513 - Blockage of IL-25 pathway as a potential target therapy for atopic dermatitis

Abstract

Abstract Introduction Interleukin 25 (IL-25) is an alarmin that binds to its receptor composed of IL-17RA and IL-17RB and is known to induce the production of type 2 cytokines, leading to T helper type 2 (Th2) inflammatory responses. Atopic dermatitis (AD) is an autoimmune and chronic disorder that causes inflammation, dryness, redness and irritation of the skin. It is well-­documented that upregulated IL-25 expression is tightly correlated with the disease severity of AD patients, suggesting that the IL-25 pathway is a potential therapeutic target of AD. SM17 is a humanized antibody of the IgG4/kappa isotype targeting the IL-25 pathway via specific binding to IL-17RB, a co-receptor for IL-25 expressed on the surface of ILC2 cells, dendritic Cells, fibroblast and epithelial cells. Therefore, we hypothesize that SM17 might serve as a potential therapeutic treatment for AD. Objectives The current study aims at investigating if blockage of IL-25 pathway through SM17 administration could ameliorate AD associated inflammation, skin pathology and pruritus. Methods To provide first evidence that SM17 could improve skin conditions, PBMCs from healthy individuals were pretreated with a cocktail of alarmins comprising IL-25, IL-33, and TSLP with or without SM17, and the mixture was co-cultured with the fully differentiated human keratinocyte cell line HaCaT in a transwell system for five days. Filaggrin level in HaCaT cells was used as an indicator for skin health. Beneficial effects of SM17 in AD was further tested in the 1-Fluoro-2,4-dinitrobenzene (DNFB) induced AD mouse model. DNFB and SM17 were administrated to the animals once per week and tissues were harvested after a month. Single cells were isolated from submental lymph nodes for ex-vivo culture while both dorsal skin and ear were collected for histological and biochemical analyses. In vivo efficacy of SM17 was further compared with upadacitinib, a JAK1 inhibitor currently approved by the FDA for the treatments of adults and adolescents aged 12+ years with moderate to severe AD, via behavioral, histological and biochemical analyses. Results We first demonstrated that SM17 could potentially ameliorate the skin condition by upregulating the filaggrin levels in keratinocyte during Th2 inflammatory responses in vitro. In the DNFB induced AD mouse model, SM17 could improve the skin conditions in both ear and dorsal skin through attenuation of Th2 cytokine levels in submental lymph node and skin samples, and reduce infiltration of mast cell and eosinophil, while upregulating filaggrin expression in the skin layer. Weekly administration of SM17 provided similar efficacy as upadacitinib (5 doses/week) to suppress DNFB induced scratching behavior, thickening of skin and ear, and global induction of Th2 inflammatory responses in multiple tissues. Conclusions In summary, these in vitro and in vivo data indicate that blockade of IL-25 pathway by SM17 could suppress Th2 mediated inflammatory response and ameliorate the AD pathology similar to that of upadacitinib, probably with a superior safety profile as demonstrated in our Phase I clinical trial (ClinicalTrials.gov Identifier: NCT05332834), where good safety profile and tolerability were observed with no reported cases of severe TEAE. We believe that SM17 could serve as a potential therapeutic treatment for AD in the future.