High efficiency cell-specific targeting of cytokine activity

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. Despite their clinical potential, cytokines can often be highly toxic in patients, due to their systemic activity. Here, the authors present a strategy to engineer immunocytokines with very high targeting efficacies using mutant cytokines linked to nanobodies that only become active when bound to a specific cell marker.