High efficiency cell-specific targeting of cytokine activity

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Drug Delivery Systems*
  • Humans
  • Interferon Type I / metabolism
  • Interferon-alpha / metabolism
  • Interleukin-15 / metabolism
  • Interleukin-2 / metabolism
  • Leptin / metabolism*
  • Mice
  • Protein Binding
  • Receptor, Interferon alpha-beta / metabolism
  • Receptors, Cytokine / metabolism*
  • Receptors, Leptin
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Single-Domain Antibodies / metabolism*

Substances

  • Cytokines
  • IFNA2 protein, human
  • IFNAR1 protein, human
  • IFNAR2 protein, human
  • Interferon Type I
  • Interferon-alpha
  • Interleukin-15
  • Interleukin-2
  • Leptin
  • Receptors, Cytokine
  • Receptors, Leptin
  • Receptors, Tumor Necrosis Factor, Type I
  • Single-Domain Antibodies
  • leptin receptor, mouse
  • Receptor, Interferon alpha-beta