The potential of recombinant proteins to transform industries such as therapeutics, nutraceuticals and cosmetics is well-known due to the many functions that proteins play in biology. But the technical challenges of commercial scaling can be underestimated or seen by key decision makers as too risky. This deters strategic investment and leaves recombinant protein possibilities under-explored.
These long-held perceptions of risk and what is technically possible have unfortunately prevented a number of products that can improve customer health and wellbeing from seeing the light of day. Even when transformative technologies come along that substantially lower the risk profile of recombinant protein manufacture, decision makers and investors’ attitudes can be slow to change – until success in the marketplace tells them otherwise.
Inaccurate risk assessments are still causing substantial commercial opportunities to be missed.
The challenges of scale
Scaling recombinant protein manufacture often requires substantial capital expenditure long before revenue starts to flow from sale of the product. For example, fermentation vessels may need to be large scale to serve a bigger market if the titre of manufacturing is low. Even when headline titre is high, net yield post-processing can suffer if a series of successive downstream processing columns are needed.
Estimated cost of goods also impacts on decisions about whether to scale or not. When gross margins are seen as too low, or the product is assessed as uncompetitive in a price-sensitive market, decision makers may decide that their minimum requirements for a return on investment are not being met.
Technical complexity is another blocker. Sometimes the difficulties of manufacturing a particular protein or peptide at commercial scale are too much of a risk to consistency of quality. This can act as a barrier to entry that incumbent manufacturers of an existing product benefit from, especially when they have secret know-how tied up in their manufacturing processes.
Existing solutions only work selectively
Not all proteins and peptides can be manufactured at scale using conventional methodologies. For those that can, Chinese Hamster Ovary cells, E. coli, standard Saccharomyces cerevisiae and Pichia pastoris will probably deliver acceptable commercial viability, consistency of quality and a competitive advantage.
A protein like recombinant albumin, however, requires a bespoke solution that is optimised for the peculiarities of their markets. Vaccines use recombinant albumin, which is also a key consumable in the fast-growing gene and cell therapy areas of R&D. In these cases, conventional methods simply aren’t up to the job.
Patents that once protected the market dominance of a single manufacturer of recombinant albumin have now expired. But the incumbent’s know-how remains a formidable barrier to entry. That’s because conventional methods struggle to consistently secrete high quality protein at sufficient titre, while also navigating the various downstream processing and purification steps that are needed.
Multi-parameter optimisation enables tailored solutions
Fortunately, Quantitative Trait Loci (QTL) technology now exists to unlock the full power of biology by means of multi-parameter optimisation. This enables manufacturing strains to be tailored to the needs of individual products, transforming both the protein generated and the manufacturing process itself to achieve viable commercial scale and quality.
This entirely new approach to recombinant protein manufacture enables identification of the manufacturing strains relevant to the protein, leading to a detailed understanding of the regions and variations of the genome for that specific strain.
On this basis, the Phenotypeca team can deploy its expertise in breeding diverse strains to establish what biology can deliver naturally while avoiding the functional limitations and genome damage associated with mutagenesis. The dexterity of QTL technology gives us far greater scope for problem solving than conventional strain engineering, which is limited by the number of strains and genome diversity.
Using QTL technology, upstream processing can be tailored to the needs of the project, enabling the reduction of downstream processing.
Commercial opportunities for QTL technology go far beyond the market for vaccines and therapeutics. Spider silk, for example, is a super-material whose natural strength, elasticity and lightness could be used in sutures, artificial ligaments and tendons, drug delivery, wound dressings and nerve regeneration products, as well as innovative products like biodegradable fishing nets, if only the technical challenges of manufacture could be overcome. With QTL technology, production strains can be optimised even for specialised proteins such as spider silks.