Momenta Pharmaceuticals, Cambridge, MA.
Maternal-Fetal Pharmacology and Bio-Development Laboratories, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
Am J Obstet Gynecol. 2019 May;220(5):498.e1-498.e9. doi: 10.1016/j.ajog.2019.02.058. Epub 2019 Mar 5.
The transfer of pathogenic immunoglobulin G antibodies from mother to fetus is a critical step in the pathophysiology of alloimmune and autoimmune diseases of the fetus and neonate. Immunoglobulin G transfer across the human placenta to the fetus is mediated by the neonatal Fc receptor, and blockade of the neonatal Fc receptor may provide a therapeutic strategy to prevent or minimize pathological events associated with immune-mediated diseases of pregnancy. M281 is a fully human, aglycosylated monoclonal immunoglobulin G1 antineonatal Fc receptor antibody that has been shown to block the neonatal Fc receptor with high affinity in nonclinical studies and in a phase 1 study in healthy volunteers.
The objective of the study was to determine the transplacental transfer of M281 and its potential to inhibit transfer of immunoglobulin G from maternal to fetal circulation.
To determine the concentration of M281 required for rapid cellular uptake and complete saturation of the neonatal Fc receptor in placental trophoblasts, primary human villous trophoblasts were incubated with various concentrations of M281 in a receptor occupancy assay. The placental transfer of M281, immunoglobulin G, and immunoglobulin G in the presence of M281 was studied using the dually perfused human placental lobule model. Immunoglobulin G transfer was established using a representative immunoglobulin G molecule, adalimumab, a human immunoglobulin G1 monoclonal antibody, at a concentration of 270 μg/mL. Inhibition of immunoglobulin G transfer by M281 was determined by cotransfusing 270 μg/mL of adalimumab with 10 μg/mL or 300 μg/mL of M281. Concentrations of adalimumab and M281 in sample aliquots from maternal and fetal circuits were analyzed using a sandwich enzyme-linked immunosorbent assay and Meso Scale Discovery assay, respectively.
In primary human villous trophoblasts, the saturation of the neonatal Fc receptor by M281 was observed within 30-60 minutes at 0.15-5.0 μg/mL, suggesting rapid blockade of neonatal Fc receptor in placental cells. The transfer rate of adalimumab (0.23% ± 0.21%) across dually perfused human placental lobule was significantly decreased by 10 μg/mL and 300 μg/mL of M281 to 0.07 ± 0.01% and 0.06 ± 0.01%, respectively. Furthermore, the transfer rate of M281 was 0.002% ± 0.02%, approximately 100-fold lower than that of adalimumab.
The significant inhibition of immunoglobulin G transfer across the human placental lobule by M281 and the minimal transfer of M281 supports the development of M281 as a novel agent for the treatment of fetal and neonatal diseases caused by transplacental transfer of alloimmune and autoimmune pathogenic immunoglobulin G antibodies.
母体致病性免疫球蛋白 G 抗体向胎儿的转移是胎儿和新生儿同种免疫和自身免疫性疾病病理生理学的关键步骤。免疫球蛋白 G 通过新生儿 Fc 受体在人体内向胎儿转移，而阻断新生儿 Fc 受体可能提供一种治疗策略，以预防或最小化与妊娠免疫性疾病相关的病理性事件。M281 是一种完全人源化、无糖基化的单克隆抗新生儿 Fc 受体 IgG1 抗体，在非临床研究和健康志愿者的 1 期研究中已显示出与新生儿 Fc 受体高亲和力结合，从而阻断其功能。
本研究旨在确定 M281 的胎盘转移及其抑制母体免疫球蛋白 G 向胎儿循环转移的潜力。
为了确定 M281 快速被细胞摄取并完全饱和胎盘滋养层中新生儿 Fc 受体所需的浓度，将各种浓度的 M281 孵育于原代人绒毛滋养层的受体占位测定中。使用双重灌流人胎盘小叶模型研究 M281、免疫球蛋白 G 和 M281 存在下的免疫球蛋白 G 转移。通过在 270μg/mL 浓度下共转染 270μg/mL 的阿达木单抗（一种人免疫球蛋白 G1 单克隆抗体），建立免疫球蛋白 G 转移模型。通过共转染 10μg/mL 或 300μg/mL 的 M281，测定 M281 对免疫球蛋白 G 转移的抑制作用。使用夹心酶联免疫吸附试验和 Meso Scale Discovery 测定法分别分析母胎循环样本等分试样中的阿达木单抗和 M281 的浓度。
在原代人绒毛滋养层中，在 0.15-5.0μg/mL 范围内，M281 于 30-60 分钟内即可观察到对新生儿 Fc 受体的饱和，提示 M281 可快速阻断胎盘细胞中的新生儿 Fc 受体。与 270μg/mL 的阿达木单抗相比，10μg/mL 和 300μg/mL 的 M281 使双重灌流人胎盘小叶的阿达木单抗转移率分别显著下降至 0.07±0.01%和 0.06±0.01%。此外，M281 的转移率为 0.002%±0.02%，约为阿达木单抗的 100 倍。
M281 显著抑制了人胎盘小叶中的免疫球蛋白 G 转移，并且 M281 的转移量极小，支持将 M281 开发为一种新型药物，用于治疗由同种免疫和自身免疫性致病性免疫球蛋白 G 抗体经胎盘转移引起的胎儿和新生儿疾病。
