Embryo-fetal developmental toxicity of figitumumab, an anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody, in cynomolgus monkeys.
BACKGROUND
Insulin-like growth factor (IGF) signaling has been linked to tumor cell survival and tumorigenesis. The anti-IGF-1 receptor monoclonal antibody, figitumumab, has been developed as an anti-cancer therapeutic. As part of the safety evaluation, an embryo-fetal developmental toxicity study was conducted in the cynomolgus monkey.


METHODS
Figitumumab was administered once weekly intravenously at a dose of 5, 15, or 100 mg/kg 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 dose-dependent increase in embryo-fetal loss in the presence of decreased maternal food consumption and slight reduction in body weight. Figitumumab-related embryo-fetal developmental toxicity was observed as growth retardation exhibited by reduced fetal body weights at all doses with corresponding developmental delays in morphology. Treatment-related fetal structural malformations were also observed in the mid- and high-dose 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 and/or reduced fetal growth; however, direct inhibition of IGF signaling in the conceptus cannot be ruled out. This appears to be the first report of treatment-related fetal anomalies with a monoclonal antibody when administered only during the period of major organogenesis.
Bowman
Christopher J
CJ
Drug Safety Research & Development, Pfizer, Inc, Groton, Connecticut 06340, USA. christopher.j.bowman@pfizer.com
Chmielewski
Gary
G
Oneda
Satoru
S
Finco
Deborah
D
Boucher
Mary A
MA
Todd
Marque
M
D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development; D005260:Female; D047109:Fetal Development; D016756:Immunoglobulins, Intravenous; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008252:Macaca fascicularis / Q000196:embryology / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D038081:Organogenesis; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D018675:Toxicity Tests
D000911:Antibodies, Monoclonal; D016588:Anticarcinogenic Agents; D016756:Immunoglobulins, Intravenous; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C525021:figitumumab