Session Speaker

A Fusion Protein of the Ligand- Binding Domain of the IL-6 Receptor Alpha and the Signal Transducer GP130 Acts as a Highly Potent and Specific Inhibitor of Human IL-6
Peter C. Heinrich, Monique Y. Wiesinger, Silke Metz, Serge Haan, Gerhard Müller-Newen
Germany

Elevated interleukin-6 (IL-6) levels have been observed in a variety of inflammatory and autoimmune disease such as rheumatoid arthritis, Crohn’s disease and lupus erythematosus. Therefore IL-6 has emerged as in important target molecule in the therapy of inflammatory diseases and potent and specific IL-6 inhibitors are highly desired. Based on molecular modelling guided structural analysis, a receptor fusion of the ligand- binding domain of human IL-6 receptor alpha and human gp130 (domains D1, D2 and D3) was generated. The fusion protein acts as a highly potent and specific inhibitor of human IL-6. Because murine IL-6 does not bind to human IL-6 receptor alpha, this inhibitor is not suited for the application in animal models which are a pre-requisite for clinical trials in humans. Therefore we set out to generate a receptor fusion protein for the inhibition of murine IL-6 and found that the Iglike domain (D1) of the murine IL-6Ralpha is required for receptor surface expression and IL6-binding. Based on these findings we present of a novel receptor fusion protein consisting of domains D1, D2 and D3 of murine IL-6 receptor alpha fused to the domains D1, D2 and D3 of murine gp130. This fusion protein acts as a highly potent inhibitor for murine, rat and human IL-6. The new pan-IL6 inhibitor is effective in the inhibition of classical IL-6 signaling through the membrane receptor complex as well as trans-signaling mediated by IL-6 and soluble IL-6Ralpha. Related cytokines such as IL-11 and oncostatin M that share the cytokine receptor subunit gp130 are not affected by the new IL-6 R fusion protein. Our new inhibitor has the great advantage that it is encoded by a single gene as compared to antibodies or cytokine traps where two subunits have to be expressed in parallel. This strategy offers interesting possibilities for specific cytokine inhibition in gene delivery approaches based on viral vectors, transgenic animals and finally gene therapy.