title: Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease.
abstract: The antibody-based pharmacodelivery of cytokines to sites of disease has been extensively studied for various indications but not for the treatment of inflammatory bowel diseases. Here, we report that the alternatively spliced EDA domain of fibronectin, a marker of angiogenesis and of tissue remodeling, is expressed in the dextran sodium sulfate mouse model of colitis and in patients with inflammatory bowel conditions, while being virtually undetectable in most normal adult tissues. Radiolabeled preparations of the F8 antibody, specific to the EDA domain of fibronectin, were shown to selectively localize to sites of inflammation in mice with colitis, as revealed by autoradiographic analysis. Fusion proteins of the F8 antibody with various murine payloads (interleukin-4, the p40 subunit of interleukin-12, interleukin-13) were administered to mice with colitis. IL12p40-F8 mediated an anti-inflammatory activity, which was comparable with the one of cyclosporine, whereas F8-IL4 did not inhibit colitis and F8-IL13 worsened the inflammatory conditions.
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zürich (ETH Zürich), Zürich, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Bootz
authors.forename: Anja Sophie
authors.initials: AS
authors.lastname: Schmid
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D005353:Fibronectins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C528643:F8 monoclonal antibody; D005353:Fibronectins; D016264:Dextran Sulfate