SYNERKINE | IL4-10 fusion protein for the treatment of inflammatory diseases

Abstract

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 are 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 (IL-4) and Interleukin-10 (IL-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, mitigated the disease. In addition, IL4-10 fusion protein better reduced pain in inflammatory pain models then the combination therapy of both individual cytokines. Upon repeated administration, the fusion protein was even able to permanently and completely resolve pain. Combining IL-4 and IL-10 in a fusion protein, also prolongs the systemic half-life and improves its effects upon administration. In a pharmacokinetics study a four-fold improved half-life of IL4-10 fusion protein as compared to the individual cytokines was shown. Modification of the biochemical properties of IL4-10 fusion protein by so-called glycoengineering, modifying glycosylation sites and the degree of sialylation, further improved the characteristics of the fusion protein. In conclusion, this thesis describes several unique effects of IL4-10 fusion protein, which suggest the fusion protein is a promising potential therapeutic drug for the treatment of inflammatory diseases.