Targeting the IL-23 Pathway in Inflammatory Bowel Disease

Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, maintains intestinal homeostasis but is also implicated in the pathogenesis of inflammatory bowel diseases (IBD). The IL-23 receptor (IL-23R) is a heterodimer composed of disulfide-linked p19- and p23-subunits. Humanized monoclonal antibodies selectively targeting the p19-subunit of IL-23 are poised to become prominent drugs in IBD. In this review, we discuss pharmacodynamic and pharmacokinetic properties of the currently available IL-23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL-23-specific p19-inhibitors in the treatment of IBD and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL-23p19 inhibitors in IBD.