Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: Characterization of in vivo efficacy, pharmacokinetics, and safety

Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis i n a number of cancer cell lines and may have broad-spectrum activity agains t human malignancies. These studies have evaluated the potency of recombina nt soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with esta blished COLO205 tumors were given daily im. injections of Apo2L/TRAIL (30-1 20 mg/kg/day). Control tumors doubled in size every 2 to 3 days, while time to tumor doubling in the treatment groups was significantly longer and rel ated to dose (14-21 days). For pharmacokinetic studies, Apo2L/TRAIL was giv en as an i.v. bolus to mice (10 mg/kg), rats (10 mg/kg), cynomolgus monkeys (1, 5, and 50 mg/kg), and chimpanzees (1 and 5 mg/kg). Apo2L/TRAIL was rap idly eliminated from the serum of all species studied. Half-lives were simi lar to3 to 5 min in rodents and similar to 23 to 31 min in nonhuman primate s. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly low er than those used in xenograft studies could be effective in humans. Apo2L /TRAIL clearance was highly correlated with glomerular filtration rate acro ss species, indicating that the kidneys play a critical role in the elimina tion of this molecule. Safety evaluations in cynomolgus monkeys and chimpan zees revealed no abnormalities associated with Apo2L/TRAIL exposure. In con clusion, these studies have characterized the disposition of Apo2L/TRAIL in rodents and primates and provide information that will be used to predict the pharmacokinetics of Apo2L/TRAIL in humans.