Chemistry PhD Final Defense — Austin Ryan
About the event
Title:
Development of Imidazoquinoline Prodrugs for use in Targeted Immunotherapy of Various Pathologies
Abstract:
The field of immunotherapy has been historically dominated by macromolecular biologic treatments, including monoclonal antibodies, cytokines, and heat-inactivated bacteria. Recent advances in the field have indicated that small molecule immunostimulants can induce anti-cancer and anti-bacterial immunity, and several of these compounds (imiquimod, monophosphoryl lipid A) have acquired FDA approval for the treatment of various types of cancer. However, the clinical success of small molecule immunostimulants in general has been seriously hampered by adverse side-effects associated with indiscriminate immune cell stimulation and systemic inflammation. Our group has recently established a technique termed Bystander Assisted Immunotherapy (BAIT), wherein an enzyme-directed immunostimulant prodrug platform can be selectively metabolized by multi-drug resistant cancer cells to activate immunogenicity. The BAIT mechanism employs an inactive immunostimulant prodrug which is targeted to a pathologically relevant enzyme. Hydrolysis of the prodrug directing group by the enzyme target leads to formation of an active immunostimulant which is then effluxed to the extracellular space where it can engage with nearby immune cells to induce an immune response local to the pathogen. This dissertation expands upon the framework of BAIT by exploring the impact of several parameters including enzyme-directing group, immunostimulant payload, and target cell type. Specifically, we report the development of prodrugs of resiquimod and imiquimod – members of the imidazoquinoline class of toll-like receptor agonists – that are targeted to various hydrolases that are upregulated by cancer cells, β-lactamases that are uniquely expressed in drug-resistant bacteria, and avidin which we have used as a model protein target for our proof-of-concept Ligand-Directed Nitrophenol Carbonate (LDNPC) affinity labeling and drug delivery platform. We envision that these developments will propel our BAIT technology toward in vivo application, with the hope that this drug delivery technique may enhance the safety and efficacy of future small molecule immunotherapies.