Gastroenterology. 2025 Jan;168(1):29-52.e3. doi: 10.1053/j.gastro.2024.05.036.Epub 2024 Jun 28.

Arno R Bourgonje ¹, Ryan C Ungaro ², Saurabh Mehandru ¹, Jean-Frédéric Colombel ³

Author information

¹The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

²The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

³The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: jean-frederic.colombel@mssm.edu.

Abstract

Interleukin (IL) 23, a member of the IL12 family of cytokines, maintains intestinal homeostasis, but is also implicated in the pathogenesis of inflammatory bowel diseases (IBDs). IL23 is a heterodimer composed of disulfide-linked p19 and p40 subunits. Humanized monoclonal antibodies selectively targeting the p19 subunit of IL23 are poised to become prominent drugs in IBDs. In this review, we discuss the pharmacodynamic and pharmacokinetic properties of the currently available IL23p19 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 IL23p19 inhibitors in the treatment of IBDs 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 IL23p19 inhibitors in IBD.