title: Cytokine traps: multi-component, high-affinity blockers of cytokine action.
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.
authors.affiliation: Department of BioMolecular Science, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: Laura Rocco
authors.initials: LR
authors.lastname: Carpenter
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Vivien
authors.initials: V
authors.lastname: Wong
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Koehler-Stec
authors.forename: Christopher
authors.initials: C
authors.lastname: Hartnett
authors.forename: Erica A
authors.initials: EA
authors.lastname: Pyles
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Xu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Daly
authors.forename: Michael R
authors.initials: MR
authors.lastname: Young
authors.forename: James P
authors.initials: JP
authors.lastname: Fandl
authors.forename: Frank
authors.initials: F
authors.lastname: Lee
authors.forename: Scott
authors.initials: S
authors.lastname: Carver
authors.forename: Jennifer
authors.initials: J
authors.lastname: McNay
authors.forename: Kevin
authors.initials: K
authors.lastname: Bailey
authors.forename: Swayampakula
authors.initials: S
authors.lastname: Ramakanth
authors.forename: Renta
authors.initials: R
authors.lastname: Hutabarat
authors.forename: Tammy T
authors.initials: TT
authors.lastname: Huang
authors.forename: Czeslaw
authors.initials: C
authors.lastname: Radziejewski
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D011897:Random Allocation; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050822:Cytokine Receptor gp130