A new type of cytokine receptor antagonist directly targeting gp130.
The interleukin-6-type family of cytokines bind to receptor complexes that share gp130 as a common signal-transducing subunit. So far, receptor antagonists for interleukin-6-type cytokines have been constructed that still bind to the specific ligand binding subunit of the receptor complex, but have lost the ability to stimulate gp130. Such receptor antagonists compete for a specific receptor of a member of the cytokine family. Interleukin-6 only binds to gp130 when complexed with the interleukin-6 receptor that exists as a membrane bound and soluble molecule. Here we have constructed fusion proteins that consist of the soluble form of the human interleukin-6 receptor covalently linked to interleukin-6 receptor antagonists. These fusion proteins directly bind to gp130. Moreover, at concentrations of 10-50 nM they completely neutralize not only the biological activity of interleukin-6 but also of other cytokines of the interleukin-6-type family that act via gp130 homodimers or gp130/LIF-R heterodimers. Therefore, these gp130 targeting cytokine antagonists might be useful therapeutic tools in disease states that are related to cytokines of the interleukin-6 family.
I. Medizinische Klinik, Abteilung Pathophysiologie, Johannes Gutenberg Universität Mainz, Obere Zahlbacher Strasse 63, D-55101 Mainz, Germany.
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Renné
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Kallen
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Müllberg
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Jostock
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Grötzinger
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Rose-John
D015703:Antigens, CD / Q000378:metabolism*; D020934:Ciliary Neurotrophic Factor; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D017354:Point Mutation; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C508351:OSM protein, human; D010455:Peptides; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D053683:Oncostatin M; D050822:Cytokine Receptor gp130