Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases.
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.
Elliott
Michael
M
TransForm Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA. MElliot2@its.jnj.com
Benson
Jacqueline
J
Blank
Marion
M
Brodmerkel
Carrie
C
Baker
Daniel
D
Sharples
Kristin Ruley
KR
Szapary
Philippe
P
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
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053762:Interleukin-12 Subunit p40; D018664:Interleukin-12; D000069549:Ustekinumab