Anti-REG3A monoclonal antibody

Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.

Most treatments for epithelial injury target hematopoietic mechanisms, possibly causing immunosuppression. Interleukin (IL)-22 promotes tissue regeneration, acting directly on epithelial cells. UTTR1147A, a human IL-22Fc (immunoglobulin G (IgG)4) fusion protein, activates IL-22 signaling. This phase I placebo-controlled trial of single, ascending, i.v. (1-120 mu g/kg) and s.c (3-120 mu g/kg) doses of UTTR1147A analyzed its effects on safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers in healthy volunteers. Most adverse events (AEs) were mild or moderate. The maximum tolerated i.v. dose in healthy volunteers was 90 mu g/kg. Predominant AEs were dose-dependent reversible skin effects consistent with IL-22 pharmacology. UTTR1147A exposure increased approximately dose-proportionally, with a half-life of similar to 1 week. IL-22 biomarkers (regenerating islet protein 3A (REG3A), serum amyloid A (SAA), and C-reactive protein (CRP)) increased dose-dependently. Neither inflammatory symptoms and signs nor cytokines increased with CRP elevations. UTTR1147A demonstrated acceptable safety, pharmacokinetics, and IL-22R engagement, supporting further clinical development.