title: High efficiency cell-specific targeting of cytokine activity.
abstract: Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This 'activity-by-targeting' concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.
authors.affiliation: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Garcin
authors.affiliation: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France.
authors.forename: Franciane
authors.initials: F
authors.lastname: Paul
authors.affiliation: Division of Biophysics, Department of Biology, University of Osnabrück, 49069 Osnabrück, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Bordat
authors.affiliation: Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BE 9000, Belgium.
authors.forename: José
authors.initials: J
authors.lastname: Van der Heyden
authors.affiliation: Division of Biophysics, Department of Biology, University of Osnabrück, 49069 Osnabrück, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilmes
authors.affiliation: 1] CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France [2] Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, 80 avenue Augustin Fliche, 34295 Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
authors.affiliation: INSERM U844, University Hospital Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Apparailly
authors.affiliation: Department for Molecular Biomedical Research, Ghent University, Technologiepark 927, 9052 Zwijnaarde, Belgium.
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Koker
authors.affiliation: 1] Division of Biophysics, Department of Biology, University of Osnabrück, 49069 Osnabrück, Germany [2].
authors.forename: Jacob
authors.initials: J
authors.lastname: Piehler
authors.affiliation: 1] Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BE 9000, Belgium [2].
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.affiliation: 1] CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France [2].
authors.forename: Gilles
authors.initials: G
authors.lastname: Uzé
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism*; D054411:Receptors, Leptin; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D061905:Single-Domain Antibodies / Q000378:metabolism*
chemical_list: D016207:Cytokines; C554158:IFNA2 protein, human; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D019409:Interleukin-15; D007376:Interleukin-2; D020738:Leptin; D018121:Receptors, Cytokine; D054411:Receptors, Leptin; D047888:Receptors, Tumor Necrosis Factor, Type I; D061905:Single-Domain Antibodies; C515447:leptin receptor, mouse; D053633:Receptor, Interferon alpha-beta