An Epigenetic Understanding of Transcriptional Regulation in Chinese Hamster Ovary Cells

Suny At Albany, Albany NY

Investigators

Abstract

This NSF award by the Biotechnology, Biochemical and Biomass Engineering program supports work to characterize cell lines producing recombinant monoclonal antibodies with an objective of identifying the characteristics of high productivity cell lines. Monoclonal antibodies represent a significant fraction of the recently approved and pipeline biopharmaceuticals, providing critical new therapies for diseases such as breast cancer and rheumatoid arthritis. However, cell-line development currently requires screening hundreds to thousands of clones to identify cell lines exhibiting high levels of specific productivity and rapid growth rates, limiting the rate at which compounds can be brought into clinical trials and ultimately, to market. The ability to improve productivity from a rational approach will improve the rates of bioprocess development, which will, in turn, improve human health by allowing novel biopharmaceutical products to reach the market more quickly and inexpensively. The intellectual merit of this proposal is to analyze the epigenetic differences (heritable traits that do not involve changes in the DNA sequence) between highly productive cell lines and culture conditions and lower productivity systems to understand regulation of transcription. Specifically, we will compare (i) parental cell clones and their methotrexate-amplified progeny, to identify epigenetic changes that occur upon gene amplification; (ii) cell clones arising from independent transfection events, to identify the interactions between transgene localization and epigenetic modifications, and (iii) butyrate-treated and untreated cell clones, to identify the epigenetic changes that occur upon treatment with a histone-deacetylase inhibitor known to increase specific productivity. The broader impacts of the proposed work are (i) to provide fundamental knowledge to the biotechnology and biopharmaceutical industry thus speeding bioprocess development, which will, in turn, have a significant impact on human health by allowing novel biopharmaceutical products to reach the market more quickly and inexpensively; (ii) to train graduate and undergraduate students, with a particular emphasis on undergraduates from historically minority institutions, in mammalian cell bioprocessing, meeting a critical need in the biotechnology/biopharmaceutical industry; (iii) to incorporate the results of the proposed work into instructional materials for undergraduate and graduate courses including a new graduate course at the Biomanufacturing Training and Education Center at NC State; (iv) to continue outreach activities, particularly focusing on recruiting young women into scientific careers.