Search

BACKGROUND:Insulinlike growth factor IGF signaling has been linked to tumor cell survival and tumorigenesis. The antiIGF1 receptor monoclonal antibody, figitumumab, has been developed as an anticancer therapeutic. As part of the safety evaluation, an embryofetal developmental toxicity study was conducted in the cynomolgus monkey. METHODS:Figitumumab was administered once weekly intravenously at a dose of 5, 15, or 100 mgkg during the period of major organogenesis gestation days GD 20–48 with scheduled cesarean section around GD100. Maternal endpoints included clinical observations, food consumption, body weights, hematology, placental weights, toxicokinetics, and immunogenicity. Fetal evaluations included viability; body weights; external, visceral, and skeletal examination and measurements; drug exposure; and immunogenicity. RESULTS:There was a dosedependent increase in embryofetal loss in the presence of decreased maternal food consumption and slight reduction in body weight. Figitumumabrelated embryofetal developmental toxicity was observed as growth retardation exhibited by reduced fetal body weights at all doses with corresponding developmental delays in morphology. Treatmentrelated fetal structural malformations were also observed in the mid and highdose groups. CONCLUSIONS:Maternal figitumumab dosing only during the period of organogenesis was associated with pregnancy loss and fetal growth deficits; both considered consistent with inhibition of IGF signaling. Fetal malformations were also observed, and were considered secondary to altered placental function andor reduced fetal growth; however, direct inhibition of IGF signaling in the conceptus cannot be ruled out. This appears to be the first report of treatmentrelated fetal anomalies with a monoclonal antibody when administered only during the period of major organogenesis. Birth Defects Res Part B89:326–338, 2010.© 2010 WileyLiss, Inc.