Why Some Therapeutic Proteins Defy Production in CHO Cells—New Study Reveals

A new study has uncovered why some therapeutic proteins are harder to produce in Chinese hamster ovary (CHO) cells than others. Published in the Proceedings of the National Academy of Sciences, the research combines machine learning with a decade of biological mapping to explain variations in protein yield.

The findings could help improve protein design and cell engineering in drug manufacturing.

The project began around 15 years ago when Nathan Lewis, PhD, first investigated CHO-cell metabolism. Over time, the work expanded into a global effort, involving genome sequencing, metabolic modelling, and detailed mapping of CHO biology.

Using machine learning, researchers identified key protein traits linked to successful expression. These included amino-acid compositions, post-translational modifications, and physicochemical features like size and cysteine content. Together, these factors accounted for roughly 15% of the differences in protein yield.

However, the study revealed that the biggest influence came from the cells themselves. High-performing CHO cells showed greater resistance to oxidative stress and more active lipid metabolism. In contrast, poorly performing cells triggered stress responses, such as endoplasmic-reticulum-associated degradation. Surprisingly, the amount of transgene mRNA explained less than 1% of the variation in yield.

Looking ahead, the team plans to explore how metabolic 'switches'—especially those tied to lipid processing—could be adjusted to boost production efficiency.

The research provides clear insights into what makes some proteins easier to manufacture in CHO cells. By focusing on cell metabolism and protein traits, the pharmaceutical industry may now refine both protein design and cell-line engineering.

Further studies will test whether tuning specific metabolic pathways can lead to higher yields in drug production.