Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway
Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway
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DOI：
10.1089/jam.2005.18.294
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发表时间：
2005-09-01
期刊：
影响因子：
--
通讯作者：
Newman, SP
中科院分区：
文献类型：
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作者：
Dumont, JA;Bitonti, AJ;Newman, SP
一种新的药物释放平台已经开发出来，它利用了一种自然产生的受体，称为新生儿Fc受体(FcRN)。该受体是免疫球蛋白Fc片段的特异性受体，在上皮细胞中表达，其功能是运输免疫球蛋白穿过这些细胞屏障。已有研究表明，FcRN在非人灵长类动物的上呼吸道和中央呼吸道均有表达，在人类中也有表达。以前在非人类灵长类动物中使用FcRN途径证实了促红细胞生成素-Fc融合分子(EpoFc)的肺递送。我们现在已经进行了一项I期临床研究，以测试使用融合到人IgG1的Fc部分的人促红细胞生成素(EPO)，FcRN途径在人类中是否发挥类似的功能。该设计是一项在健康男性志愿者中进行的三组非随机研究，将融合蛋白的剂量分别增加(3、10和30微克/公斤)，靶向中央肺区。使用10-30%的肺活量和每分钟15次呼吸的目标范围，大约70%的肺沉积剂量的雾化EpoFc被安全有效地输送到中央肺区。我们发现融合蛋白在血清中的浓度呈剂量依赖关系，在最高剂量组循环中网织红细胞明显增加，从而证明大的治疗分子可以通过FcRN介导的转运途径通过肺传递到人体，并保持生物活性。
A novel drug delivery platform has been developed that utilizes a naturally occurring receptor known as the neonatal Fc receptor (FcRn). The receptor is specific for the Fc fragment of IgG and is expressed in epithelial cells where it functions to transport immunoglobulins across these cell barriers. It has been shown that FcRn is expressed in both the upper and central airways in non-human primates as well as in humans. Pulmonary delivery of an erythropoietin-Fc fusion molecule (EpoFc) was previously demonstrated in non-human primates using this FcRn pathway. We have now conducted a phase I clinical study to test whether the FcRn pathway functioned similarly in man using human erythropoietin (Epo) fused to the Fc portion of human IgG1. The design was a three leg, non-randomized study conducted in healthy male volunteers with rising doses (3, 10, and 30 mu g/kg) of the fusion protein targeted to the central lung regions. Using a target range of 10-30% vital capacity and 15 breaths per minute, approximately 70% of the lung-deposited dose of aerosolized EpoFc was delivered safely and effectively to the central lung regions. We showed dose-dependent concentrations of the fusion protein in the serum and an increase in circulating reticulocytes was evident in the highest dose group, thus demonstrating that large therapeutic molecules can be delivered to humans via the lung, with retention of biological activity, using the FcRn-mediated transport pathway.