Epigenetic Regulation of FcRn Expression in Human Lung and its Role in the Disposition of Monoclonal Antibody Drugs

项目摘要 开发单克隆抗体药物（mAb），如赫赛汀（曲妥珠单抗）和修美乐 阿达木单抗（阿达木单抗）已经彻底改变了各种疾病的临床治疗，包括乳腺癌和乳腺癌。 类风湿关节炎在美国和欧洲市场上有47种mAb，预计 到2020年，市场上将有超过70种单克隆抗体。新生儿受体FcRn，它调节 治疗性mAb的血清持久性和细胞内运输对于药代动力学和 治疗性mAb的药效学。FcRn由FCGRT基因（染色体19）编码。详细 关于控制FCGRT基因在各种组织中表达的因素的信息相对较少。 关于FCGRT表达调控的知识上的这一空白阻碍了对受体的充分利用。 开发单克隆抗体创新疗法的潜力。这种知识差距很重要，因为 FCGRT基因表达是一类新型mAb药理学特征的关键， 通过吸入途径给药以治疗肺部疾病，如癌、哮喘和慢性肺疾病。 阻塞性肺病该项目的重点是系统地识别和表征 参与人肺组织FCGRT基因表达的表观遗传控制的特异性因子。激动人心 初步数据表明，特定的microRNAs（miRNAs）和DNA甲基化控制着 FCGRT。目标1中的研究将确定候选miRNAs调节FCGRT表达的能力， FcRn在支气管上皮、肺内皮和肺泡上皮的体外模型中的功能。的 FCGRT（mRNA和FcRn蛋白）肺表达的个体间变异程度， 将在来自非吸烟供体的肺样品中检查调节性miRNA。目标2中的研究将确定 DNA甲基化状态对肺组织样本中FCGRT基因表达的影响。的影响 DNA甲基化状态对FCGRT基因表达的影响将进一步通过进行 在模型细胞系中的功能研究。该提案中概述的研究承诺提供基本的 深入了解肺中FCGRT表达的表观遗传控制，肺是一类新型吸入性药物的靶器官。 mAb药物。我们预计，从这个项目得出的结果可以很快纳入各种 平台，以设计吸入单克隆抗体的创新治疗方法。

PROJECT SUMMARY The development of monoclonal antibody drugs (mAbs) such as Herceptin (Trastuzumab) and Humira (Adalimumab) has revolutionized clinical treatments for a wide variety of diseases including breast cancer and rheumatoid arthritis. There are forty-seven mAbs on the market in the U.S and Europe, and it is anticipated that there will be more than seventy mAbs on the market by 2020. The neonatal receptor FcRn, which regulates serum persistence and intracellular trafficking of therapeutic mAbs, is essential to the pharmacokinetics and pharmacodynamics of therapeutic mAbs. FcRn is encoded by the FCGRT gene (chromosome 19). Detailed information on the factors that control the expression of the FCGRT gene in various tissues is relatively scarce. This gap in knowledge regarding regulation of FCGRT expression hampers exploitation of the receptor's full potential for the development of innovative therapies with mAbs. This knowledge gap is important because FCGRT gene expression is key to the pharmacological profiles of a new class of mAbs that can be administered through the inhalation route to treat lung diseases such as carcinomas, asthma, and chronic obstructive pulmonary disease. This project is focused on the systematic identification and characterization of specific factors involved in the epigenetic control of FCGRT gene expression in human lung tissue. Exciting preliminary data indicate that specific microRNAs (miRNAs) and DNA methylation control the expression of FCGRT. Studies in Aim 1 will determine the capacity of candidate miRNAs to regulate FCGRT expression and FcRn function in in vitro models of bronchial epithelium, pulmonary endothelium, and alveolar epithelium. The extent of interindividual variability in the pulmonary expression of FCGRT (mRNA and FcRn protein) and regulatory miRNAs will be examined in lung samples from non-smoking donors. Studies in Aim 2 will determine the impact of DNA methylation status on expression of the FCGRT gene in lung tissue samples. The impact of DNA methylation status on the expression of the FCGRT gene will be further examined by performing functional studies in model cell lines. The studies outlined in this proposal promise to provide fundamental insights into the epigenetic control of FCGRT expression in lung, the target organ for a novel class of inhaled mAbs drugs. We anticipate that the findings derived from this project can be quickly incorporated into various platforms to design innovative therapeutic approaches with inhaled mAbs.