Discovery and Characterization of Novel, Oral Peptide Antagonists of Human IL-23 Receptor That Are Efficacious in a Rat Model of IBD

Genome-wide association studies have demonstrated significant association of the IL-23 receptor (IL-23R) gene with inflammatory bowel disease (IBD) suggesting that perturbation of IL-23 signaling could be relevant to the pathogenesis of the disease.  Here, we propose to modulate the IL-23 pathway through selective antagonism of IL-23R by oral treatment with peptides that are stable and restricted to the gastrointestinal (GI) tissue.  Using a combination of medicinal chemistry and phage display, we have identified inhibitory peptides that are uniquely resistant to oxidative/reductive conditions and proteolytic degradation in a variety of assays that mimic the various compartments of the GI environment.  Functionally, these peptides potently neutralize IL-23 mediated signaling in a transformed human cell line and in human primary cells.  The binding for IL-23R is selective since they do not antagonize the IL-12 signaling pathway.  Furthermore, we have shown that these orally delivered peptides are efficacious in attenuating colitis in a DSS induced acute rat model of IBD as shown by a significant reduction in the disease activity index score, ratio of colon weight to length and colon macroscopic score.  Overall, these data support the therapeutic potential of GI restricted IL-23R antagonists for the treatment of IBD.