Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease

Abstract

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

Keywords: IL-12/23 p40 subunit; IL-23 p19 subunit; JAK inhibitors; JAK/STAT signaling; anti-IL12/23 biologics; inflammatory bowel disease; proteolysis targeting chimera (PROTAC).

Figure 1

Mucosal injury and bowel inflammation. The intestinal epithelium is disrupted in IBD, thereby permitting more microbiota to cross the barrier, activating macrophages and antigen-presenting cells (APCs). Activated macrophages engulf the microbiota and produce increased levels of interleukin-23 and interleukin-12, resulting in the polarization of Th1 cells and Th17 cells, which produce proinflammatory cytokines such as IFN-γ, IL-17A, IL-17F and IL-22. After contact with an antigen, antigen-presenting cells (APCs), such as dendritic cells, present antigen to naive T cells, which proliferate and differentiate into effector T-cell subsets, such as Th1 cells and Th17 cells. Additionally, ILCs contribute to cytokine production and inflammation. IL-12 and IL-23 are heterodimeric cytokines that share an IL-12p40 subunit. IL-12p35 binds to its receptor IL-12Rβ2, and IL-23p19 binds to IL-23R, leading to structural alterations that facilitate high-affinity association of the IL-12p40 subunit with the IL-12Rβ1 chain. Thus, JAK2 and TYK2 are activated, triggering the phosphorylation and homodimerization of STATs, which translocate into the nucleus and activate distinct transcriptional programs. Treatment strategies in various phases of clinical development are shown in pink boxes. The monoclonal antibody ustekinumab can bind to the IL-12p40 subunit, interfering with both IL-12 and IL-23 signaling. In addition, several antibodies, including risankizumab, brazikumab, mirikizumab and guselkumab, recognize the IL-23p19 subunit and are being evaluated in clinical trials in patients with Crohn’s disease or ulcerative colitis. Moreover, JAK inhibitors such as tofacitinib, peficitinib, upadacitinib and decucravacitinib are also good options for IBD treatment.