Pharmacology and placental transfer of a human alphav integrin monoclonal antibody in rabbits.
BACKGROUND
Intetumumab is a human IgG1 anti-alphav-integrin monoclonal antibody that inhibits angiogenesis. Integrin binding and angiogenesis are important in reproduction including fertilization, implantation, and embryofetal development. These studies were designed to determine the pharmacological relevance of the rabbit for the evaluation of potential effects on embryofetal development and to evaluate the placental transfer of intetumumab in rabbits.


METHODS
In vitro pharmacology studies evaluated the binding of intetumumab to rabbit cells and the inhibition of vessel sprouting from rabbit aorta. For the evaluation of placental transfer, pregnant rabbits (8/group) were injected intravenously with intetumumab 50 or 100 mg/kg every 2 days from Gestation Day (GD)7 to GD19. Maternal sera, fetal homogenates/sera, and amniotic fluid were collected at necropsy on GD19 or GD28 for evaluation of intetumumab concentrations. Clinical condition of the dams was monitored and fetuses were screened for abnormalities.


RESULTS
Intetumumab (5-40 microg/mL) inhibited aortic cell adhesion to vitronectin and vessel sprouting from rabbit aortic rings. Immunohistochemical staining of rabbit tissues demonstrated binding of intetumumab to placenta. Administration of intetumumab to pregnant rabbits was well tolerated by the dams and the fetuses did not show major abnormalities. Fetal exposure to intetumumab relative to maternal exposure was <0.1% on GD19 and 100-130% on GD29.


CONCLUSIONS
The rabbit is a pharmacologically relevant species for evaluation of potential developmental effects of intetumumab. Intetumumab crosses the rabbit placenta during the fetal period (GD 19-28).
Martin
Pauline L
PL
Centocor Research and Development, Inc., Radnor, Pennsylvania 19087, USA. pmarti27@its.jnj.com <pmarti27@its.jnj.com>
Zhou
Zhao
Z
Van den Bulck
Kathleen
K
Kwok
Deborah
D
Powers
Gordon
G
Jiao
Qun
Q
Schantz
Allen
A
Treacy
George
G
D000653:Amniotic Fluid / Q000187:drug effects / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D039482:Integrin alpha5 / Q000276:immunology*; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange / Q000187:drug effects* / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039482:Integrin alpha5; C486839:intetumumab