Pharmacodynamic And Pharmacokinetic Study Of Recombinant Human Serum Albumin-Inteleukin-1Receptor Antagonist

Background:Interleukin-1receptor antagonist (IL-1ra) is highly therapeutic to rheumatoid arthritis and several other inflammatory diseases. A general drawback of its in vivo application is the rapid clearance from circulation and lack of specificity to the target tissue, leading to quite a few side-effects. Albumin has been widely employed as drug delivery system to extend the half-life of therapeutic molecules. Additionally, albumin has been shown to selectively accumulate and metabolize in the inflamed joint of rheumatoid arthritis patients. This makes albumin an ideal drug carrier for arthritis treatment.Results:(1) successfully expressed the fusion protein were identified by Western blot, and the high purity of the fusion protein using nickel ion affinity chromatography;(2) fusion protein IL-1ra inhibition of IL-1β in a dose-dependent killing of A375-S2cells, by MTT method to calculate the IC50of both fusion protein IC50is0.74nmol/ml, IL-1ra IC50for0.73nmol/ml in both biological activity;(3) established collagen-induced rheumatoid arthritis model, fusion protein of the pharmacokinetic studies show I showed a much longer serum half-life of around10h as compared to approximately0.34h for IL-1ra.. Fusion protein to demonstrate the specificity of the aggregation,48hours after injection, its distribution is15times that of healthy joints in inflammatory joint inflammation of the joints of rheumatoid arthritis model mice, IL-1ra distribution in other organs (such as:liver, kidney, spleen, lung);(4) CIA mice after secondary immunization, the fusion protein and IL-1ra treatment of CIA mice, from the delay in onset, inflammation score, observation of the biopsy, fluorescence quantitative PCR detection of arthritis factor expression levels fusion protein showed a better suppression of RA.Conclusions:The findings reported herein indicate that the fusion protein is likely to have greater clinical applications in areas such as the treatment of rheumatoid arthritis, and that albumin fusion technology may be a promising tool for targeting small-mass protein drugs to the inflamed joints for rheumatoid arthritis therapy.