Trace metals impact various cellular functions in Chinese hamster ovary (CHO) during mAb production including lactate metabolism, energy metabolism, specific productivity, and product quality. The impact of metals on oxidative stress, apoptosis, and mAb production are well studied; however, the mechanisms behind metal-induced changes in lactate profiles and product quality are poorly understood as the role of metal ratios and metal competition during production are difficult to characterize. Understanding the route of action of metal co-factors during production and their effects on lactate consumption and post translational modifications could improve current fed-batch processes by establishing trace metals as a process control lever. This project aims to investigate these mechanisms via an integrated “-omics” approach, where cell culture samples under various metal ratio conditions are compared based on changes in cell culture performance (i.e. lactate metabolism), mRNA expression (transcriptomics), metabolite profiling (metabolomics) as well as protein expression (proteomics) and product quality profiles. The experimental design focuses on varying the levels of three metals that have known effects on mAb glycosylation and/or lactate metabolism to different degrees – zinc, copper, and manganese. Manganese is a well-known cofactor for several enzymes involves in N-linked glycosylation, while copper and zinc can modulate glycosylation and basic charge variants, respectively. Preliminary results confirm supplementation of zinc or copper alone (up to 100uM) leads to decreased peak viable cell density and increased specific productivity across three cell lines. These two metals also demonstrate the ability to delay or inhibit lactate consumption in batch cultures, and lactate phenotypes are cell-line dependent. Glycan profiles from the DoE with Zn, Mn, and Cu will be evaluated to determine the bioprocess impact of trace metal ratios and subsequent lactate profiles on product quality attributes. Then genomic, metabolomic, and proteomic analyses of metal-spiked cultures will provide the bases for functional and pathway analysis (fluxomics). Finally, all significant findings will be integrated into a multivariate data analysis model to assess the mechanisms most impacted by metal cofactors during production and hypothesize metal ratio limits that modulate both lactate metabolism and key product quality attributes in a cell-line specific manner. 

Integrated omics modeling of trace metal effects on lactate metabolism and product quality for improved bioprocess control

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.