Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer
Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer
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DOI：
10.1016/j.jri.2016.04.284
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发表时间：
2016-08-01
影响因子：
3.4
通讯作者：
Nesbitt, Andrew
中科院分区：
文献类型：
--
作者：
Porter, Charlene;Armstrong-Fisher, Sylvia;Nesbitt, Andrew
抗肿瘤坏死因子抗体（抗TNF）用于治疗炎症性疾病，这些疾病通常影响育龄妇女。这些抗体通过Fc区与新生儿Fc受体（FcRn）结合而主动转移穿过胎盘，可能导致对胎儿或新生儿的不良影响。与其他抗TNF相比，赛妥珠单抗缺乏Fc区。本研究的目的是确定certolizumab pegol的结构是否限制主动胎盘transfer.Binding亲和力certolizumab pegol，英夫利昔单抗，阿达木单抗和依那西普与人FcRn和FcRn介导的转胞吞作用进行了测定使用体外试验。离体灌注人胎盘以测量certolizumab pegol和阳性对照抗-D IgG从母体循环到胎儿循环的转移。英夫利昔单抗、阿达木单抗和依那西普的FcRn结合亲和力（K-D）分别为132 nM、225 nM和1500 nM。与阴性对照相似，未检测到赛妥珠单抗的结合亲和力。FcRn介导的跨细胞层转胞吞（平均值+/- SD; n=3）为249.6 +/- 25.0（英夫利昔单抗）、159.0 +/- 20.2（阿达木单抗）和81.3 +/- 13.1 ng/mL（依那西普）。Certolizumab pegol转胞吞作用（3.2 +/- 3.4 ng/mL）低于阴性对照抗体（5.9 +/- 4.6 ng/mL）。在离体灌注模型中证实阳性对照IgG转运的6个胎盘中，有5个未观察到certolizumab pegol从母体循环向胎儿循环的可测量转移。总之，这些结果支持以下假设：赛妥珠单抗的独特结构限制了其通过胎盘转移至胎儿，并且可能是先前报告的其他抗TNF从母体转移至胎儿的差异的原因。(C)2016作者由Elsevier爱尔兰有限公司发布。这是CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Antibodies to tumor necrosis factor (anti-TNF) are used to treat inflammatory diseases, which often affect women of childbearing age. The active transfer of these antibodies across the placenta by binding of the Fc-region to the neonatal Fc receptor (FcRn) may result in adverse fetal or neonatal effects. In contrast to other anti-TNFs, certolizumab pegol lacks an Fc-region. The objective of this study was to determine whether the structure of certolizumab pegol limits active placental transfer.Binding affinities of certolizumab pegol, infliximab, adalimumab and etanercept to human FcRn and FcRn-mediated transcytosis were determined using in vitro assays. Human placentas were perfused ex vivo to measure transfer of certolizumab pegol and positive control anti-D IgG from the maternal to fetal circulation.FcRn binding affinity (K-D) was 132 nM, 225 nM and 1500 nM for infliximab, adalimumab and etanercept, respectively. There was no measurable certolizumab pegol binding affinity, similar to that of the negative control. FcRn-mediated transcytosis across a cell layer (mean +/- SD; n=3) was 249.6 +/- 25.0 (infliximab), 159.0 +/- 20.2 (adalimumab) and 81.3 +/- 13.1 ng/mL (etanercept). Certolizumab pegol transcytosis (3.2 +/- 3.4 ng/mL) was less than the negative control antibody (5.9 +/- 4.6 ng/mL). No measurable transfer of certolizumab pegol from the maternal to the fetal circulation was observed in 5 out of 6 placentas that demonstrated positive-control IgG transport in the ex vivo perfusion model. Together these results support the hypothesis that the unique structure of certolizumab pegol limits its transfer through the placenta to the fetus and may be responsible for previously reported differences in transfer of other anti-TNFs from mother to fetus. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).