FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma
Year: 2025
Type: article
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.
DOI: 10.5167/uzh-277969
Authors: Beffinger, Michal, Schellhammer, Linda, Taskoparan, Betül, Deplazes, Sereina, Salazar, Ulisse, Tatari, Nazanin, Seehusen, Frauke, von Balthazar, Leopold, Zinner, Carl Philipp, Spath, Sabine, Shekarian, Tala, Ritz, Marie-Françoise, McDaid, Marta, Egloff, Pascal, Zimmermann, Iwan, Okada, Hideho, Ward, E Sally, Rohrer, Jack, Seeger, Markus A, Buch, Thorsten, Hutter, Gregor, vom Berg, Johannes
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6929861921
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