Abstract
The effects of treatment with a soluble IL-4 receptor (sIL-4R) on reproduction and neonatal development were assessed in pregnant cynomolgus monkeys and mice. When pregnant cynomolgus monkeys were administered a human sIL-4R intravenously twice a week during organogenesis (GD 20–51) at 0, 0.2 or 2.0 mg/kg, there was an increase in abortion/embryo–fetal death in the 0.2 (42.9%) and 2.0 (26.3%) mg/kg groups compared to controls (17.6%). All fetuses removed at cesarean sectioning on GD 100–102 were alive and no abnormalities were noted. There were three stillborn neonates (2.0 mg/kg group), which were determined to have died before birth. No neonates died after birth and no abnormalities were noted. Due to the unanticipated results in the monkey study, a mouse developmental study with a murine surrogate molecule was conducted. When pregnant Crl:CD-1 ®(ICR)BR mice were administered murine sIL-4R intravenously once daily during the organogenesis period (GD 6–15) at 0, 25, 75, 250, or 625 μg/mouse (∼20 mg/kg), there were no test-article-related abnormalities in any parameters. Antibody development to the drug did not influence toxicity in the monkey or mouse. In conclusion, evaluation of reproductive effects in mice administered murine soluble IL-4R was not predictive of reproductive effects noted in cynomolgus monkeys administered human soluble IL-4R.
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