Inhibition of IL-17 as a pharmacological approach for IBD

Abstract

Several experimental approaches have been utilized, in order to critically examine the roles of IL-17 family members in intestinal inflammation. These approaches have included: (1) the use of IL-17A and IL-17F-deficient mice, (2) specific antibodies directed against IL-17, (3) an IL-17 vaccine, (4) methods to block the IL-17 receptor and (5) small-molecule inhibitors of IL-17. Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease (IBD), using specific strains of IL-17-deficient mice. This paper will review the preclinical results using various pharmacological approaches [specific IL-17 antibodies, an IL-17 receptor fusion protein, IL-12/IL-23 p40 subunit and IL-17 vaccine approaches, as well as a small molecule inhibitor (Vidofludimus)] to inhibit IL-17 in animal models of IBD. Recent clinical results in patients with IBD will also be discussed for Secukinumab (an IL-17A antibody), Brodalumab (an IL-17 receptor antibody) and two small-molecule drugs (Vidofludimus and Tofacitinib), which inhibit IL-17 as part of their overall pharmacological profiles. This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti-IL-17 drugs, as related to drug pharmacodynamics, IL-17 receptor subtypes and other pertinent factors. Finally, future pharmacological approaches of interest will be discussed, such as: (1) Retinoic acid receptor-related orphan nuclear receptor gamma t (Rorγt) antagonists, (2) Retinoic acid receptor alpha (RARα) antagonists, (3) Pim-1 kinase inhibitors and (4) Dual small-molecule inhibitors of NF-κB and STAT3, like synthetic triterpenoids.