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Studies on molecular basis of the pharmacokinetic regulation of protein drugs consisting of immunoglobulin Fc region

免疫球蛋白Fc区蛋白药物药代动力学调控的分子基础研究

基本信息

批准号：
18590163
负责人：
KAWANISHI Toru
金额：
$ 2.57万
依托单位：
National Institute of Health Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590163/
关键词：
FcRn Fc domain receptor protein drugs serum half life タンパク質医薬品タンバク質体内動態

项目摘要

The neonatal Fc receptor (FcRn) is a receptor that protects IgG from catabolism and is important in maintaining high serum antibody levels. In order to elucidate the role of FcRn in pharmacokinetics of Fc domain-containing protein drugs, this study focused on (1) establishment of Surface Plasmon Resonance (SPR) analysis that can measure the affinity of Fc domain-containing protein drugs to FcRn; (2) evaluation of the affinity between FcRn and Fc domain-containing protein drugs by SPR analysis; (3) establishment of in vitro method to measure the protein recycling via FcRn; and (4) regulation of FcRn expression by inflammatory cytokines.(1) SPR analysis method using extracellular domain of FcRn as the ligand was established. (2)The affinity of Fc domain-containing protein drugs to FcRn was almost correlated with the serum half lives in humans, suggesting the importance of FcRn in regulating serum half lives of these drugs. The analytes used were human antibody (Adalimumab), humanized antibodies (Daclizumab and Omalizumab), chimeric antibody (Infliximab), and Fe-fusion proteins (Etanercept and Alefacept). (3) ELISA method to quantify the 0.1〜10ng/ml of biotinylated Infliximab was established. Concentrations of biotinylated Infliximab in culture supernatant of human umbilical vein endothelial cells (HUVECs) those were pulse-labeled with it was measured. (4) In HUVECs, FcRn expression was suppressed by TNFα, IL-1β, or IL-6. The possibility of regulating the FcRn expression level by these inflammatory cytokines was suggested.

新生儿Fc受体（FcRn）是一种保护IgG免受卡他霉素的受体，在维持高血清抗体水平方面很重要。为了阐明FcRn在含Fc结构域蛋白药物药代动力学中的作用，本研究的重点是：（1）建立表面等离子体共振（SPR）分析法，测定含Fc结构域蛋白药物与FcRn的亲和力;（2）SPR分析法评价含Fc结构域蛋白药物与FcRn的亲和力;（3）建立体外FcRn蛋白再循环检测方法;（4）炎性细胞因子对FcRn表达的调控。(1)建立了以FcRn胞外区为配体的SPR分析方法。（2）含Fc结构域蛋白药物与FcRn的亲和力与其在人体内的血清半衰期基本相关，提示FcRn在调节这些药物的血清半衰期中具有重要作用。使用的分析物是人抗体（阿达木单抗）、人源化抗体（达克珠单抗和奥马珠单抗）、嵌合抗体（英夫利昔单抗）和Fe融合蛋白（依那西普和阿法西普）。(3)建立了定量0.1 ~ 10 ng/ml生物素化英夫利昔单抗的ELISA方法。测量了用生物素化英夫利西单抗脉冲标记的人脐静脉内皮细胞（HUVEC）的培养上清液中的生物素化英夫利西单抗的浓度。(4)在HUVECs中，TNFα、IL-1β或IL-6可抑制FcRn表达。提示这些炎性细胞因子可能通过调节FcRn的表达水平而发挥作用。