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FAP-retargeted Ad5 enables in vivo gene delivery to stromal cells in the tumor microenvironment

Hartmann, K. P.; van Gogh, M.; Freitag, P. C.; Kast, F.; Nagy-Davidescu, G.; Borsig, L.; Plueckthun, A.

2022-12-19 biochemistry
10.1101/2022.12.19.520931 bioRxiv
Show abstract

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 (DARPin)-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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