1. Cytokine traps: multi-component, high-affinity blockers of cytokine action.
- Author
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Economides AN, Carpenter LR, Rudge JS, Wong V, Koehler-Stec EM, Hartnett C, Pyles EA, Xu X, Daly TJ, Young MR, Fandl JP, Lee F, Carver S, McNay J, Bailey K, Ramakanth S, Hutabarat R, Huang TT, Radziejewski C, Yancopoulos GD, and Stahl N
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD immunology, Cell Division physiology, Cell Line, Cytokine Receptor gp130, Cytokines immunology, Dimerization, Humans, Immunoglobulin Fc Fragments genetics, Immunoglobulin Fc Fragments immunology, Immunoglobulin G genetics, Immunoglobulin G immunology, Macaca fascicularis, Male, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Mice, Mice, Inbred Strains, Protein Binding, Random Allocation, Receptors, Interleukin-6 genetics, Receptors, Interleukin-6 immunology, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins metabolism, Time Factors, Antigens, CD metabolism, Cytokines antagonists & inhibitors, Cytokines metabolism, Immunoglobulin Fc Fragments metabolism, Membrane Glycoproteins metabolism, Receptors, Interleukin-6 metabolism
- 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.
- Published
- 2003
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