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Vol. 299, Issue 1, 31-38, October 2001
Departments of Pharmacologic Sciences, Genentech, Inc., South San
Francisco, California (S.K.K., L.A.H., D.X., L.D., K.T., J.A.F.); and
Department of Toxicology, Immunex Corp., Seattle, Washington (J.B.)
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.
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C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone Reply Clin. Cancer Res., February 1, 2003; 9(2): 913 - 914. [Full Text] [PDF]
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