Cytokine traps: multi-component, high-affinity blockers of cytokine action.
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.
Economides
Aris N
AN
Department of BioMolecular Science, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
Carpenter
Laura Rocco
LR
Rudge
John S
JS
Wong
Vivien
V
Koehler-Stec
Ellen M
EM
Hartnett
Christopher
C
Pyles
Erica A
EA
Xu
Xiaobing
X
Daly
Thomas J
TJ
Young
Michael R
MR
Fandl
James P
JP
Lee
Frank
F
Carver
Scott
S
McNay
Jennifer
J
Bailey
Kevin
K
Ramakanth
Swayampakula
S
Hutabarat
Renta
R
Huang
Tammy T
TT
Radziejewski
Czeslaw
C
Yancopoulos
George D
GD
Stahl
Neil
N
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
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