# Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease
## 3 Targeting IL-36R in Soriasis  
The binding of IL-36 Ra and IL-38 to IL-36R inhibits the activation of intracellular pathways, and the impact of IL-36 blockade in psoriasis has been widely studied. Several experimental models have shown potential for IL-36R inhibiting antibodies. Mice deficient in IL-36R or treated with IL-36R antibodies are protected from imiquimod (IMQ)-induced skin inflammation [49; 50]. In murine models of IL-23 or IL-36\(\alpha\) injection, IL-36R antibodies inhibit inflammatory responses, with significant attenuation of skin thickening and expression of psoriasis-relevant genes [51]. [PERSON] and colleagues studied a mouse model with decreased affinity of IL-36 Ra to IL-36R, leading to enhanced IL-36R signaling [52]. Using IL-36R monoclonal antibodies, they demonstrated that IL-36R blockade led to the down-regulation of IL-17A, IL-17F, and IL-23, as well as to reduced skin thickness and reduced IL-6, IL-18, and TNF\(\alpha\) cytokines in the skin [52]. In addition, they found comparable efficacy of anti-IL36R and anti-IL-12p40 (a murine surrogate of ustekinumab) antibodies in reducing IMQ-induced skin inflammation in vivo [52]. Moreover, while anti-IL36R administration led to decreased levels of IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\); anti-IL-12p40 antibody only achieved a significant reduction of IL-36\(\gamma\)[52]. Blocking the IL-36 pathway might also be of use in PsA patients, especially in those refractory to treatment. High levels of IL-36\(\alpha\) expression were found in synoyium of patients with PsA not responding to disease-modifying anti-rheumatic drugs (DMARDs). Moreover, high expression remained unchanged after DMARDs treatment, with PsA-derived synovial fibroblasts exhibiting higher production of IL-36 agonists with downregulation of antagonists and other pro-inflammatory cytokines such as IL-1\(\beta\) and TNF\(\alpha\). Finally, treatment with IL-36 Ra was associated with down-regulation of CXCL8 production by PsA-FLS [47]. Regarding safety, genetic studies with individuals carrying loss-of-function mutations in the IL-36R gene show that immune function is preserved in these patients, suggesting that IL-36 can be targeted without compromising host defense [53]. Altogether, these findings support the clinical development of IL-36R blocking antibodies, and currently, there are two molecules undergoing phase II and III clinical trials. Spesolimab (Bl655130, Boehringer Ingelheim) has demonstrated efficacy in a phase I, open-label, proof-of-concept study of seven biologic-naive adult patients with a moderate GPP flare. All patients treated exhibited rapid skin improvement after the administration of a single intravenous dose of 10 mg/kg of spesolimab [54]. A 73.2% and 79.8% Generalized Pustular Psoriasis Area and Severity Index reduction was observed at 2 and 4 weeks, respectively, and it was maintained at week 20 [54]. No serious adverse events were reported. Spesolimab was effective regardless of the presence of GPP-associated mutations (three patients had homozygous IL-36 RN mutations and one had a heterozygous CARD14 mutation) [54]. Molecular response was characterized by the rapid downregulation of genes involved in the innate immune response, Th1/Th17-mediated inflammation and neutrophabil groups, both in the skin and serum of treated patients [54]. Phase II and III studies of spesolimab are currently being performed in GPP, palmoplantar pustulosis, and other potential indications under study, including ulcerative colitis, Crohn's disease, and atopic dermatitis [55]. An ongoing Phase II study of imsidolimab (ANB019, AnaptsBio) with GPP and PPP patients will assess the efficacy and safety of this anti IL-36R monoclonal antibody. Reported results of a phase I study suggest a favorable side effect profile [56]. Other therapeutic approaches targeting IL-36 signaling pathways are under study. IL-36y blockade with a small IL-36y-binding molecule has shown inhibition of inflammation, both in vitro and in vivo, through the blockade of interactions with IL-36R [57].