Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders

Abstract

Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors. Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target. In particular, the authors start by giving a brief historical excursus on biologic agent development up until the success of TNF-α inhibitors, and continue with an overview of IL12/23 pathway inhibition. Next, they describe Th17 cell biology, focusing on the role of IL-17 in host defense and in human immune-inflammatory diseases, discussing the use and side effects of IL-17 inhibitors. Expert opinion: The IL-23/Th17 signaling pathway plays a central role in the pathogenesis of several inflammatory diseases, such as psoriasis. Recent data has demonstrated that biologics neutralizing IL-17 (ixekizumab, secukinumab) or its receptor (brodalumab) are highly effective with a positive safety profile in treating moderate to severe psoriasis, offering new treatment possibilities, especially for patients who do not respond adequately to anti-TNF-α therapies.

Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin

“…Currently, the efficacy of three biological agents targeting IL-17 signalling, secukinumab (anti-IL-17A mAb), ixekizumab (anti-IL-17A mAb) and brodalumab (anti-IL-17RA mAb), have been evaluated in the clinic, and the assessments have mainly focused on autoimmune diseases such as psoriasis, rheumatoid arthritis and asthma 42. The side effects of these agents need to be evaluated further.…”

Limitations of current monoclonal antibodies for plaque-type psoriasis and an outlook for the future

“…One of the supposed reasons for secondary failure has been attributable to their immunogenicity, resulting in the development of antibodies targeting the therapeutic molecule (antidrug antibodies-aDAb) [6]. Nowadays, the world of biologics is not just anti-TNF-α with anti-IL-17 drugs showing an equal or greater chance of leading patients to PASI improvement when compared with other biologics or small molecule inhibitors [4,7]. All immunobiological agents can induce antibodies against themselves, but their clinical utility as well as their impact on clinical response course is a hot point still opened.…”

Interleukin‐17 receptor A blockade with brodalumab in palmoplantar pustular psoriasis: Report on four cases

“…The pro‐inflammatory cytokine interleukin (IL)‐17 is one of the major drivers in different chronic inflammatory skin diseases and a key cytokine in the pathogenesis of PsO . In lesional PPP, mRNA of isoforms of IL‐17, including IL‐17A, IL‐17C and IL‐17F were found to be elevated compared with healthy controls .…”

“…1 The pro-inflammatory cytokine interleukin (IL)-17 is one of the major drivers in different chronic inflammatory skin diseases and a key cytokine in the pathogenesis of PsO. 2 In lesional PPP, mRNA of isoforms of IL-17, including IL-17A, IL-17C and IL-17F were found to be elevated compared with healthy controls. 3 The IL-17A blockers secukinumab and ixekizumab, as well as the IL-17 receptor A (IL-17RA) blocker brodalumab, that can inhibit multiple IL-17 isoforms (IL-17A, C, E, F), have shown efficacy not only in PsO, but also in generalized pustular psoriasis.…”