The potential of VHH therapies to treat chronic diseases has been thwarted by the risks, costs and long timelines associated with switching between different expression platforms on the journey from discovery to manufacture. Fortunately a new technology using Saccharomyces cerevisiae (baker’s yeast) enables the same production strain to be used for both discovery and large-scale commercial manufacture in a rapid and seamless process that is also more regulatory-friendly.
VHH therapies for chronic disease are thwarted by old approaches
VHH are Single-Domain Antibodies (sdAbs) comprising the antigen-binding portion of these heavy chain-only antibodies. They are the smallest naturally occurring functional units of an antibody. Their small size and high stability give them major advantages as therapeutic proteins. Compared to conventional large monoclonal antibodies with heavy chains and light chains, VHHs penetrate dense tissues much more effectively and can be combined to bind multiple targets with high affinity and specificity.
This makes VHHs well suited for treating chronic diseases in ageing populations. However, most development programs have stuck with traditional monoclonal antibodies due to concerns about the existing approach to VHH, where discovery is generally undertaken using E. coli followed by a switch to Chinese Hamster Ovaries (CHO) during the manufacturing phase.
E. coli is a prokaryotic bacteria that is useful during the phage-display of VHH antibodies for discovery and maturation, but it produces endotoxins that can trigger strong immune responses in humans and animals, interfering with the immunological testing of antibody therapeutics in vitro. Regulatory concerns around these issues motivate the switch to CHO during manufacturing, which can be costly, slow and also presents technical risks to the success of the end-product. Delays are often exacerbated by limited CHO manufacturing capacity.
Baker’s yeast offers a safer, faster and more affordable way
Fortunately, VHHs can now be more easily manufactured in Saccharomyces cerevisiae (baker’s yeast) following a breakthrough in Quantitative Trait Loci (QTL) technology. This combines the power of evolution using strain breeding with functional genomics in an iterative process to generate the optimum strains for any given project.
Baker’s yeast completely lacks the toxic endotoxins of E. coli, so the batches for discovery, pre-clinical and clinical requirements can be created safely, quickly and affordably. VHH antibody libraries can be displayed on the surface of the yeast cells, allowing the same production strain to be used for both discovery and large-scale commercial manufacture.
Whether a yeast strain is able to secrete the relevant VHH can be established quickly. This avoids wasting time, money and resources on developing a manufacturing process that might not deliver the desired result while also providing a reliable source of promising antibody candidates for pre-clinical testing. Thereafter the strain optimisation work can continue in parallel to the discovery and pre-clinical testing to dramatically shorten timeframes. This can result in a manufacturing strain optimised for commercial activity being ready for the beginning of clinical development. These strains can then produce clinical testing batches, avoiding further delay and expense.
Baker’s yeast is well-established and regulatory-friendly, which smoothes the way for clinical development, regulatory application and subsequent commercial manufacture, partly because the same host is used for both discovery and manufacturing.
Affordable VHH discovery empowers precious research
Biotechnology is expected to make big advances in the treatment of chronic diseases and the promotion of healthy ageing over the coming years. Because these treatments are likely to require innovative and complex mechanisms of action for efficacy, VHHs have a distinct advantage over traditional monoclonal antibodies in that they can be tailor-designed for multiple targets. With QTL technology, VHHs now have a fast and affordable means of creating a commercially scalable manufacturing process to turn that promise into reality. By making VHH discovery work more affordable, QTL also promises to broaden the search for efficacy against highly complex diseases, with far-reaching consequences for the future of biological therapeutics.
