Fig. 3

Mode of action of anti-HER2 based ADCs, T-DM1 and the Biparatopic anti-HER2 ADC. a - In HER2 positive cancer cells, T-DM1 is internalized via clathrin coated pits and reaches endosomes where the antibody is degraded leading to the release of DM1. A small fraction of T-DM1 reaches the lysosomes where it can also be degraded. DM1 traverse the lysosomal/endosomal membrane and accesses the cytosol. DM1 can then bind the microtubules, triggering depolymerisation leading to cell death. b - In cancer stem cells, T-DM1 is endocytosed via autophagy. It reaches autophagosomes and later autolysosomes where it is degraded leading to the release of DM1. DM1 accesses the cytosol and inhibits microtubules polymerization leading to cell death. c - The biparatopic anti-HER2 ADC has more efficient trafficking to the lysosomes compared to the monoclonal T-DM1. Its drug tubulysin is liberated in the lysosomes and accesses the cytosol where it can induce the depolymerization of microtubules. In addition, it can exert a bystander effect