Biochemical and metabolic engineering approaches to enhance production of therapeutic proteins in animal cell cultures

Over the past two decades, recombinant protein therapeutics have altered the landscape of treatments for infectious diseases, cancer, and autoimmune diseases. Unfortunately, these biopharmaceuticals are among the most expensive of all drugs to manufacture. Furthermore, variability in host metabolic phenotypes from run-to-run can affect product yield and quality in unexpected ways. The rapid emergence of biosimilars is transforming cost competition in the biopharma industry, driving trends toward smaller, flexible single-use facilities and continuous biomanufacturing. As a result, there is a critical need to identify engineering strategies at both the process and cellular levels that can be applied to maximize the productivity of animal cell cultures used to manufacture protein therapeutics. Doing so will translate into lower drug production costs and shed light on the intermediary pathways that enable high protein expression. Identifying specific biochemical pathways that control the production rate and quality of recombinant proteins will enable a vertical advance in our ability to rationally engineer industrial host lines with high-productivity metabolic phenotypes. This review will highlight both the technical and economic drivers behind the rapidly changing landscape of cell culture research, while emphasizing several important knowledge gaps that remain to be filled.