title: Analysis of the mechanism of action of anti-human interleukin-6 and anti-human interleukin-6 receptor-neutralising monoclonal antibodies.
abstract: Anti-human interleukin-6 (human IL-6) and anti-human IL-6 receptor (IL-6R)-neutralising monoclonal antibodies (mAbs) are among the most promising human IL-6-specific inhibitors and have been shown to exert short-term beneficial effects in clinical trials. Simultaneous treatment with different anti-human IL-6 or anti-human IL-6R mAbs was recently suggested to be a potent way to inhibit the action of the cytokine in vivo. Although some of these mAbs are already used, their mechanisms of action and the location of their epitopes on the surface of human IL-6 and human IL-6R are still unknown. Here, we analysed the capacity of several anti-human IL-6 and anti-human IL-6R mAbs to inhibit the interaction between human IL-6, human IL-6R, and human glycoprotein 130 (gp130). We mapped the epitopes of several of these mAbs by studying their binding to human IL-6 and human IL-6R mutant proteins. Our results show that several anti-human IL-6 and anti-human IL-6R-neutralising mAbs block the binding between human IL-6 and human IL-6R, whereas others block the binding to gp130. We provide evidence that some of the latter mAbs inhibit interaction with gp130beta1, whereas others interfere with the binding to gp130beta2. Our results suggest that residues included in the C'D' loop of human IL-6R interact with gp130beta2.
authors.affiliation: Institut Pasteur de Bruxelles, Département de Virologie, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Kalai
authors.forename: F A
authors.initials: FA
authors.lastname: Montero-Julian
authors.forename: J P
authors.initials: JP
authors.lastname: Brakenhoff
authors.forename: V
authors.initials: V
authors.lastname: Fontaine
authors.forename: L
authors.initials: L
authors.lastname: De Wit
authors.forename: A
authors.initials: A
authors.lastname: Wollmer
authors.forename: H
authors.initials: H
authors.lastname: Brailly
authors.forename: J
authors.initials: J
authors.lastname: Content
authors.forename: J
authors.initials: J
authors.lastname: Grötzinger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D050822:Cytokine Receptor gp130; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009500:Neutralization Tests; D011233:Precipitin Tests; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse