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Engineering next-generation fusion proteins to dress the cell membrane with functionally enhanced receptors

Project description

Protein engineering to enhance cell membrane receptors

Effective drug delivery is crucial, yet transmembrane receptors remain largely unexplored as therapeutic proteins. Their delivery often requires costly gene therapy, which is not widely accessible. The ERC-funded DRESSCODE project will advance protein engineering to enhance cell membrane receptors using recombinant proteins. By engineering various receptor domains separately and then combining them, the project aims to develop cost-effective therapies. It will focus on creating fusion proteins that improve receptor sensing and signalling. The project will demonstrate its effectiveness in two clinical applications: engineering VEGFR-2 for therapeutic angiogenesis and modifying CAR for T cell-based cancer immunotherapy, ultimately leading to innovative therapeutic proteins and new research tools.

Objective

No drug can be effective without an appropriate delivery system; this is why the development of formulations for effective and safe drug delivery currently raises major interests, in all clinical applications. While the use of therapeutic proteins has substantially increased in the last four decades, there is an entire class of proteins that has not yet been explored as drugs: the transmembrane receptors. In fact, the delivery of receptors for clinical applications remains very challenging and has only been achieved via genetic engineering of cells, referred as gene therapy. To date, most gene therapies remain extremely expensive and therefore, poorly accessible to patients.
DRESSCODE proposes to innovate cutting-edge protein engineering technologies to deliver and enhance receptors at the cell membrane, using recombinant proteins only. By doing so, we aim to create a paradigm shift from genetic engineering to protein engineering of the cell membrane, with the ambition of developing cost-effective protein-based therapies.
In DRESSCODE, we will first engineer independently the extracellular, intracellular, and transmembrane parts of a receptor, before combining our technologies to reconstruct functional receptors with enhanced bioactivity. Particularly, we will generate fusion proteins that 1) target the cell surface with super-avidity, to enhance receptor sensing; 2) penetrate the cell membrane and target its inner side, to enhance receptor signaling; and 3) insert across the cell membrane to reconstitute the receptor transmembrane domain using pH-low inserting peptides.
DRESSCODE will demonstrate Proof-of-Technologies in two high-impact clinical applications, focusing on the engineering of VEGFR-2 for therapeutic angiogenesis and of the CAR for T cell-based cancer immunotherapy. Its success will lead to the development of novel therapeutic proteins and inspire the future use of receptors as drugs, while providing valuable tools for biological research.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

(opens in new window) ERC-2023-STG

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Host institution

UNIVERSITAETSKLINIKUM FREIBURG
Net EU contribution
€ 1 497 778,00
Address
HUGSTETTER STRASSE 49
79106 Freiburg
Germany
Region
Baden-Württemberg Freiburg Freiburg im Breisgau, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 497 778,00

Beneficiaries (1)