Directed evolution of a soluble human IL-17A receptor for the inhibition of psoriasis plaque formation in a mouse model

Chem Biol. 2013 Feb 21;20(2):202-11. doi: 10.1016/j.chembiol.2012.11.012.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Directed Molecular Evolution*
  • Disease Models, Animal
  • Humans
  • Interleukin-17 / metabolism*
  • Kinetics
  • Mice
  • Mutation
  • Protein Binding
  • Protein Stability
  • Psoriasis / drug therapy*
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / metabolism
  • Receptors, Interleukin-17 / therapeutic use*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / therapeutic use

Substances

  • IL17A protein, human
  • Interleukin-17
  • Receptors, Interleukin-17
  • Recombinant Proteins