Glucose Transporter-Targeting\nChimeras Enabling Tumor-Selective\nDegradation of Secreted and Membrane Proteins

Tumor-selective degradation of target proteins has the\npotential\nto offer superior therapeutic benefits with maximized therapeutic\nwindows and minimized off-target effects. However, the development\nof effective lysosome-targeted degradation platforms for achieving\nselective protein degradation in tumors remains a substantial challenge.\nCancer cells depend on certain solute carrier (SLC) transporters to\nacquire extracellular nutrients to sustain their metabolism and growth.\nThis current study exploits facilitative glucose transporters (GLUTs),\na group of SLC transporters widely overexpressed in numerous types\nof cancer, to drive the endocytosis and lysosomal degradation of target\nproteins in tumor cells. GLUT-targeting chimeras (GTACs) were generated\nby conjugating multiple glucose ligands to an antibody specific for\nthe target protein. We demonstrate that the constructed GTACs can\ninduce the internalization and lysosomal degradation of the extracellular\nand membrane proteins streptavidin, tumor necrosis factor-alpha (TNF-α),\nand human epidermal growth factor receptor 2 (HER2). Compared with\nthe parent antibody, the GTAC exhibited higher potency in inhibiting\nthe growth of tumor cells in vitro and enhanced tumor-targeting capacity\nin a tumor-bearing mouse model. Thus, the GTAC platform represents\na novel degradation strategy that harnesses an SLC transporter for\ntumor-selective depletion of secreted and membrane proteins of interest.