Public Funding for Hothouse Therapeutics Limited

Adjuvants are a critical component of many vaccines, providing an essential stimulus to the immune system that enables the body to mount a protective response to a vaccine antigen. The vaccine industry currently has access to only a limited range of useful adjuvants, leading to a significant unmet need for new adjuvant modalities. The bark of wild Chilean _Quillaja_ (soapbark) trees is currently the only source of a highly potent saponin adjuvant, QS21, that is used in 4 marketed vaccines and is in development with several more. Interestingly, the _Quillaja_ tree makes over 200 closely related saponins, including the related QS7 that is both more potent as an adjuvant and less toxic, but is present in such low amounts that its extraction is not commercially viable. A sustainable supply of QS7 or other molecules with similar properties would be of considerable interest to vaccine development companies. We have identified and cloned the entire biosynthetic pathways that make QS21 and QS7 and intend to deploy certain of those genes (alongside genes from other species) to demonstrate bioproduction of novel adjuvant molecules via transformation of the pathways into a heterologous host plant. We further intend to manipulate the biosynthetic pathways to achieve variant molecules that will have improved properties (increased potency, reduced toxicity or both) using proprietary machine learning and AI-based predictive algorithms to direct changes to the pathway and consequently to the chemical structure produced. Finally, we intend to explore potential routes to the large scale production of such molecules through manipulation of the biosynthetic pathways of certain plant species, that naturally make very similar molecules in high amounts, directing their saponin synthesis machinery toward the production of adjuvants. If successful, the outcomes of this project will be a suite of new adjuvant molecules and a viable route to sustainable methods of bio-production. Of significant note, the processes and methods validated by this project will be directly applicable to the production and development of other promising bioactive molecules that could lead to new drug modalities in multiple areas of application including oncology, immunomodulation and several orphan diseases.