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FAP-retargeted Ad5 enables in vivo gene delivery to stromal cells in the tumor microenvironment.
Hartmann, K Patricia; van Gogh, Merel; Freitag, Patrick C; Kast, Florian; Nagy-Davidescu, Gabriela; Borsig, Lubor; Plückthun, Andreas.
Afiliación
  • Hartmann KP; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • van Gogh M; Department of Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Freitag PC; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Kast F; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Nagy-Davidescu G; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Borsig L; Department of Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Plückthun A; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: plueckthun@bioc.uzh.ch.
Mol Ther ; 31(10): 2914-2928, 2023 Oct 04.
Article en En | MEDLINE | ID: mdl-37641405
Fibroblast activation protein (FAP) is a cell surface serine protease that is highly expressed on reactive stromal fibroblasts, such as cancer-associated fibroblasts (CAFs), and generally absent in healthy adult tissues. FAP expression in the tumor stroma has been detected in more than 90% of all carcinomas, rendering CAFs excellent target cells for a tumor site-specific adenoviral delivery of cancer therapeutics. Here, we present a tropism-modified human adenovirus 5 (Ad5) vector that targets FAP through trivalent, designed ankyrin repeat protein-based retargeting adapters. We describe the development and validation of these adapters via cell-based screening assays and demonstrate adapter-mediated Ad5 retargeting to FAP+ fibroblasts in vitro and in vivo. We further show efficient in vivo delivery and in situ production of a therapeutic payload by CAFs in the tumor microenvironment (TME), resulting in attenuated tumor growth. We thus propose using our FAP-Ad5 vector to convert CAFs into a "biofactory," secreting encoded cancer therapeutics into the TME to enable a safe and effective cancer treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos