Summary of Pharmacokinetic Parameters After Dosing With Anti‒IL-20.

<p>AUC = area under the curve; C_max = maximum concentration; CV = coefficient of variation; IL-20 = interleukin 20; t_½ = half-life.</p><p>Summary of Pharmacokinetic Parameters After Dosing With Anti‒IL-20.</p

Patient and Disease Characteristics for Patients Receiving Single Doses.

<p>BSA = body surface area; IL-20 = interleukin 20; PASI = Psoriasis Area and Severity Index score.</p><p>Patient and Disease Characteristics for Patients Receiving Single Doses.</p

Suppression of Molecular Inflammatory Pathways by Toll-Like Receptor 7, 8, and 9 Antagonists in a Model of IL-23-Induced Skin Inflammation

<div><p>Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th) 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs) 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the dorsum. Two TLR antagonists were compared: IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8 and 9, both of which previously have been shown to reduce epidermal hyperplasia in this model. Skin gene expression profiles of IL-23-induced inflammation were compared with or without TLR antagonist treatment. IL-23 injection resulted in alteration of 5100 gene probes (fold change ≥ 2, FDR < 0.05) including IL-17 pathways that are up-regulated in psoriasis vulgaris. Targeting TLRs 7, 8 and 9 with IMO-8400 resulted in modulation of more than 2300 mRNAs while targeting TLRs 7 and 9 with IMO-3100 resulted in modulation of more than 1900 mRNAs. Both agents strongly decreased IL-17A expression (>12-fold reduction), normalized IL-17 induced genes such as beta-defensin and CXCL1, and normalized aberrant expression of keratin 16 (indicating epidermal hyperplasia). These results suggest that IL-23-driven inflammation in mouse skin may be dependent on signaling mediated by TLRs 7, 8, and 9 and that these receptors represent novel therapeutic targets in psoriasis vulgaris and other diseases with similar pathophysiology.</p> </div

Patient and Disease Characteristics for Patients Receiving Multiple Doses.

<p>BSA = body surface area; IL-20 = interleukin 20; PASI = Psoriasis Area and Severity Index score.</p><p>Patient and Disease Characteristics for Patients Receiving Multiple Doses.</p

Study design.

<p>The first dose in the multiple-dose dose-escalation phase was administered after the third dose level of the single-dose dose-escalation phase (0.2 mg/kg) was evaluated by a study safety group; thereafter, the single- and multiple-dose dose-escalation phases were performed in parallel.</p

Consort flow diagram.

<p>Patient disposition in (A) the single-dose and multiple-dose dose-escalation phases and (B) the multiple-dose expansion phase. Represents the safety analysis set. AE = adverse event.</p

Mean PASI total score by visit.

<p>Mean PASI total score by visit following (A) single dosing or (B) multiple dosing in the dose-escalation phase and (C) multiple dosing in the expansion phase. PASI = Psoriasis Area and Severity Index.</p

Enrichment of cytokine-related inflammatory pathways (gene sets) in human psoriasis transcriptomes as compared with murine models of psoriasis.

<p>Each panel represents NES values and p-values of GSEA analysis for LS and NL comparisons of STAT3, Tie2, and TGF<i>β</i> transgene models and the imiquimod-induced model; KC, keratinocyte; TNF<i>α</i>, tumor necrosis factor <i>α</i>; IFN<i>α</i>, interferon <i>α</i>; IFNγ, interferon γ; PMBCs: peripheral blood mononucleated cells; DCs, dendritic cells; iDCs, immature dendritic cells; BDCA, blood dendritic cell antigen; Treg, regulatory T cells; KC, keratinocytes; DCs, Myeloid dendritic cells; RHE, reconstituted human epidermis. (a-d) Expression of these cytokine pathways in human psoriasis vulgaris is shown for lesional (LS) versus non lesional (NL) and for NL versus normal (N) skin and scalp. (e–k) Cytokine enrichment in the six mouse models is illustrated as follows: K14-amphiregulin (AREG) ear skin (e) and tail skin (f), IL-23 (g), K5-Stat3C (Stat-3) (h), K5-Tie2 (Tie-2) (i), K5-TGF-<i>β</i>1 (TGF-<i>β</i>) (j), and Imiquimod (k).</p

Keratin and immune-set gene expression profile of scalp psoriasis vs skin psoriasis, atopic dermatitis, and alopecia areata.

<p>Average log2FCH for alopecia areata (AA), atopic dermatitis (AA), scalp psoriasis and skin psoriasis for a representative group of (a) keratin and keratin associated proteins (KRTAPs) and (b) immune-related pathways genes adjusted by region (normalized to normal scalp [AA and scalp psoriasis] or normal skin [AD and skin psoriasis].</p

Descriptive analysis of scalp vs skin transcriptomes.

<p>(a) Principal component analysis (PCA) was performed to reveal the internal structure of the individual transcriptomes and to best explain the variance among samples when comparing the studied areas. In our data, PCA showed a better discrimination for skin samples than for scalp biopsies. (b) Scatter plot of log2FCH of LS vs NL DEGs on skin vs scalp transcriptomes. (c) Venn diagram of LS vs NL DEGs on scalp vs skin or MAD5 transcriptomes. (d) Heat map of genomic expression differences in scalp or skin psoriasis comparing LS, NL and N samples and (e) heat map showing three clusters of genes involved in differentiation of LS/NL samples in scalp vs skin areas. (f) Clustering heatmap of GSVA estimate values for a group of immune-related gene-sets comparing LS vs NL on scalp vs skin psoriasis. Terms of the X-axis refer to several set of genes up-regulated in cell culture by addition of cytokines. Unique: when a gene set is unique for that cell-cytokines combination, and no gene appears in other gene set. Synergistic: effect due to adding two cytokines to the cell culture at the same time. Additive: effect due to adding two cytokines to the cell culture sequentially. KC: Keratinocytes; RHE: Reconstituted Epidermis; DC: Dendritic Cells; iDC: inflammatory Dendritic Cells.</p