The pleiotropic cytokine interleukin-6 (IL-6) shows a wide spectrum of biological functions among which stimulation of B cells and induction of acute phase protein synthesis in liver are mostly notable. IL-6 exerts its activity on target cells via binding to an IL-6 specific surface receptor (“IL-6R” or “gp80”). This receptor/ligand complex facilitates homodimerization of gp130, the second subunit of the IL-6 receptor complex. Dimerization of gp130 results in transduction of an IL-6 signal. Soluble forms of the IL-6R (sIL-6R) which are generated by two mechanisms (alternative splicing and shedding) are also able to trigger gp130 dimerization and signalling when complexed with IL-6.
Since the cytoplasmic portion of the IL-6R does not contribute to signal transduction, signalling by a gp130 homodimer can be induced by IL-6 in complex with membrane bound or soluble IL-6R. The presence of sIL-6R, however, leads to sensitization of IL-6 responsive cells towards the ligand, as described previously for human hepatoma cells HepG2. Furthermore, it has been shown that strictly IL-6 dependent hybridoma cells do not proliferate in response to very low amounts of IL-6 when sIL-6R present in culture media is continuously removed.
Initially described as the interleukin-6 signal transducer, gp130 is a transducer chain shared by many cytokines, such as IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF). All of these cytokines act via a bi- or tripartite receptor complex in which signalling is triggered by homodimerization (for IL-6) or heteradimerization with LIF-Rb/gp130 protein (for IL-11, LIF, OSM and CNTF) of gp130. These cytokines thus mediate similar biologic activities in various tissues.
While gp130 can be found on nearly all cell types, the IL-6R shows a much more restricted expression. The release of sIL-6R by one cell type renders other cells, which only express gp130 responsive to IL-6. This scenario is called trans-signalling. Indeed, several cellular activities have been described which require the complex of sIL-6R and IL-6 and are not seen with IL-6 alone. Soluble gp130 protein is found in high concentrations in human plasma. Recently the designer-cytokine hyper-LL-6 (H-IL-6), in which the C-terminus of sIL-6R is covalently fused to the N-terminus of mature IL-6 by a flexible peptide linker, has been described. As seen with the complex of IL-6/sIL-6R, H-IL-6 also acts on cells which only express gp130. In contrast to the separate components IL-6 and sIL-6R, a 100 to 1000 lower concentration of this fusion molecule is sufficient to induce comparable biological signals.
For the treatment of various diseases such as Crohn's disease etc. the specific blocking of IL-6 responses dependent on soluble IL-6R might be desirable for treatment. Unfortunately, the compounds available so far for this purpose are characterised by several disadvantages like low production rate, high clearance rate, low half life, etc.
Thus, the technical problem underlying the present invention was to provide means suitable for treating diseases where the specific blocking of IL-6 responses dependent on sIL-6R might have a beneficial effect that overcome the disadvantages of the means of the prior art.
USPTO Backgrounds
USPTO Backgrounds