title: Antibody-mediated delivery of interleukin 4 to the neo-vasculature reduces chronic skin inflammation.
abstract: BACKGROUND
  The antibody-mediated delivery of cytokines ("immunocytokines") to sites of pathological angiogenesis represents an attractive strategy for the development of innovative biopharmaceuticals, capable of modulating the activity of the immune system in cancer and in chronic inflammatory conditions.
  
  
  OBJECTIVE
  Recombinant IL4 has previously been shown to be therapeutically active in patients with psoriasis. The antibody-mediated delivery of this cytokine to sites of chronic skin inflammatory conditions should lead to an improved potency and selectivity, compared to non-targeted IL4.
  
  
  METHODS
  The therapeutic activity of F8-IL4, a fusion protein of the F8 antibody (specific to the alternatively-spliced EDA domain of fibronectin) with murine IL4, was investigated in three immunocompetent mouse models of skin inflammation: two induced by the TLR7/8 ligand imiquimod (in Balb/c and C57BL/6) and one mediated by the over-expression of VEGF-A.
  
  
  RESULTS
  The EDA domain of fibronectin, a marker for angiogenesis, is expressed in the inflamed skin in all three models and F8-IL4 selectively localized to inflamed skin lesions following intravenous administration. The F8-IL4 fusion protein mediated a therapeutic benefit, which was superior to the one of a non-targeted version of IL4 and led to increased levels of key regulatory cytokines (including IL5, IL10, IL13, and IL27) in the inflamed skin, while IL2 levels were not affected in all treatment groups. A murine version of etanercept and a murine anti-IL17 antibody were used as positive control in the therapy experiments.
  
  
  CONCLUSIONS
  Skin inflammatory lesions can be selectively targeted using anti-EDA antibody-cytokine fusion proteins and the pharmacodelivery of IL4 confers a therapeutic benefit by shifting the cytokine balance.
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
authors.forename: Teresa
authors.initials: T
authors.lastname: Hemmerle
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
authors.forename: Silvana
authors.initials: S
authors.lastname: Zgraggen
authors.affiliation: Philochem AG, Libernstrasse 3, CH-8093 Otelfingen, Switzerland.
authors.forename: Mattia
authors.initials: M
authors.lastname: Matasci
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Halin
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland. Electronic address: neri@pharma.ethz.ch.
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D002908:Chronic Disease; D003872:Dermatitis / Q000517:prevention & control*; D005353:Fibronectins / Q000276:immunology*; D015847:Interleukin-4 / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D005353:Fibronectins; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4
keywords: Antibody-cytokine fusion protein; Chronic skin inflammation; Fibronectin; Interleukin 4; Psoriasis