Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2

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#Generalized pustular psoriasis (GPP) is a rare disease for which there is a dearth of clinical research and no universally accepted evidence-based guidelines for its treatment and management (Benjegerdes et al. Psoriasis (Auckl) 2016; 6:131-44.). Biologic therapies that are effective in the more common plaque form of psoriasis are ineffective in GPP (Benjegerdes et al. Psoriasis (Auckl) 2016; 6:131-44. Mansouri et al. Expert Opin Biol Ther 2013; 13(12):1715-30.), and much needed treatments that directly target GPP have not been developed (Mahil et al. Semin Immunopathol 2016; 38(1):11-27. Navarini et al. J Eur Acad Dermatol Venereol 2017; 31(11):1792-9. Robinson et al. J Am Acad Dermatol 2012; 67(2):279-88.

#FIG. 1A-1AJ provides particular structures for compounds described herein.

#FIG. 2A-D shows the gating scheme used to identify iDC, neutrophils and CD4+αβ T cells isolated from IL-36-treated skin as discussed in FIG. 3, FIG. 5, and FIG. 10. The cells were first gated on the Live, CD45+ population, followed by the Thy-1 vs CD11b gating (Panel A). The cells circled in the lower left corner were gated on Ly6C vs Ly6G to identify iDCs and neutrophils (Panel B). The circled cells in the upper left corner of panel A were then gated on TCRαβ vs TCRγδ (Panel C). The cells circulated in panel C were gated on CD8α vs CD4 to identify CD4+αβ T cells (Panel D).

#FIG. 3A-D shows the markedly different inflammatory cell skin infiltrates generated in the Imiquimod model of Plaque Psoriasis and the IL-36 Model of GPP. Panels A and B show the number of cells per gram isolated from mouse skin after four daily treatments with IMQ (A, grey bars with horizontal stripes) or IL-36α (B, grey bars with diagonal stripes). Black bars indicate the number of cells per gram isolated from control-treated skin, topical Vaseline (VAS) for the imiquimod experiments (A) and intradermal PBS for the IL-36 experiments (B). Panel C displays relative representation of leukocyte subsets within IL-36-treated versus imiquimod-treated skin: comparison among individual experiments. The percentage of T cells, neutrophils and iDC was calculated for the total live CD45+ infiltrate for 5 individual imiquimod experiments and 7 individual IL-36 experiments, each experiment utilizing at least 5 individual mice. The mean of the means (and SEM) for these experiments is shown. Panel D shows that percent of T cells that expressed the indicated immunophenotype isolated from the skin of mice after treatment with imiquimod (grey bars with horizontal stripes) or IL-36α (grey bars with diagonal stripes). Each bar indicates the mean and SEM of ten mice from a single experiment, representative of at least 5 repeats. All populations shown were first gated as live (AQUA-live/dead negative) and CD45+. For panels a and b, T cells were gated as Thy-1+/CD11b− cells expressing either TCRβ or TCRγδ. Ly6G+ and Ly6Chi/Ly6G− cells were gated within the Thy-1−/CD11b+ population. For panel c, each of the indicated populations was calculated as percent of the total Thy-1+/CD11b− population expressing either TCRβ or TCRγδ.

#General

#Generalized pustular psoriasis (GPP) is a rare inflammatory skin disorder with an etiology distinct from the more common plaque psoriasis. GPP patients often do not respond to therapeutic agents typically used for plaque psoriasis. Antagonists of CCR6 and/or CXCR2 including the compounds disclosed herein have been previously shown to ameliorate inflammation in a model of plaque psoriasis. Surprisingly, the present disclosure demonstrates that an antagonist of CCR6 and/or CXCR2 can be used to effectively treat generalized pustular psoriasis (GPP). In addition to treating GPP, related diseases such as palmo-plantar psoriasis (PPP), acute generalized exanthematous pustulosis (AGEP), hydradenitis suppurativa (HS), dermatitis herpetiformis, and pemphigus vulgaris can also be treated using the methods described herein.

#Chemokine directed therapy is designed to block the migration of inflammatory leukocytes into tissues from the peripheral blood, thus preventing them from participating in and amplifying any existing autoimmune lesions, thereby allowing the inflammatory cytokine environment to dissipate. Genetic studies demonstrate that GPP is strongly associated with dysfunctions in the IL-36 cytokine axis, and many aspects of GPP can be re-created in the mouse by intradermal injection of pre-activated IL-36α cytokine. The present disclosure demonstrates that the immune cells infiltrating IL-36α-injected mouse skin are of dramatically different composition than those infiltrating imiquimod- (IMQ-) treated skin, an accepted model of plaque psoriasis in Balb/c mice. The findings disclosed herein suggest that CCR6 and CXCR2 antagonists may constitute a novel target class for a mechanistically distinct therapeutic approach to treat GPP as well as related PPP, AGEP, HS, dermatitis herpetiformis, and pemphigus vulgaris diseases.