Optimization of small molecule immunomodulators as combination therapy for IBD - PROJECT SUMMARY/ABSTRACT: Despite the availability of current biologics, such as anti-tumor necrosis factor (anti-TNF), anti-integrins, anti-interleukins, and small molecules such as tofacitinib, the rates of primary and secondary treatment failure remain high in inflammatory bowel disease (IBD). This highlights the unmet need for the identification of rational combinations of therapies for IBD with complementary mechanisms of action. Dual targeting of cluster of differentiation 28 (CD28) and inducible T cell costimulation (ICOS), closely related costimulatory molecules that play partially overlapping roles in the pathogenesis of IBD, has revealed remarkable success as a potential therapeutic strategy for IBD as well as other inflammatory diseases. However, dual CD28/ICOS blockade is currently restricted to protein-based therapeutics associated with unwanted immunogenicity and an increased risk of adverse events (AEs). In comparison to therapeutic proteins, small molecules will minimize the immunogenicity risk and enable better management of AEs based on their amenability for pharmacokinetic optimization. However, there are no small molecules in existence that target ICOS or CD28. To fill this gap, we have developed an innovative platform, Small Molecules from Antibody Pharmacophores (SMAPs), that can identify small molecule inhibitors of immune cell receptors with high binding affinity and selectivity. Our SMAPs platform is based on utilizing cocrystal structures of immune cell receptors with antibodies (Abs) in building pharmacophore maps from clusters of key interacting residues of Abs with immune cell receptors to identify small molecules that function as Ab-mimetics. Building on our successful work in drugging immune cell receptors with small molecule inhibitors, we propose to perform preclinical validation of small molecule-based dual CD28/ICOS inhibition as a therapeutic strategy for IBD based on small molecule CD28 and ICOS inhibitors identified from the SMAPs platform. We hypothesize that small molecule-based dual CD28/ICOS inhibition will result in improved therapeutic outcomes in preclinical models of IBD in comparison to single- targeted CD28 and ICOS small molecules. We will test our hypothesis and attain our objective via the following specific aims: (1) optimization of small molecule CD28 inhibitors, followed by validation using biophysical screening and cell-based assays, (2) assessment of the pharmacokinetic profiles of the optimized CD28 leads, followed by preclinical validation of small molecule-based dual CD28/ICOS blockade using clinical samples from IBD patients as well as a mouse T cell transfer model of chronic colitis. Collectively, the proposed investigations have the potential to identify clinically translatable CD28 inhibitors that can be used in combination therapy for IBD with small molecule ICOS inhibitors. Successful completion of this work will enable the initiation of Investigational New Drug (IND)-enabling studies for the optimized therapeutic leads.
