title: TGF-β1 monoclonal antibody: Assessment of embryo-fetal toxicity in rats and rabbits.
abstract: A humanized monoclonal antibody targeting transforming growth factor β1 (TGF-β1 mab) has been used in development for the treatment of chronic kidney disease. Embryo-fetal development studies were conducted in rats and rabbits using 30 and 25 animals per group, respectively. The TGF-β1 mab was administered subcutaneously to rats at 0, 2, or 50 mg/kg/dose on gestation days (GDs) 6, 10, and 14 and intravenously to rabbits at 0 or 3 mg/kg/dose on GDs 7, 12 to 19, and at 30 mg/kg/dose on GDs 7, 12, 14, 16, and 18. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated. There was no indication of maternal or embryo-fetal toxicity in the rat. Effects in the rabbit were limited to the fetus where the 30 mg/kg TGF-β1 mab dose produced a slight decrease in fetal weight and an increase in the incidence of retrocaval ureter and an absent and/or malpositioned kidney/ureter in two fetuses. In conclusion, TGF-β1 mab produced no adverse maternal or embryo-fetal findings in rats when administered ≤50 mg/kg on GDs 6, 10, and 14. TGF-β1 mab did not demonstrate maternal toxicity or embryo-fetal lethality at doses as high as 30 mg/kg when administered on GDs 7, 12, 14, 16, and 18 in rabbits. Fetal growth and morphology were affected only at 30 mg/kg; thus, the no observed adverse effect level was 3 mg/kg in rabbits. The margin of safety for both rats and rabbits was ≥37-fold the clinical exposure level.
authors: Lilly Research Laboratories, Corporate Center, Indianapolis, IN, USA. kgh@lilly.com.
authors: Kim G
authors: KG
authors: Hilbish
authors: Lilly Research Laboratories, Corporate Center, Indianapolis, IN, USA.
authors: Jennifer A
authors: JA
authors: Martin
authors: Lilly Research Laboratories, Corporate Center, Indianapolis, IN, USA.
authors: Anja J
authors: AJ
authors: Stauber
authors: WIL Research, Ashland, OH, USA.
authors: Tammye L
authors: TL
authors: Edwards
authors: Lilly Research Laboratories, Corporate Center, Indianapolis, IN, USA.
authors: William J
authors: WJ
authors: Breslin
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005333:Fetus / Q000187:drug effects; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D018675:Toxicity Tests; D066007:Toxicokinetics; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053773:Transforming Growth Factor beta1
keywords: developmental; rabbit; rat; toxicity; transforming growth factor