From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
Neurol Neuroimmunol Neuroinflamm. 2021 May 27;8(4). doi: 10.1212/NXI.0000000000001011. Print 2021 Jul.
To determine whether blocking the neonatal Fc receptor (FcRn) during gestation with an anti-FcRn monoclonal antibody (mAb) reduces transfer of pathogenic maternal antibodies in utero and decreases the likelihood of maternal antibody-mediated neonatal disease in the offspring.
Using a previously established maternal-to-fetal transfer mouse model of arthrogryposis multiplex congenita (AMC), we assessed the effect of 4470, an anti-FcRn mAb, on the transfer of total human immunoglobulin G (IgG) and specific acetylcholine receptor (AChR)-antibodies from mother to fetus, as well as its effect on the prevention of neurodevelopmental abnormalities in the offspring.
Offspring of pregnant dams treated with 4470 during gestation showed a substantial reduction in total human IgG and AChR antibody levels compared with those treated with the isotype mAb control. Treatment with 4470 was also associated with a significant reduction in AMC-IgG-induced deformities (limb or spinal curve malformations) when compared with mAb control-exposed embryos and a nonsignificant increase in the percentage of fetuses showing spontaneous movements. 4470 exposure during pregnancy was not associated with changes in general parameters of maternal well-being or fetal development; indeed, male neonates showed faster weight gain and shorter time to reach developmental milestones.
FcRn blockade is a promising therapeutic strategy to prevent the occurrence of AMC and other human maternal autoantibody-related diseases in the offspring.
确定在妊娠期间使用抗 FcRn 单克隆抗体 (mAb) 阻断新生 Fc 受体 (FcRn) 是否会减少母体致病性抗体在子宫内的转移，并降低后代中由母体抗体介导的新生儿疾病的可能性。
我们利用先前建立的多发性先天性关节挛缩症（AMC）的母体向胎儿转移的小鼠模型，评估了抗 FcRn mAb 4470 对总人免疫球蛋白 G (IgG) 和特定乙酰胆碱受体 (AChR) 抗体从母体向胎儿转移的影响，以及其对预防后代神经发育异常的影响。
与用同种型 mAb 对照物治疗的怀孕母鼠的后代相比，用 4470 治疗的后代的总人 IgG 和 AChR 抗体水平显著降低。与 mAb 对照物暴露的胚胎相比，用 4470 治疗还与 AMC-IgG 诱导的畸形（肢体或脊柱曲线畸形）显著减少相关，而自发运动的胎儿比例略有增加。在妊娠期间暴露于 4470 与母体健康或胎儿发育的一般参数变化无关；事实上，雄性新生儿的体重增加更快，达到发育里程碑的时间更短。
FcRn 阻断是一种有前途的治疗策略，可预防 AMC 和其他人类母体自身抗体相关疾病在后代中的发生。
