Development of a novel antibody-based platform for lysosome-mediated targeted protein degradation

As much as 85% of the human proteome is considered to be undruggable as many proteins lack well-defined pockets for small-molecule drugs to bind and modulate their function. This has been challenged with the emergence of targeted protein degradation approaches, that make use of the cytosolic waste disposal system for the removal of a disease-causing protein, ablating all of its functions. However, such strategies have been limited to target engagement within the intracellular environment. We propose here a novel platform that couples a newly developed protein-based binder of the cation-independent mannose-6-phosphate receptor (CI-M6PR) to a protein-based binder of an extracellularly-accessible protein of interest, to target this latter protein for lysosomal degradation. To establish proof of concept, our technology will be tested in the context of epithelial cancers. To this end, we will produce protein constructs targeting a receptor of which the overexpression is often linked to the occurence of such cancers. We suggest that degradation of this receptor, mediated by our proposed protein-based constructs, could lead to a potent anti-tumor effect, both in vitro and in vivo, above and beyond what can be achieved with the existing therapeutic antibodies.