Specific inhibition of IL-6 signalling with monoclonal antibodies against the gp130 receptor.

A family of cytokines [IL-6, IL-11, oncostatin M (OM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1] involved in various inflammatory or tumoral diseases share the same gp130 signal transducer chain. The complex formed with their specific receptors associates with a common transducing gp130 membrane protein (gp130) resulting in the formation of high avidity receptor and activation of tyrosine kinases. With the view of identifying gp130 domains specifically involved in IL-6 signalling, the authors prepared 37 new anti-gp130 mAb and analysed the structure-function relationship of the molecule. By cross-competition ELISA, the mAb were classified in 10 subgroups called A to J. By ELISA and BIAcore analysis, the mAb were found to recognize at least 18 antigenic specificities of the gp130 chain. The mAb reacted against the soluble and the membrane forms of gp130 as well. Their ability to inhibit the proliferation of the human myeloma cell line XG-4 of which the growth is strictly dependent on the presence of either exogenous IL-6, or LIF, or OM, or CNTF was studied. Besides mAb with no evident neutralizing effect (G and H) and mAb which neutralized equally well the activity of all tested cytokines (all mAb of groups A, I and J), some showed a selective effect. Those of group F inhibited also the proliferation induced by the 4 cytokines, but more specifically that dependent on the CNTF. mAb of groups B and E specifically inhibited the growth induced by IL-6, whereas those of group C inhibited that induced by LIF and OM. These results show the presence of different gp130 epitopes specifically involved in the signaling induced by the cytokines of the gp130 family. In ELISA, only mAb of group B and E were found to inhibit the binding of the IL-6-IL-6R complex to gp130, showing that they identified one or two domains of gp130 involved in its interaction with the IL-6-IL-6R complex. Precise identification of this(ese) epitope(s) would be useful to better understand the mechanisms of the IL-6 signalling.