Fig 1: The effects of IL‐17 on RA‐CPCs: expression of IL‐17RA and IL‐17RC receptor mRNA (A), Western blots (B), and immuncytochemistry (C) of the IL‐17RA and IL‐17RC proteins. RA‐CPCs are also positive for IL‐6 (D, upper), as well as IL‐10 (D, lower). MMP3 mRNA was significantly upregulated by IL‐17 (E). TIMP1 (F) and TIMP3 (G) were significantly downregulated. However, IL‐6 was significantly upregulated by IL‐17 (H). In contrast, blocking IL‐17 (IL‐17AB) produced the opposite effects (E–H). Western blot analysis (I, J), secukinumab significantly reduced the amount of RUNX2 (K), as well as the amount of IL‐6 (L). Western blots of low molecular weight enriched medium from RA‐CPCs treated with adalimumab or secukinumab (M) exhibited significantly more IL‐10 than the controls (N). (O) Role of IL‐17 on RA‐CPCs, with IL‐17 promoting IL‐6, while antagonizing IL‐17 promotes IL‐10 and chondrogenesis. All figures are representative of at least three different experiments (n = 3). Significant differences (*p ≤ 0.05); error bars denote the means ± SD.
Fig 2: Phase 1c PK profile of DC-806 through 28 days after the first dose.Graph detailing the group mean ± SD DC-806 plasma concentration by 200 mg BID (green circle) and 800 mg BID (blue diamond) groups on a semilogarithmic scale through Study Day 29. PK in psoriasis patients was comparable to healthy volunteer PK, with consistent trough levels over 28 days after achieving steady state around Day 3. The dotted line represents IC50 for recombinant human IL-17AA, as obtained using HEK-blue IL-17 cell-based assay (S1 Table). PK Concentration Analysis Set. Abbreviations: BID, twice daily; HEK: human embryonic kidney; IC50, half-maximal inhibitory concentration; IL-17, interleukin-17; PK, pharmacokinetic; SD, standard deviation.
Fig 3: Preclinical evaluation of IL-17 inhibition by small molecule DC-806.(A) Inhibition of IL-17 bioactivity as secreted by human TH17 cells and assayed by a reporter cell assay. Dotted lines represent positive and negative assay controls. 1 representative of 7 experiments with different donors is shown. The error bars represent the SEM. (B, C) Evaluation of DC-806 in rat CIA. Rats were randomized on Day 11 and dosed as indicated. Daily measurements of ankle thickness (B) and terminal measurement of footpad weights (C) were used as efficacy readouts. (D) Preclinical evaluation of DC-806 serum levels. PK sampling for exposure determination was performed on Days 11, 16, at 1 and 12 hours post dose. The dotted lines represent the uncorrected IC50 for rat IL-17AA and rat IL-17AF as listed in S1 Table. The dashed line represents the LLQ of the quantification assay. All error bars represent the SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Abbreviations: anti-F, anti-IL-17F; BID, twice daily; CIA, collagen-induced arthritis; Dex, dexamethasone; IC50, half-maximal inhibitory concentration; IL-17, interleukin-17; LLQ, lower limit of quantification; PK, pharmacokinetic; QD, once daily; SEM, standard error of mean; TH17, T-helper 17.
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