AcTakines
Systemic toxicity still prevents full clinical application of cytokines such as type I Interferons (IFNs), Interleukin-1 (IL-1) or Tumor Necrosis Factor (TNF). Whereas immunocytokines (cytokines equipped with a targeting antibody) display a 10-fold increased activity on target cells, off-target side effects experienced by patients are expected to remain a major obstacle. AcTakines (Activity-on-Target cytokines) resemble classical immunocytokines but employ mutant cytokines with reduced binding affinity for their cognate receptor complex. These modifications cause AcTakines to remain inactive 'en route' through the body and to unveil their activity only on specifically targeted cell types which greatly reduces undesired side effects. This AcTakine project is carried out in close collaboration with Gilles Uzé (CNRS, Montpellier).
Proof-of-concept was obtained for structurally divergent cytokines like interferons, interleukin-1, and tumor necrosis factor, underscoring the broad applicability of this concept.
This work was supported by an Advanced ERC grant awarded to Prof. Dr. Jan Tavernier.
Related publications:
- Garcin et al. High efficiency cell-specific targeting of cytokine activity. Nat Commun. (2014)
- Uzé et al. High efficiency targeting of IFN-α activity: possible applications in fighting tumours and infections. Cytokine Growth Factor Rev. (2015)
- Cauwels et al. A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment. Oncoimmunology (2017)
- Cauwels et al. Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments. Cancer Res. (2018)
- Cauwels et al. Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice. J. Autoimmun. (2019)
- Huyghe et al. Safe eradication of large established tumors using neovasculature-targeted tumor necrosis factor-based therapies. EMBO Mol. Med. (2020)
