Andreas Plückthun

Making a tumor produce highly potent drugs

There are several fundamental limitations in how therapeutic proteins are used today. First, they are usually applied individually and not in combinations. Secondly, when used systemically, they -- at best -- preferentially localize to the site of action, never exclusively. And third, molecules with high systemic toxicity cannot be used, even if they are very efficacious.

To solve all these problems, we have used several protein engineering technologies to devise  a new platform, termed SHielded, REtargeted ADenovirus (SHREAD). It is based on virus-like particles that are devoid of any viral genes, but contain 36 kb of DNA that can encode multiple genes and complex regulatory regions. To target particular cells and organs, an adapter strategy has been devised, based on the DARPin platform, to selectively target any surface receptor of interest. To hide the particles from the immune system and to minimize liver targeting, a shield was developed based on a trimerized single-chain Fv fragment, covering the facets of the icosahedron.

Applications will be shown to target tumors in vivo via different cell types and express therapeutic antibodies in situ. Additionally, several therapeutic cytokines were expressed simultaneously, to modulate the tumor microenvironment. Finally, experiments will be discussed to infect and reprogram T-cells in vivo. We believe that this versatile technology holds great promise to change the paradigm of precision delivery of therapeutic proteins.