Modulating Oral Delivery and Gastrointestinal Kinetics of Recombinant Proteins via Engineered Fungi

A new modality in microbe-mediated drug delivery has recently emerged wherein genetically engineered microbes are used to locally deliver recombinant therapeutic proteins to the gastrointestinal tract. These engineered microbes are often referred to as live biotherapeutic products (LBPs). Despite advanced genetic engineering and recombinant protein expression approaches, little is known on how to control the spatiotemporal dynamics of LBPs and their secreted therapeutics within the gastrointestinal tract. To date, the fundamental pharmacokinetic analyses for microbe-mediated drug delivery systems have not been described. Here, we explore the pharmacokinetics of an engineered, model protein-secreting Saccharomyces cerevisiae, which serves as an ideal organism for the oral delivery of complex, post-translationally modified proteins. We establish three methods to modulate the pharmacokinetics of an engineered, recombinant protein-secreting fungi system: (i) altering oral dose of engineered fungi, (ii) co-administering antibiotics, and (iii) altering recombinant protein secretion titer. Our findings establish the fundamental pharmacokinetics which will be essential in controlling downstream therapeutic response for this new delivery modality.