Ontogeny of Placental FcRn Protein During Human and Animal Pregnancy to Inform Developmental Toxicity Testing

INTRODUCTION: Species differences exist in Fc domain-containing molecule transfer/biodistribution to the embryo-fetus during pregnancy. Placentation was reviewed and placental neonatal Fc receptor (FcRn) quantitation in the chorioallantoic placenta (CAP) and/or inverted yolk sac placenta (InvYSP) was investigated across species throughout gestation to further understand and inform developmental toxicity testing of Fc domain-containing molecules. METHODS: Quantitative mass spectrometry was used to quantify FcRn protein in CAP and/or InvYSP throughout gestation in mouse, rat, guinea pig, rabbit, and nonhuman primate (NHP). In human placental tissues, immunohistochemistry was used to localize FcRn distribution during each trimester. RESULTS: FcRn protein was detected and concentration increased throughout gestation in mouse, rat, guinea pig, and rabbit; with InvYSP concentration markedly higher compared with CAP at all gestational ages. In contrast, NHP FcRn protein concentration in the CAP remained constant throughout gestation. In humans, during 1st trimester, FcRn occurred in decidua, maternal endothelium, and maternal and fetal macrophages. During 2nd trimester, fetal FcRn increased in syncytiotrophoblasts and fetal chorionic vessels. FcRn expression decreased in maternal endothelium near term. CONCLUSIONS: FcRn protein was detected throughout gestation (including organogenesis) in placental tissue of all animal species. Regardless of FcRn location, these data support that Fc domain-containing molecules can access the embryo-fetus throughout gestation in all species, with the extent of transfer likely depending on FcRn concentration and size of the placenta. This information on placental FcRn ontogeny will help improve study design and translation of nonclinical developmental toxicity data to human safety assessment of Fc domain-containing molecules.