Abstract
Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis in a number of cancer cell lines and may have broad-spectrum activity against human malignancies. These studies have evaluated the potency of recombinant soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with established COLO205 tumors were given daily i.v. injections of Apo2L/TRAIL (30–120 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 related to dose (14–21 days). For pharmacokinetic studies, Apo2L/TRAIL was given 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 rapidly eliminated from the serum of all species studied. Half-lives were ∼3 to 5 min in rodents and ∼23 to 31 min in nonhuman primates. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly lower than those used in xenograft studies could be effective in humans. Apo2L/TRAIL clearance was highly correlated with glomerular filtration rate across species, indicating that the kidneys play a critical role in the elimination of this molecule. Safety evaluations in cynomolgus monkeys and chimpanzees revealed no abnormalities associated with Apo2L/TRAIL exposure. In conclusion, 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.
Footnotes
- Abbreviations:
- TNF
- tumor necrosis factor
- Apo2L/TRAIL
- tumor necrosis factor-related apoptosis-inducing ligand
- DR
- death receptor
- DcR
- decoy receptor
- OPG
- osteoprotegerin
- ELISA
- enzyme-linked immunosorbent assay
- OD
- optical density
- AUC
- area under the Apo2L/TRAIL serum concentration versus time curve
- Cmax
- model-predicted maximum serum Apo2L/TRAIL concentration
- Vss
- estimated steady-state volume of distribution
- GFR
- glomular filtration
- SBI
- Sierra Biomedical, Inc
- NIRC
- New Iberia Research Center
- Received March 15, 2001.
- Accepted June 14, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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