An interspecies comparison of placental antibody transfer: New insights into developmental toxicity testing of monoclonal antibodies

Abstract

There are profound differences in maternofetal transfer of immunoglobulins between species with extensive gestational transfer of maternal immunoglobulins in primates (including humans) via the chorioallantoic placenta as well as in rabbits and guinea pigs via the inverted yolk sac splanchnopleure. In contrast, other neonatal rodents (rats and mice) receive passive immunity predominantly postnatally. This transfer is mediated principally via FcRn receptors. Therapeutic monoclonal antibodies (mAbs) are most commonly of the IgG1 subclass, which is transported most efficiently to the fetus. In all animal species used for testing developmental toxicity, fetal exposure to IgG is very low during organogenesis, but this increases during the latter half of gestation such that the neonate is born with an IgG1 concentration similar to the mother (but not rats and mice). Review of mAb developmental toxicity studies of licensed products reveals Cynomolgus monkey as the species used in the majority of the cases (10 out of 15). Pregnancy outcome data from women gestationally exposed to mAb is limited. In general, the findings are consistent with the expected low exposure during organogenesis. Guinea-pigs and rabbits are potential candidates as "alternatives" to the use of nonhuman primates as the maternofetal transfer in the last part of gestation is at a level similar in humans. Based on the pattern of placental transfer of IgG in humans, study designs that allow detection of both the indirect effects in early gestation plus the effects of direct fetal exposure in mid and late gestation are recommended for developmental toxicity of mAbs.

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

“…(iv) In contrast to many other mammalian species, mice lack expression of the neonatal Fc receptor (FcRn) on their trophoblasts in the chorioallantoic placenta (98). Instead, FcRn is expressed in the mouse yolk sac endoderm (98), and the transfer of IgG in mice occurs predominantly at the suckling stage (99). As reduced levels of transport of maternal or exogenous IgG into the fetus occur in mice, protection by a given antibody or vaccine may be underestimated.…”

Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge

“…This is further supported by the fact that, during the first trimester, there is an additional layer of cytotrophoblast, which is initially broken by week 14-16 of gestation [15]. The fetal IgG concentration starts to rise smoothly until week 18, with a sharp increase in total IgG levels observed between weeks 22 and 26 of gestation.…”

Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

“…The role of the second placental barrier, the fetal capillary endothelium, is not yet clear. The expression of FcRn is known to be relatively low on fetal vessels' endothelium, suggesting possible other mechanism(s) involved in IgG transport across this placental layer (98). The challenge of drug concentration measurements for fetal tissues limits placental transport studies.…”