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• W2289241446 abstract "Background ABT-981 is a novel human Dual-Variable Domain Immunoglobulin (DVD-Ig™) that inhibits interleukin (IL)-1α and IL-1β. Objectives To evaluate IL-1α and IL-1β protein levels in serum, and IL-1α, IL-1β, and IL-1Ra (IL-1 receptor antagonist) mRNA levels in peripheral blood leukocytes (PBLs) in patients with knee osteoarthritis (OA). Methods In a randomized, double-blind, placebo (PBO)-controlled, multiple dose study (NCT01668511), 27 knee OA patients received ABT-981 (0.3, 1, or 3 mg/kg; n=7 each group) or PBO (n=6) subcutaneously every 2 weeks (4 doses total). Serum samples were collected on days 1 (predose), 5, 15, 19, 29, 33, 43, 47, 57, and 113. Peripheral blood was collected in PAXgene RNA tubes on days 1, 5, 57, and 113. Imperacer® Immuno-PCR assays (Chimera Biotec) were used to detect free protein concentration of IL-1α and IL-1β in serum. Total RNA isolated from PBLs was converted to cDNA for quantitative PCR detection of IL-1a, IL-1b, and IL-1Ra mRNAs. Changes in biomarkers in the ABT-981 groups were compared with baseline and with PBO. Repeated measures analysis was performed using SAS 9.2. Adjusted P values were calculated using the Bonferroni method. Results The mean baseline serum IL-1α level was 7.1 pg/mL. In all ABT-981 groups serum IL-1α levels significantly ( P P P =.005). The IL-1α level in the 0.3 mg/kg group recovered to near baseline level on day 113. Compared with PBO, serum IL-1α levels in all ABT-981 groups were significantly decreased from day 5 to 113 ( P The mean baseline serum IL-1β level was 0.46 pg/mL. In the 1 and 3 mg/kg groups serum IL-1β levels significantly decreased 48.7-87.1% from baseline (P≤.01) throughout the study. Compared with PBO, serum IL-1β levels were significantly decreased in the 1 and 3 mg/kg groups (P PBL IL-1a mRNA was undetectable by quantitative PCR (cycle threshold >35) in all dose groups and at all time points. At day 5, IL-1b mRNA expression significantly decreased in in the 3 mg/kg group ( P P =.092). IL-1Ra mRNA expression levels in PBLs did not show dose dependent changes in the treatment groups. Conclusions Simultaneous robust inhibition serum of IL-1α and IL-1β with ABT-981 was observed in this study in a dose-dependent manner. The prolonged inhibition of IL-1α and IL-1β in the 1 and 3 mg/kg groups indicates a long lasting biological effect of ABT-981 even after the drug has been ∼97% cleared from the system (day 113). The dose-dependent decrease of IL-1b mRNA expression in PBLs on day 5 coincides with the decrease in serum IL-1β protein. However, the transient decrease in PBL IL-1b mRNA, despite persistent decreases in serum IL-1a and IL-1b levels, suggest that other cytokines also play a role in regulating IL-1b transcription in these cells. In conclusion, serum levels of IL-1a and IL-1b proteins and PBL IL-1b mRNA are dose-dependently inhibited in knee OA subjects dosed with ABT-981 and represent candidate measurements of target engagement. Disclosure of Interest S. Wang Shareholder of: AbbVie, Employee of: AbbVie, R. Loebbert Shareholder of: AbbVie, Employee of: AbbVie, E. Sampson Shareholder of: AbbVie, Employee of: AbbVie, M. Saltarelli Shareholder of: AbbVie, Employee of: AbbVie, J. Medema Shareholder of: AbbVie, Employee of: AbbVie, F. Hong Shareholder of: AbbVie, Employee of: AbbVie" @default.
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• W2289241446 date "2015-06-01" @default.
• W2289241446 modified "2023-09-27" @default.
• W2289241446 title "THU0491 Dual Variable Domain-Immunoglobulin (DVD-IG™) ABT-981 Simultaneously and Dose-Dependently Inhibits Interleukin-1 Alpha and -1 Beta in Subjects with Knee Osteoarthritis" @default.
• W2289241446 doi "https://doi.org/10.1136/annrheumdis-2015-eular.5091" @default.
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