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Nat Commun. 2014;5:3016. doi: 10.1038/ncomms4016.

High efficiency cell-specific targeting of cytokine activity.

Author information

1
CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France.
2
Division of Biophysics, Department of Biology, University of Osnabrück, 49069 Osnabrück, Germany.
3
Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BE 9000, Belgium.
4
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.
5
INSERM U844, University Hospital Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier, France.
6
Department for Molecular Biomedical Research, Ghent University, Technologiepark 927, 9052 Zwijnaarde, Belgium.
7
1] Division of Biophysics, Department of Biology, University of Osnabrück, 49069 Osnabrück, Germany [2].
8
1] Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Ghent, BE 9000, Belgium [2].
9
1] CNRS UMR 5235, University Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France [2].

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.

PMID:
24398568
DOI:
10.1038/ncomms4016
[Indexed for MEDLINE]

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