Expanding the Therapeutic Capacity of Engineered Commensal Microbes

One of the great challenges in the development of biotherapeutics is the high cost associated with these drugs, both in terms of manufacturing cost and the patient’s cost for treatment. Dosing regimens requiring repeated administration, trips to a healthcare provider, and large amounts of formulated therapeutic, are a significant driver of these costs. The goal of our research is to leverage the inherent capabilities of the diverse microbial community of the human gut to reduce these costs by acting as therapeutic factories in situ. Recent developments in microbial genetics, synthetic biology, and the study of niche-optimized, non-pathogenic members of the human gut microbiota have paved the way for the engineering of commensal bacteria to carry out novel functions. Using species-specific genetic components, therapeutic production can be achieved in both transiently and persistently colonizing members of the gut microbiota. While these engineered strains can be used to treat conditions localized to the gastrointestinal tract, we are currently utilizing a protein engineering approach to expand the potential applications of engineered microbes to systemic conditions. We have fused small (15 amino acid) peptides that mimic the neonatal Fc receptor (FcRn)-binding epitopes of IgG and albumin to single-chain Fv antibody fragments. These modifications enable pH-dependent FcRn engagement and FcRn-mediated salvage or transport across polarized epithelial cell barriers, functionally mimicking the native FcRn-mediated half-life extension and transport of IgG and albumin. This work demonstrates the potential utility of peptide-modified scFvs either as purified therapeutics or as part of an in situ engineered microbial delivery system.