Ustekinumab: Lessons Learned from Targeting Interleukin-12/23p40 in Immune-Mediated Diseases

• Published in: Annals of the New York Academy of Sciences 2009-12, Vol.1182 (1), p.97-110
• Main Authors: Elliott, Michael, Benson, Jacqueline, Blank, Marion, Brodmerkel, Carrie, Baker, Daniel, Sharples, Kristin Ruley, Szapary, Philippe
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic - drug therapy; Arthritis, Psoriatic - immunology; Clinical Trials as Topic; Crohn Disease - drug therapy; Crohn Disease - immunology; Crohn's disease; Diseases; Disorders; Human; Humans; Interleukin; interleukin-12; Interleukin-12 - immunology; Interleukin-12 Subunit p40 - immunology; interleukin-12/23p40; interleukin-23; Mice; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Pathogenesis; psoriasis; psoriatic arthritis; Safety; Ustekinumab
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2009.05070.x

Interleukin (IL)‐12 and IL‐23 are related cytokines that have been implicated in the pathogenesis of several immune‐mediated disorders. IL‐12 and IL‐23 are heterodimers made up of a common p40 subunit complexed to unique p35 (IL‐12) or p19 (IL‐23) subunits. Ustekinumab is a human monoclonal antibody that specifically binds the p40 subunit of IL‐12/23. Ustekinumab prevents IL‐12 and IL‐23 from binding their cell surface receptor complexes, thereby blocking the T helper (Th) 1 (IL‐12) and Th17 (IL‐23) inflammatory pathways. Here, we discuss the preclinical and human translational data supporting a role for IL‐12/23 in the pathogenesis of immune‐mediated disorders, and how that rationale was challenged in the clinic during the course of the ustekinumab development program in several indications including psoriasis, psoriatic arthritis, Crohn's disease, and multiple sclerosis. We review the key efficacy and safety data in each of these immune‐mediated diseases and compare and contrast the safety lessons learned from IL‐12/23 genetically‐deficient mice and humans in context of the overall clinical trial experience with ustekinumab.