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 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 and Johannes vom Berg ()
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Michal Beffinger: University of Zurich
Linda Schellhammer: University of Zurich
Betül Taskoparan: University of Zurich
Sereina Deplazes: University of Zurich
Ulisse Salazar: University of Zurich
Nazanin Tatari: University Hospital and University of Basel
Frauke Seehusen: University of Zurich
Leopold Balthazar: Zurich University of Applied Sciences
Carl Philipp Zinner: University of Zurich
Sabine Spath: InCephalo AG
Tala Shekarian: University Hospital and University of Basel
Marie-Françoise Ritz: University Hospital and University of Basel
Marta McDaid: University Hospital and University of Basel
Pascal Egloff: University of Zurich
Iwan Zimmermann: University of Zurich
Hideho Okada: University of California
E. Sally Ward: University of Southampton
Jack Rohrer: Zurich University of Applied Sciences
Markus A. Seeger: University of Zurich
Thorsten Buch: University of Zurich
Gregor Hutter: University Hospital and University of Basel
Johannes vom Berg: University of Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59971-0

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