Clinical improvement in psoriasis with specific targeting of interleukin-23

Abstract

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways

“…Their involvement in human diseases has been strongly indicated by the clinical efficacy of anti-IL-17 monoclonal antibodies such as secukinumab in psoriasis, 6 rheumatoid arthritis, 7 and ankylosing spondylitis 8 of anti-IL12/IL23 p40 antibodies such as ustekinumab in psoriasis 9,10 and Crohn's disease; 11 and of anti-IL-23 p19 antibodies such as tildrakizumab in psoriasis. 12 IL-23 is a heterodimer composed of two subunits, p19 and p40, 13 the latter being shared withIL-12, which is composed of p35 and p40. These cytokines are produced by antigen-presenting cells, mainly activated dendritic cells (DCs), with IL-12 driving the differentiation of Th1 cells and IL-23-stabilizing and expanding Th17 cells.…”

Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function

“…For example, it is currently unclear whether it is primarily immune cell biology that is deregulated (e.g., in form of exaggerated IL-23 and IL-17 production), or if keratinocyte biology is at the root of the problem (e.g., via increased production of chemokines). Although therapeutic approaches targeting key inflammatory effector mechanisms, such as IL-23 and IL-17, are producing important benefits in a large percentage of patients, it is likely that a better understanding of causative factors will be relevant to further improve therapeutic strategies, not least from the perspective of prevention (11)(12)(13).…”

Immunopathologie du psoriasis

“…En particulier, une étude de phase I a évalué l'efficacité et la tolérance du tildrakizumab (MK-3222) développé par le laboratoire pharmaceutique Merck [14]. Dans cette étude, conduite sur 77 patients atteints de psoriasis modéré à sévère, trois injections de tildrakizumab à J1, J56 et J84 ont induit chez les patients une réduc-tion moyenne du score PASI de 50 à 80 % après 112 jours, qui était maintenue à J196, c'est-à-dire près de trois mois après la dernière injection.…”

“…Plus récemment, la découverte du rôle prépondérant des lymphocytes T CD4 de type Th17 dans la maladie a conduit au développement d'inhibiteurs spécifiques de cette voie, tels que les anticorps anti-IL(interleukine)-23 (cytokine favorisant la différenciation des lymphocytes en Th17), anti-IL-17, anti-IL-17RA (récepteur de l'IL-17) et IL-22 (cytokine produite notamment par les lymphocytes Th17). < le psoriasis ayant été montré [10], de nombreuses biothérapies ciblant l'IL-23 [11][12][13][14], l'IL-22 [15,16], l'IL-17A [17,18] ou son récepteur IL-17RA (interleukin 17A receptor) [19] ont été développées ou sont actuellement à l'étude dans le traitement de la maladie. Cette revue propose une synthèse des mécanismes d'action de ces biothérapies du psoriasis en relation avec la physiopathologie de la maladie.…”