The fickle CHO: a review of the causes, implications, and potential alleviation of the CHO cell line instability problem

Chinese hamster ovary (CHO) cell-based bioproduction of recombinant proteins can now routinely achieve >5 g/L titers in fed-batches. This progress is partly due to the rapid adaptability of CHO cells to various genetic manipulations and changing process conditions. An inherently plastic genome allows for this adaptability; however, it also gives CHO cells the propensity for genomic rearrangements. In combination with the genomic and metabolic demand of high producer cells, CHO cell plasticity manifests itself in the bioproduction process as cell line instability, by way of a decline in productivity and product quality. In this review, we provide a definition for titer and quality stability and discuss the main causes of the CHO instability phenomenon and advances in clone selection and genetic manipulations. We also discuss advances in systems biology efforts that can provide new strategies for early prediction of CHO cell instability, which will help to identify multi-gram per liter titer cell lines that can maintain production stability and reproducible product quality over extended culture durations.