Jacobsen Björn, Hill Marilyn, Reynaud Lucie, Hey Adam, Barrow Paul
Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland
Novartis Pharma AG, Basel, Switzerland.
Toxicol Pathol. 2016 Apr;44(3):486-91. doi: 10.1177/0192623315610821. Epub 2015 Oct 28.
Developmental toxicity testing of therapeutic antibodies is most often conducted in nonhuman primates owing to lack of cross-reactivity in other species. Minipigs may show cross-reactivity for some humanized antibodies but have not been used for developmental toxicity testing due to an assumed lack of embryo-fetal exposure. Unlike in humans, maternal IgGs do not cross the porcine placenta to reach the fetus. Some humanized IgGs, however, have a higher affinity for the neonatal Fc receptor (FcRn) and are more likely than endogenous antibodies to cross the placenta of animals. The major site of prenatal IgG transfer is the placenta, though FcRn in fetal intestine could also uptake maternal IgGs from swallowed amniotic fluid. Using immunohistochemistry andin situhybridization in this experiment, FcRn was found in minipig placenta and fetal intestine during early, mid-, and late gestation. To date, however, fetal exposure to maternally administered IgGs has never been demonstrated in the minipig.
由于在其他物种中缺乏交叉反应性,治疗性抗体的发育毒性测试通常在非人类灵长类动物中进行。小型猪可能对某些人源化抗体表现出交叉反应性,但由于假定缺乏胚胎 - 胎儿暴露,尚未用于发育毒性测试。与人类不同,母体IgG不会穿过猪胎盘到达胎儿。然而,一些人源化IgG对新生儿Fc受体(FcRn)具有更高的亲和力,并且比内源性抗体更有可能穿过动物的胎盘。产前IgG转移的主要部位是胎盘,尽管胎儿肠道中的FcRn也可以从吞咽的羊水中摄取母体IgG。在本实验中使用免疫组织化学和原位杂交技术,在小型猪妊娠早期、中期和晚期的胎盘和胎儿肠道中发现了FcRn。然而,迄今为止,在小型猪中从未证明胎儿暴露于母体给予的IgG。