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

人肺中 FcRn 表达的表观遗传调控及其在单克隆抗体药物处置中的作用

• 批准号: 9311548
• 负责人: Javier Guillermo Blanco
• 金额: $ 19.88万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311548
• 关键词: Adverse reactions; Anatomy; Area; Asthma; Blood Circulation; Breathing; Carcinoma; Cell Line; Cell model; Cells; Chromosomes, Human, Pair 19; Chronic Obstructive Airway Disease; Clinical Treatment; Collection; DNA Methylation; Data; Development; Disease; Dose; Drug Kinetics; Endothelium; Epigenetic Process; Epithelial; Europe; Frequencies; Gene Expression; Gene Proteins; Goals; Hematopoietic; Human; Humira; In Vitro; Innovative Therapy; Knowledge; Lead; Lung; Lung diseases; Messenger RNA; MicroRNAs; Modality; Molecular; Monoclonal Antibodies; Neonatal; Organ; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Process; Property; Proteins; Regulation; Research; Rheumatoid Arthritis; Role; Route; Sales; Sampling; Serum; Site; Structure of parenchyma of lung; Therapeutic; Therapeutic Monoclonal Antibodies; Tissue Sample; Tissues; Trastuzumab; Treatment Efficacy; Work; adalimumab; alveolar epithelium; bronchial epithelium; design; epigenetic drug; epigenetic regulation; human disease; improved; in vitro Model; inhibitor/antagonist; innovation; insight; mRNA Expression; malignant breast neoplasm; neonatal Fc receptor; non-smoking; novel; novel therapeutics; protein expression; receptor; trafficking

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.

项目总结 Herceptin(曲妥珠单抗)和Humira等单抗药物的研究进展 (Adalimumab)彻底改变了各种疾病的临床治疗方法，包括乳腺癌和 类风湿关节炎。在美国和欧洲市场上有47种单抗，预计 到2020年，市场上将有超过70种单抗。新生儿受体FcRN，它调节 治疗性单抗的血清持久性和细胞内转运对药物动力学和 治疗性单抗的药效学。FcRN由FCGRT基因(19号染色体)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。 这种关于FCGRT表达调控的知识缺口阻碍了对受体全部 利用单抗开发创新疗法的潜力。这种知识鸿沟之所以重要，是因为 FCGRT基因表达是一类新的单抗药理学特性的关键，这种单抗可以 通过吸入途径治疗肺部疾病，如癌症、哮喘和慢性 阻塞性肺病。本项目的重点是系统地鉴定和表征 人肺组织中FCGRT基因表达的表观遗传调控的特殊因素。令人兴奋 初步数据表明，特定的microRNAs(MiRNAs)和DNA甲基化控制着 FCGRT。目标1的研究将确定候选miRNAs调节FCGRT表达和 FcRN在体外模型的支气管上皮、肺内皮细胞和肺泡上皮细胞中的作用。这个 肺组织FCGRT(mRNA和FcRN蛋白)和FcRN蛋白表达的个体间差异程度 将在来自不吸烟捐赠者的肺样本中检查受调控的miRNAs。目标2中的研究将确定 DNA甲基化状态对肺组织中FCGRT基因表达的影响网络的影响 FCGRT基因表达的DNA甲基化状态将通过执行 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 对FCGRT在肺中表达的表观遗传控制的认识 单抗药物。我们预计，从这个项目中得出的结果可以很快被纳入各种 利用吸入型单抗设计创新治疗方法的平台。