Most protein-based drugs currently in clinical use are based on soluble proteins that are administered to patients as bulk formulations or via smart drug-delivery systems with controlled release kinetics. To date, these delivery systems do not enable the use of transmembrane proteins as drugs, particularly synthetic signalling receptors. Nevertheless, recent advances in gene therapy and cell-based therapy have demonstrated that such synthetic receptors could be highly promising therapeutic agents. For example, chimeric antigen receptor (CAR) T-cell therapy against cancer has revolutionised cancer treatment. However, both gene and cell-based therapies rely on genetic engineering of cells, which remains expensive and is not widely accessible.
The challenge of DRESSCODE is to push the boundaries of protein engineering, by developing innovative protein-based drug-delivery systems capable of delivering functional transmembrane receptors to cells without altering the cell genome. Such delivery systems would offer facilitated manufacturing, improved cost-effectiveness, and off-the-shelf therapeutic products for clinical use. The overall objective of the project is to provide proof-of-concept for the successful delivery of (1) a functional CAR receptor to T cells for cancer immunotherapy and (2) a functional VEGFR-2 receptor to endothelial cells to enhance angiogenesis in wound healing—two high-impact medical applications. Using a step-by-step approach involving multivalency-based proteins, membrane-insertion peptides, cell-penetrating peptides, delivery of signalling domains and protein–protein fusions, we aim to reconstruct the extracellular, transmembrane, and intracellular domains of single-pass transmembrane receptors.
The success of DRESSCODE will establish a novel category of therapeutic proteins—recombinant transmembrane receptors—as drugs for clinical application.
