EMBO Molecular Medicine (Mar 2024)

A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors

  • Giulia Rotta,
  • Ettore Gilardoni,
  • Domenico Ravazza,
  • Jacqueline Mock,
  • Frauke Seehusen,
  • Abdullah Elsayed,
  • Emanuele Puca,
  • Roberto De Luca,
  • Christian Pellegrino,
  • Thomas Look,
  • Tobias Weiss,
  • Markus G Manz,
  • Cornelia Halin,
  • Dario Neri,
  • Sheila Dakhel Plaza

DOI
https://doi.org/10.1038/s44321-024-00034-0
Journal volume & issue
Vol. 16, no. 4
pp. 904 – 926

Abstract

Read online

Abstract Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named “Intra-Cork”) to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice.

Keywords