FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma
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.
Authors
- Tala Shekarian (ORCID: https://orcid.org/0000-0002-3964-5354)
- Carl Zinner (ORCID: https://orcid.org/0000-0003-1609-0920)
- Marie‐Françoise Ritz (ORCID: https://orcid.org/0000-0002-5650-9987)
- Gregor Hütter (ORCID: https://orcid.org/0000-0002-7570-3902)
- Sereina Deplazes
- Jack Rohrer (ORCID: https://orcid.org/0000-0002-2058-490X)
- Betül Taşkoparan (ORCID: https://orcid.org/0000-0003-1890-1547)
- E. Sally Ward (ORCID: https://orcid.org/0000-0003-3232-7238)
- Marta McDaid
- Hideho Okada (ORCID: https://orcid.org/0000-0003-0076-9920)
- Leopold von Balthazar
- Nazanin Tatari (ORCID: https://orcid.org/0000-0002-0003-6121)
- Michał Beffinger (ORCID: https://orcid.org/0000-0002-6916-7517)
- Iwan Zimmermann (ORCID: https://orcid.org/0000-0003-3476-4749)
- Ulisse Salazar (ORCID: https://orcid.org/0009-0008-8041-3222)
- Sabine Spath (ORCID: https://orcid.org/0000-0002-2689-1951)
- Thorsten Buch (ORCID: https://orcid.org/0000-0002-2236-9074)
- Frauke Seehusen (ORCID: https://orcid.org/0000-0001-6701-7868)
- Pascal Egloff (ORCID: https://orcid.org/0000-0001-8948-3704)
- Linda Schellhammer (ORCID: https://orcid.org/0000-0001-6044-033X)
- Markus A. Seeger (ORCID: https://orcid.org/0000-0003-1761-8571)
- Johannes vom Berg (ORCID: https://orcid.org/0000-0002-4086-1564)
Institutions
- University of California, San Francisco (US)
- University of Zurich (CH)
- University Hospital of Basel (CH)
- Parker Institute for Cancer Immunotherapy (US)
- Linkster Therapeutics (Switzerland) (CH)
- Polyphor (Switzerland) (CH)
- Neurological Surgery (US)
- NIHR CRUK Experimental Cancer Medicine Centre (GB)
- ZHAW Zurich University of Applied Sciences (CH)
- Actelion (Switzerland) (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1038/s41467-025-59971-0
- Citations
- 1
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 1.36
Funders
- National Science Foundation
- Novartis Foundation
- University of Southampton
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Kommission für Technologie und Innovation
- Brain Tumour Charity
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Universität Zürich
- Universitätsspital Zürich
- Innosuisse - Schweizerische Agentur für Innovationsförderung
- Swiss Cancer Research Foundation
- Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa