| Embryo-fetal developmental toxicity of figitumumab, an anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody, in cynomolgus monkeys. | |
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MedLine Citation:
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PMID: 20540090 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Christopher J Bowman; Gary Chmielewski; Satoru Oneda; Deborah Finco; Mary A Boucher; Marque Todd |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Birth defects research. Part B, Developmental and reproductive toxicology Volume: 89 ISSN: 1542-9741 ISO Abbreviation: Birth Defects Res. B Dev. Reprod. Toxicol. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-30 Completed Date: 2010-12-14 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101155115 Medline TA: Birth Defects Res B Dev Reprod Toxicol Country: United States |
Other Details:
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Languages: eng Pagination: 326-38 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Wiley-Liss, Inc. |
Affiliation:
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Drug Safety Research & Development, Pfizer, Inc, Groton, Connecticut 06340, USA. christopher.j.bowman@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Abnormalities, Drug-Induced
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embryology* Animals Antibodies, Monoclonal / toxicity* Anticarcinogenic Agents / toxicity* Dose-Response Relationship, Drug Embryonic Development Female Fetal Development Insulin-Like Growth Factor I / physiology Macaca fascicularis / embryology, metabolism Maternal-Fetal Exchange Organogenesis Pregnancy Receptor, IGF Type 1 / antagonists & inhibitors* Toxicity Tests |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Anticarcinogenic Agents; 0/figitumumab; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.10.1/Receptor, IGF Type 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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