Moffat Graeme J, Retter Marc W, Kwon Gayle, Loomis Mark, Hock M Benjamin, Hall Colin, Bussiere Jeanine, Lewis Elise M, Chellman Gary J
Amgen, Inc, Seattle, Washington.
Birth Defects Res B Dev Reprod Toxicol. 2014 Apr;101(2):178-88. doi: 10.1002/bdrb.21105.
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.
了解单克隆抗体胎盘转运的物种差异对于指导非临床安全性评估的物种选择、解释这些研究中观察到的胚胎 - 胎儿变化以及推断它们与人类的相关性非常重要。此处给出的关于一种全人源免疫球蛋白G2单克隆抗体（IgG2X）的数据显示，在器官形成期，食蟹猴（妊娠第35天[gd35]）和大鼠（gd10）中IgG2X的胎盘转运程度（约为母体血浆浓度的0.5%，MPC）与已发表的关于内源性IgG的有限人类数据相似。在这个妊娠早期阶段，IgG2X在兔（gd10）中的胎盘转运比上述物种约高6倍。到器官形成期末，大鼠胚胎血浆浓度（gd16）比食蟹猴（gd50）中的浓度高出约3倍。这些数据表明，相对于食蟹猴，兔（以及程度稍轻的大鼠）可能会高估在这个关键发育时期对人类胚胎的潜在有害影响。在器官形成期之后，食蟹猴在妊娠中期早期（gd50 - 70）胎儿IgG2X血浆浓度增加了约10倍，此后保持相对稳定（约为5% MPC）。由于免疫原性，兔无法进行妊娠晚期评估，但在大鼠中，胎儿IgG2X血浆浓度从gd16到gd21增加了超过6倍（达到约15% MPC）。在大鼠中，与ICH S6(R1)高剂量选择标准所达到的母体暴露一致，导致胚胎血浆浓度在器官形成期达到药理相关水平。此外，母体和胚胎中的剂量比例暴露表明，在人类使用的较低治疗剂量水平下不太可能出现这种情况。
