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Ustekinumab: Lessons Learned from Targeting Interleukin‐12/23p40 in Immune‐Mediated Diseases
Author(s) -
Elliott Michael,
Benson Jacqueline,
Blank Marion,
Brodmerkel Carrie,
Baker Daniel,
Sharples Kristin Ruley,
Szapary Philippe
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.05070.x
Subject(s) - ustekinumab , interleukin 23 , medicine , immune system , immunology , psoriasis , context (archaeology) , interleukin 17 , biology , tumor necrosis factor alpha , adalimumab , paleontology
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.