Non-internalizing ADCs have the ability to induce a potent anticancer activity in vivo when used with a suitable payload and may target a broad variety of different malignancies. At present, they mainly rely on labile linkers for drug release in close proximity to the target because the intact ADC cannot passively diffuse into cells. Sufficient experimental data prove the fact that collagen IV, tenascin-C, fibrin, the alternatively spliced extra domains A and B (EDA and EDB) of fibronectin and galectin-3-binding protein (Gal-3BP) are appealing targets for non-internalizing ADC development. Scientific findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that does not rely upon antigen internalization.
