Anti-
cytokine therapies have substantially improved the treatment of inflammatory and
autoimmune diseases.
Cytokine-targeting drugs are usually biologics such as
antibodies or other engineered
proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic
cytokine inhibitor and the
protein producing capacity of the host. Here, we engineered and characterized a receptor fusion
protein, mIL-6-RFP-Fc, for the inhibition of
interleukin-6 (IL-6), a well-established target in anti-
cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the
transcription factor STAT3 and ERK1/2
kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic
acute phase protein synthesis and improved kidney function in an
ischemia and
reperfusion injury model. Our study establishes receptor fusion
proteins as promising agents in anti-
cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many
cytokines involved in inflammatory and other diseases.