Unlocking Affordable Biologics: VHH Antibodies in Baker’s Yeast
The production of traditional IgG monoclonal antibodies has long been hindered by their complexity. These molecules require complex and costly manufacturing processes, with estimated production costs ranging from $95 to $200 per gram. As well as contributing to issues with patient access, this high cost also prohibits the use of many monoclonal antibodies in cost-sensitive markets that require bulk product such as for topical application. Emerging bi-specific monoclonal antibodies in development face additional challenges, such as issues with product heterogeneity, further driving up production costs and complexity.
Fortunately, VHH antibodies (also known as nanobodies) present an exciting alternative. Concretely, they offer a unique route to high-quality but low-cost antibody products.
VHH antibodies are small, robust, and stable molecules with unique properties that make them highly suitable for expression from simple microbial hosts.
Their expression in Baker’s yeast (Saccharomyces cerevisiae) systems in particular offers a transformative approach to biologics production.
The eukaryotic microbe Baker’s yeast has a proven history in biopharmaceutical manufacturing, including insulin production for the past 35 years. It combines the rapid growth advantages of microbial systems like E. coli with the ability to express more complex molecules, more commonly linked with mammalian cells. This marriage of VHH antibodies and Baker’s yeast unlocks a cost-effective platform with scalable manufacturing potential. A recent collaboration between Isogenica and Phenotypeca showcases the power of this approach.
The project successfully demonstrated the potential to optimize Baker’s yeast for manufacturing a variety of VHH molecules, including both mono- and bi-specific formats. This is particularly critical for bi-specific antibodies, where bi-specific VHHs are expressed as a monogenetic product, instead of multiple chains which need to be assembled into the correct format.
In this collaborative project, supported by Innovate UK, we demonstrated effective secreted and displayed expression of mono- and bi-specific VHHs. This supported the development of Phenotypeca’s QTL Technology, which achieved a 10-20-fold increase in fully active VHH product.
Furthermore, one of the most striking results in the project was how clean the crude, unprocessed supernatants from yeast expressions were. One of the reasons that purification from mammalian systems is so costly is that the growth medium is so complex. As well as being a high material cost, separated from all the other proteins present in the growth medium using expensive affinity resins and multi-step processes. By contrast, VHHs expressed from Baker’s yeast could be isolated readily with optimized methods.
Conclusions:
This collaboration highlights the promise of VHH antibodies as a disruptive force in biologics. By leveraging the advantages of yeast expression systems, these molecules can potentially democratisze access to advanced therapies, breaking the previous barriers of cost and complexity associated with traditional monoclonal antibodies.
As the biopharmaceutical industry continues to innovate, partnerships like these pave the way for a new era of affordable and scalable biologics, ensuring that cutting-edge treatments can reach those who need them most.
“Isogenica’s vast knowledge and deep understanding of VHHs contributed greatly to the project’s success, especially in generating the high-quality data needed to demonstrate the full functionality of the VHHs we produced.” – Chris Finnis – Founder, Phenotypeca Ltd
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