General Background

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General Background

The biotherapeutic market continues to expand, driven by the emergence of follow-on biologics and innovators response to this. Monoclonal antibodies (mAbs) are the leading source of growth

New manufacturers face challenges to match the productivity and quality of the currently branded products, whilst process engineers involved with branded products, including novel BLAs and biosuperiors, will be challenged to enhance product quality, product consistency and process robustness

In recent times, innovation in biotherapeutic production has been focused on accelerating drugs to market – optimising all of the multiple steps required in the production process, including use of gene synthesis, generation of high-expression cell lines, development of high-throughput screening technologies, adoption and optimisation of cell media enhancement, use of large-scale transfection technologies and perfusion bioreactors.

Today, however, many CMOs are able to produce protein yields of at least 3g/L – and there are increasing reports of methods to produce yields of >20g/L. Stable pools of cells can readily be achieved within 2-3 months, with production quality clones being possible within 4-5 months. Consequently, many believe that we are already approaching the limits of improvement to current systems and in optimisation of core cell lines.

Attention has recently been shifting towards improving product quality, especially with regard to batch to batch homogeneity and in the reduction of associated immunogenicity. The importance of glycosylation is becoming well-understood, such that the analysis & purification of proteins is now of fundamental importance in biotherapeutic production. Novel tools that can perform glycan profiling efficiently and cost-effectively are highly sought after.

Manipulation of glycans – and other post-translational modifications – enables the development of biotherapeutics with improved profiles. Indeed, the next wave of biotherapeutics will be designer-drugs with tailored PTM profiles. In fact, the highest unmet need today relates to development & production of such novel drugs. Alongside this, there is a strong market need for the development of novel, proprietary cell lines that can produce these, often difficult to express, proteins, in large quantities. Such technologies are at a premium for biologic producers and innovators.

Mammalian cell lines are the most favoured approach for biotherapeutic proteins in development. CHO cells are the leading expression system of on-market biologics and will remain the predominant source for large-scale commercial production of new recombinant and glycosylated drugs due to their high viability and densities in suspension cultures, the fact that they are associated with proper protein folding and usually make correct PTMs; the glycoforms of CHO-produced IgGs are the closest to human IgGs of all cell line choices. However, they do display differences which have led to much research on development of novel cell lines which maintain the advantages of CHO, but enable scalable production of large, complex, difficult to express proteins, with engineered PTMs. Novel cell lines being utilised today now include insect, plant, moss and transgenic animals, although there is no doubt that optimised CHO-based approaches would be highly sought after by leading CMOs and biotherapeutic innovators.