Placental Transfer of a Fully Human IgG2 Monoclonal Antibody in the Cynomolgus Monkey, Rat, and Rabbit: A Comparative Assessment from during Organogenesis to Late Gestation

Abstract

Understanding species differences in the placental transfer of monoclonal antibodies is important to inform species selection for nonclinical safety assessment, interpret embryo-fetal changes observed in these studies, and extrapolate their human relevance. Data presented here for a fully human immunoglobulin G2 monoclonal antibody (IgG2X) revealed that, during organogenesis, in both the cynomolgus monkey (gestation day 35 [gd35]) and the rat (gd10) the extent of IgG2X placental transfer (approximately 0.5% maternal plasma concentration, MPC) was similar to the limited published human data for endogenous IgG. At this early gestational stage, IgG2X placental transfer was approximately 6-fold higher in the rabbit (gd10). By the end of organogenesis, rat embryonic plasma concentrations (gd16) exceeded those in the cynomolgus monkey (gd50) by approximately 3-fold. These data suggest that relative to the cynomolgus monkey, the rabbit (and to a lesser extent the rat) may overestimate potential harmful effects to the human embryo during this critical period of development. Beyond organogenesis, fetal IgG2X plasma concentrations increased approximately 10-fold early in the second trimester (gd50-70) in the cynomolgus monkey and remained relatively unchanged thereafter (at approximately 5% MPC). Late gestational assessment was precluded in rabbits due to immunogenicity, but in rats, fetal IgG2X plasma concentrations increased more than 6-fold from gd16 to gd21 (reaching approximately 15% MPC). In rats, maternal exposure consistent with that achieved by ICH S6(R1) high-dose selection criteria resulted in embryonic plasma concentrations, reaching pharmacologically relevant levels during organogenesis. Furthermore, dose proportional exposure in both mothers and embryos indicated that this was unlikely to occur at the lower therapeutic dose levels used in humans.

CGRP, Amylin, Immunology, and Headache Medicine

“…110 Given proportional dose exposure in both mothers and embryos, pharmacologically relevant embryonic plasma levels were unlikely to occur at the lower therapeutic dose levels used in humans. 110 Given proportional dose exposure in both mothers and embryos, pharmacologically relevant embryonic plasma levels were unlikely to occur at the lower therapeutic dose levels used in humans.…”

“…110 Given proportional dose exposure in both mothers and embryos, pharmacologically relevant embryonic plasma levels were unlikely to occur at the lower therapeutic dose levels used in humans. 110,111 Lily Research Labs reported that excretion of a therapeutic-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner using a rabbit model. The rabbit appears to be an appropriate maternal-fetal model, as all IgG classes appear to cross with greater efficiency than in humans.…”

Developmental and Reproductive Toxicity Testing

“…At the time of cesarean delivery, maternal and fetal blood are typically collected for toxicokinetic/ADA analysis and comparison of the fetal-to-maternal test article concentration ratio. It is important to recognize that the transfer of large molecules (e.g., immunoglobulins [Igs]) across the placenta and relative to gestational duration seems to be comparable between humans and cynomolgus monkeys based on available data and occurs mainly during the second and third trimesters of pregnancy [43][44][45][46]. This has significant implications for this developmental toxicity study design; in the case of IgG-based mAbs, dosing only throughout the period of organogenesis (GDs 20-50) may not result in significant embryo-fetal exposure.…”

“…Placental transfer of mAbs seems to occur by receptor-mediated transcytosis via FcRn in the syncytiotrophoblast of the chorioallantoic placenta of NHPs and humans. This process seems to transfer small amounts early in pregnancy but increases throughout pregnancy, culminating in fetal IgG concentrations comparable to, or exceeding, those of the dam near the time of parturition [43][44][45][46] (Figure 25.4). The expected low placental transport of antibodies during organogenesis has been given as PART 8 SPECIAL TOXICITY TESTING WITH NHP a reason not to conduct standard EFD studies with mAbs.…”

“…The embryo-fetal effects of pregnancy loss and fetal growth deficits were considered in various species including humans. This diagram is a conceptual illustration of various characteristics of the gestational periods of rats, rabbits, monkeys (cynomolgus), and humans (Courtesy of Dr. DeSesso; modified and updated from DeSesso et al [44] based on Moffat et al [46]). The durations of the gestational periods (in days) are represented by the length of the horizontal bars.…”