FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma
- Michal Beffinger
- Linda Schellhammer
- Betül Taskoparan
- Sereina Deplazes
- Ulisse Salazar
- Nazanin Tatari
- Frauke Seehusen
- Leopold von Balthazar
- Carl Philipp Zinner
- Sabine Spath
- Tala Shekarian
- Marie-Françoise Ritz
- Marta McDaid
- Pascal Egloff
- Iwan Zimmermann
- Hideho Okada
- E. Sally Ward
- Jack Rohrer
- Markus A. Seeger
- Thorsten Buch
- Gregor Hutter
- Johannes vom Berg
2025-05-22
Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases.