FPR2-selective peptide ligand NCP112 ameliorates atopic dermatitis in preclinical models through inhibition of type 2 immune response and recovery of skin barrier function

초록

Background: Atopic dermatitis is a chronic inflammatory skin dis-ease that usually develops at young age and characterized by severe pruritus, eczematous skin lesions, and lichenification. Skin barrier dysfunction and dysregulation of immune system promoted by com-plex risk factors are regarded main causes leading pathogenesis of atopic dermatitis. Although recently approved biologic Dupixent has shown efficacy for patients with moderate-to-severe symptoms, there is still a high unmet medical need for an effective topical agent with long-term safety for patients with mild-to-moderate symptoms.Method: FPR2 (formyl peptide receptor 2) is a GPCR which medi-ate process for resolution of inflammation by recognizing several pro- resolving factors including LXA4, RvD1, and annexin A1, etc. NCP112 is a FPR2-selective synthetic heptameric peptide ligand, acting as a pro-resolving factor via FPR2 activation.Results: Treatment of NCP112 in topical formulation improves clini-cal score for skin symptoms and reduces epithelial thickness both in DNCB- and Capsaicin-induced rodent models for atopic dermatitis. In addition, Enhancement of type 2 immune response along with al-lergic reactions mediated by IgE, which are characteristics of atopic dermatitis, can be relieved through treatment of NCP112 – down-regulation of expression of IL-4, IL- 13 and ILC2 expansion in skin le-sion while relieving pruritic symptoms through dampening of serum IgE level. Dysregulated expression or mutation of filaggrin, a struc-tural protein of skin epithelium, can lead to disruption of skin barrier functions. NCP112 recovers skin barrier through normalization of altered proteolysis of filaggrin by dysregulated protease system in capsaicin-induced rat model. Proteomic analysis of epidermis from capsaicin-induced animal shows that a wide range of proteins in-volved in innate immunity, wound healing, protease, and skin barrier which are affected by disease status are restored by topical treat-ment of NCP112.Conclusion: These finding indicate that NCP112 has immunoregula-tory activities to alleviate the skin manifestation of atopic dermatitis and it has the potential to be novel treatment option.Conflicts of Interest: The authors did not specify any links of interest