FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma DOI Creative Commons
Michał Beffinger, Linda Schellhammer, Betül Taşkoparan

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 22, 2025

Abstract Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility systemic treatments and immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion reduced binding to neonatal Fc receptor FcRn. FcRn-silenced avoids FcRn-mediated brain export, thus exhibits prolonged retention blood levels, which prevents In murine glioblastoma, induces more durable responses negligible exposure boosts efficacy of radio- chemotherapy. It triggers anti-tumor independently peripheral T cell influx or lymphopenia leads inflammatory polarization tumor in patient-derived glioblastoma explants. FcRn-silencing may unlock full potential IL-12 cancer could be further applied containing activity other therapeutics targeting neurological diseases.

Language: Английский

FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma DOI Creative Commons
Michał Beffinger, Linda Schellhammer, Betül Taşkoparan

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 22, 2025

Abstract Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility systemic treatments and immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion reduced binding to neonatal Fc receptor FcRn. FcRn-silenced avoids FcRn-mediated brain export, thus exhibits prolonged retention blood levels, which prevents In murine glioblastoma, induces more durable responses negligible exposure boosts efficacy of radio- chemotherapy. It triggers anti-tumor independently peripheral T cell influx or lymphopenia leads inflammatory polarization tumor in patient-derived glioblastoma explants. FcRn-silencing may unlock full potential IL-12 cancer could be further applied containing activity other therapeutics targeting neurological diseases.

Language: Английский

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