The innately fluorescent tetravalent cytotoxic conjugate TetraFHER2-vcMMAE engages aggregation-dependent endocytosis of HER2 for enhanced intracellular drug delivery

Breast cancer is the most common malignancy in women, with approximately 20-30% of all diagnosed cases characterized by HER2 overexpression. Several HER2-targeted cytotoxic conjugates have been developed, but their efficacy is limited. One of the main obstacles restraining the effectiveness of HER2-specific cytotoxic conjugates is their very low internalization, as HER2 is immobile mainly on the cell surface. Therefore, there is a need to develop novel HER2-selective cytotoxic conjugates that will overcome HER2 immovability and, by this, ensure efficient drug delivery into HER2-overexpressing cancer cells. Here, we present a novel system for generating high affinity, self-assembling, inherently fluorescent, multivalent HER2 ligands capable of HER2 clustering on the cell surface. Developed HER2-specific multivalent ligands largely overcome the innate stability of HER2 in the plasma membrane by triggering clathrin-independent, aggregation-dependent endocytosis of the receptor. To exploit the pro-endocytic potential of developed proteins, we constructed the tetravalent fluorescent cytotoxic conjugate TetraFHER2-vcMMAE and demonstrated its high potency and selectivity against HER2+ breast cancer cells. These data are raw data from publication by Porębska et al: The innately fluorescent tetravalent cytotoxic conjugate TetraFHER2-vcMMAE that engages aggregation-dependent endocytosis of HER2 for enhanced intracellular drug delivery.