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<.001) decreased from day 5 to 57 (2 weeks after the last dose), a decrease of 75-95% from baseline. These decreases were maintained until day 113 in the 1 (-69.8%, P<.001) and 3 mg/kg groups (-58.3%, 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<.001).
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<.001), and a downward trend was observed in the 0.3 mg/kg group (P=.034).
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<.001) and a downward trend in the 1 mg/kg group (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
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.