SYNERKINE

Summary

This thesis describes the development of IL4-10 fusion protein and the evaluation of its therapeutic potential in various inflammatory diseases. Inflammatory diseases, such as Rheumatoid arthritis (RA), osteoarthritis (OA), and chronic pain are difficult to treat because of the complexity of the immune system. Regulatory cytokines seem attractive candidates to treat these diseases, however as stand-alone therapy they have some drawbacks. In the IL4-10 fusion protein, two potent regulatory cytokines, Interleukin-4 and Interleukin-10, are combined. This combination leads to potent inhibition of pro-inflammatory cytokines, shifting a pro-inflammatory phenotype towards a more immunoregulatory phenotype. Furthermore, IL-4 and IL-10 in IL4-10 fusion protein neutralize each other’s unfavorable effects. Administration of IL4-10 fusion protein in experimental OA and RA animal models, resulted in a clear attenuation of the disease. In addition, in inflammatory pain models, a more potent inhibition by IL4-10 fusion protein as compared to the combination therapy of both individual cytokines was seen, and the fusion protein was even able to permanently resolve pain. Combining IL-4 and IL-10 in a fusion protein, also leads to a prolonged half-life and thereby an improved effect upon administration. In a pharmacokinetics study a four-fold improved clearance of IL4-10 fusion protein as compared to the individual cytokines was shown. Further modification of the biochemical properties of IL4-10 fusion protein, such as glycosylation sites and the degree of sialylation, can improve the effect upon administration even more. In conclusion, IL4-10 fusion protein is a promising potential therapeutic drug, since the combination of IL-4 and IL-10 in one molecule results in unique properties, and an improved therapeutic effect because of the reduced clearance.

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