title: Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases.
abstract: 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.
authors.affiliation: TransForm Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA. MElliot2@its.jnj.com
authors.forename: Michael
authors.initials: M
authors.lastname: Elliott
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Benson
authors.forename: Marion
authors.initials: M
authors.lastname: Blank
authors.forename: Carrie
authors.initials: C
authors.lastname: Brodmerkel
authors.forename: Daniel
authors.initials: D
authors.lastname: Baker
authors.forename: Kristin Ruley
authors.initials: KR
authors.lastname: Sharples
authors.forename: Philippe
authors.initials: P
authors.lastname: Szapary
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D015535:Arthritis, Psoriatic / Q000188:drug therapy / Q000276:immunology; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D000069549:Ustekinumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053762:Interleukin-12 Subunit p40; D018664:Interleukin-12; D000069549:Ustekinumab