(64f) Effect of Operating Parameters On the Product Quality of Monoclonal Antibody

Among biopharmaceutical drugs, monoclonal antibodies (mAbs) have evolved to the most successful protein-drugs in terms of clinical benefit delivered and revenue generated in the biopharmaceutical industry. To date, nearly 30 recombinant immunoglobulin G (IgG) antibody therapeutics have been approved to the market for the treatment of various diseases, particularly different forms of cancer. The efficacy of mAbs arises from their specificity to the target antigen and their ability to trigger immune responses by activating effector functions towards the targeted antigen. Especially the ability to elicit the immune response is critically dependent on appropriate posttranslational modifications of the antibody. For this reason, mAbs are commonly produced in mammalian cell culture. The use of mammalian cell-based production processes has significantly improved in the last years. Still, these processes remain rather sophisticated and require fundamental studies to be fully understood. In particular, the effect of various external factors on cell performance and the quality of the mAb has to be further investigated. External factors are, on the one hand, process operating parameters that can vary due to heterogeneities in the bioreactor or due to changes in the control strategy. Process operating parameters usually include dissolved oxygen levels, pH, hydrodynamic forces induced by agitation or sparging, osmolarity, dissolved CO₂ levels and temperature. On the other hand, cell performance in the bioreactor can be externally influenced by differences in the composition of the nutrient media. This involves different starting concentrations of the basic metabolites glucose and glutamine and all other proteinogenic amino acids.

Here we investigate, on the one hand, how external factors induce changes in cell metabolism that can for example result in the accumulation of waste metabolites, and how external parameters affect the productivity of cells. On the other hand, we aim to understand the effect of external factors on product quality attributes such as glycosylation, aggregation, C-terminal lysine truncation and deamidation, which can affect the pharmacokinetics of the antibody. Finally, the gained knowledge is used in the development of a multi-scale metabolic model that is able to describe the effect of external factors on cell growth kinetics, metabolism and on cell productivity.