Abstract
Cytokines can initiate and perpetuate human diseases, and are among the best-validated of therapeutic targets. Cytokines can be blocked by the use of soluble receptors; however, the use of this approach for cytokines such as interleukin (IL)-1, IL-4, IL-6 and IL-13 that use multi-component receptor systems is limited because monomeric soluble receptors generally exhibit low affinity or function as agonists. We describe here a generally applicable method to create very high-affinity blockers called 'cytokine traps' consisting of fusions between the constant region of IgG and the extracellular domains of two distinct cytokine receptor components involved in binding the cytokine. Traps potently block cytokines in vitro and in vivo and represent a substantial advance in creating novel therapeutic candidates for cytokine-driven diseases.
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antigens, CD / metabolism*
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Cell Division / physiology
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Cell Line
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Cytokine Receptor gp130
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Cytokines / antagonists & inhibitors*
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Cytokines / immunology
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Cytokines / metabolism*
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Dimerization
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Humans
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / immunology
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Immunoglobulin Fc Fragments / metabolism*
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology
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Macaca fascicularis
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred Strains
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Protein Binding
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Random Allocation
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Receptors, Interleukin-6 / genetics
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Receptors, Interleukin-6 / immunology
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Receptors, Interleukin-6 / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Time Factors
Substances
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Antigens, CD
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Cytokines
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IL6ST protein, human
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Il6st protein, mouse
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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Membrane Glycoproteins
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Receptors, Interleukin-6
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Recombinant Fusion Proteins
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Cytokine Receptor gp130