ADC Linker

The linker that connects the cytotoxic drug to the mAb is a key determinant of ADC activity. These linkers covalently couple the cytotoxic drug to the antibody, producing an ADC that should be relatively stable in circulation. Stability of the linker is important because it prevents damage to nontarget tissue through spontaneous release of the cytotoxic drug while maximizing tumor drug exposure. Upon internalization, however, the linkers should facilitate efficient drug release. Intracellular conditions such as the low-pH environment in lysosomes or the reducing environment of the cytosol can destabilize acid-labile hydrazone linkers or disulfide-based linkers, respectively, resulting in drug release. ADCs have entered the clinic with a variety of different linkers that all effectively balance these attributes. The properties of a successful linker can be split up into different modules that have been combined to form an effective bridge between the cytotoxic payload and the carrier antibody.