High efficiency cell-specific targeting of cytokine activity

Geneviève Garcin, Franciane Paul, Markus Staufenbiel, Yann Bordat, José Van der Heyden, Stephan Wilmes, Guillaume Cartron, Florence Apparailly, Stefaan De Koker, Jacob Piehler, Jan Tavernier and Gilles Uzé ()
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Geneviève Garcin: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon
Franciane Paul: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon
Markus Staufenbiel: University of Osnabrück
Yann Bordat: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon
José Van der Heyden: Flanders Institute for Biotechnology, Faculty of Medicine and Health Sciences, Ghent University
Stephan Wilmes: University of Osnabrück
Guillaume Cartron: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon
Florence Apparailly: INSERM U844, University Hospital Montpellier, 80 avenue Augustin Fliche
Stefaan De Koker: Ghent University, Technologiepark 927
Jacob Piehler: University of Osnabrück
Jan Tavernier: Flanders Institute for Biotechnology, Faculty of Medicine and Health Sciences, Ghent University
Gilles Uzé: CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4016

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