BACKGROUND AND PURPOSE: The TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through activation of the death receptors, TRAIL-R1 and TRAIL-R2. Recombinant human (rh) TRAIL and the TRAIL-R1 directed monoclonal antibody mapatumumab are currently clinically evaluated as anticancer agents. The objective of this study was to develop radiopharmaceuticals targeting the TRAIL-R1, suitable for clinical use to help understand and predict clinical efficacy in patients. EXPERIMENTAL APPROACH: rhTRAIL was radioiodinated with (125) I, and conjugated mapatumumab was radiolabelled with (111) In. The radiopharmaceuticals were characterized, their in vitro stability and death receptor targeting capacities were determined and in vivo biodistribution was studied in nude mice bearing human tumour xenografts with different expression of TRAIL-R1. KEY RESULTS: Labelling efficiencies, radiochemical purity, stability and binding properties were optimized for the radioimmunoconjugates. In vivo biodistribution showed rapid renal clearance of [(125) I]rhTRAIL, with highest kidney activity at 15 min and almost no detectable activity after 4 h. Activity rapidly decreased in almost all organs, except for the xenografts. Radiolabelled mapatumumab showed blood clearance between 24 and 168 h and a reduced decrease in radioactivity in the high receptor expression xenograft. CONCLUSIONS AND IMPLICATIONS: rhTRAIL and mapatumumab can be efficiently radiolabelled. The new radiopharmaceuticals can be used clinically to study pharmacokinetics, biodistribution and tumour targeting, which could support evaluation of the native targeted agents in phase I/II trials.
