TY - JOUR
T1 - Directed evolution of a soluble human IL-17A receptor for the inhibition of psoriasis plaque formation in a mouse model
AU - Zaretsky, Marianna
AU - Etzyoni, Revital
AU - Kaye, Joel
AU - Sklair-Tavron, Liora
AU - Aharoni, Amir
N1 - Funding Information:
The research was supported by the Teva Pharmaceutical Industries and a grant from the European Research Council (ERC) “Ideas Program.” The authors from Ben-Gurion University of the Negev have no commitments or obligations to Teva Pharmaceutical Industries.
PY - 2013/2/21
Y1 - 2013/2/21
N2 - Interleukin-17 (IL-17) is a T-cell-derived cytokine that promotes inflammatory pathology in autoimmune diseases. Blocking IL-17A interactions with its endogenous IL-17 receptor (IL-17RA) can constitute an important target for therapeutic intervention. Here, we utilized a directed evolution approach to generate soluble IL-17RA mutants that exhibit increased IL-17A binding affinity and thermostability, relative to the wild-type. Human fibroblast cell-based assay and in vivo analysis in mice indicated that two improved IL-17RA mutants efficiently inhibit the secretion of IL-17A-induced proinflammatory cytokines. Analysis of one of these mutants in a psoriasis mouse model showed its efficacy in promoting the recovery of psoriasis plaques. This mutant can be used as a promising drug candidate for the treatment of psoriasis and may be a therapeutic agent for various other autoimmune diseases.
AB - Interleukin-17 (IL-17) is a T-cell-derived cytokine that promotes inflammatory pathology in autoimmune diseases. Blocking IL-17A interactions with its endogenous IL-17 receptor (IL-17RA) can constitute an important target for therapeutic intervention. Here, we utilized a directed evolution approach to generate soluble IL-17RA mutants that exhibit increased IL-17A binding affinity and thermostability, relative to the wild-type. Human fibroblast cell-based assay and in vivo analysis in mice indicated that two improved IL-17RA mutants efficiently inhibit the secretion of IL-17A-induced proinflammatory cytokines. Analysis of one of these mutants in a psoriasis mouse model showed its efficacy in promoting the recovery of psoriasis plaques. This mutant can be used as a promising drug candidate for the treatment of psoriasis and may be a therapeutic agent for various other autoimmune diseases.
UR - http://www.scopus.com/inward/record.url?scp=84874302384&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2012.11.012
DO - 10.1016/j.chembiol.2012.11.012
M3 - Article
AN - SCOPUS:84874302384
SN - 1074-5521
VL - 20
SP - 202
EP - 211
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 2
ER -
