32: M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex-vivo placental perfusion model

Abstract

M281 is an anti-FcRn antibody which demonstrated IgG lowering in a phase I study in normal human subjects. The neonatal Fc receptor (FcRn) is required for transplacental IgG transfer and helps maintain serum IgG half-life. Inhibition of FcRn in severe alloimmune or autoimmune diseases of the fetus and neonate should inhibit pathogenic IgG transfer and improve fetal/neonatal outcomes. This ex vivo study evaluated M281’s ability to inhibit transplacental IgG transfer and tested M281’s potential for maternal to fetal transfer across the human placenta. Using the technique of dual perfusion of term human placental lobule, normal placentas were transfused with varying concentrations of M281 (0, 0.01, 0.3, 3 mg/ml) or adalimumab (270 μg/ml), a representative IgG, in the maternal reservoir to determine M281 blockade of maternal to fetal (M→F) transfer up to 6 hrs. To further investigate the M281 M→F transfer, studies were conducted with addition of M281 alone (0.3-20 mg/mL) in the maternal reservoir. Samples from maternal and fetal circuits were collected at time intervals to determine the concentrations of adalimumab and M281 in the perfusion medium using a sandwich ELISA and MSD method, respectively. Antipyrine (AP 100 μg/ml) was added as a marker compound to account for inter-placental variations. The M→F transfer rates (TRf, %) were calculated from the ratio of the concentration of the test substance in the fetal perfusate at the end of the experiment/concentration of the test substance in the maternal perfusate at the start of the experiment. The (M→F) transfer rate of AP was >40% in all experiments, indicating high perfusion overlap between the maternal and fetal circuits. Under these experimental conditions, the average TRf of M281 was 0.002 ± 0.002% (n=14), suggesting insignificant transfer of M281 across the placenta. The average TRf of adalimumab was 0.23 ± 0.21% (range 0.03 – 0.65%, n=8), which was decreased significantly in the presence of M281 to 0.06 ± 0.01%, p<0.01 (range 0.05 to 0.08%, n=5). This decrease was further observed to be independent of M281 concentration. Transfer of M281 across human placenta to the fetal circuit is minimal. M281 significantly decreased the transfer of adalimumab from maternal to fetal circuit. These findings support evaluation of M281 as a potential therapeutic agent for fetal and neonatal diseases caused by transplacental transfer of allo/auto-immune pathogenic IgG antibodies.