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

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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.