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

Descripción del proyecto

Ingeniería de proteínas para mejorar los receptores de las membranas celulares

La administración eficaz de fármacos es crucial, pero los receptores transmembrana siguen estando en gran medida inexplorados como proteínas terapéuticas. Su administración suele requerir una costosa terapia génica, que no está al alcance de todos. El proyecto DRESSCODE, financiado por el Consejo Europeo de Investigación, avanzará en la ingeniería de proteínas para mejorar los receptores de membrana celular utilizando proteínas recombinantes. Mediante la ingeniería de varios dominios de receptores por separado y su posterior combinación, el proyecto pretende desarrollar terapias rentables. Se centrará en la creación de proteínas de fusión que mejoren la detección y señalización de receptores. El proyecto demostrará su eficacia en dos aplicaciones clínicas: la ingeniería del VEGFR-2 para la angiogénesis terapéutica y la modificación del CAR para la inmunoterapia contra el cáncer basada en linfocitos T, lo que en última instancia dará lugar a proteínas terapéuticas innovadoras y nuevas herramientas de investigación.

Objetivo

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.