Acid-labile Linkers

Acid-labile linkers (pH-sensitive linkers) are a class of chemically cleavable linkers that were explored during the early development of antibody–drug conjugates (ADCs) and are still used widely. In fact, the first ADC approved by the FDA, Mylotarg®, used a hydrazine-based acid-cleavable linker. Despite serum stability issues, acid-labile linkers are frequently employed in ADC applications due to their cleavage propensity within acidic subcellular compartments following the internalization of the ADC-biomarker complex. Indeed, the ideal characteristic of an acid-labile linker is that its linkage to the drug payload remains stable in circulation at physiological pH while effectively releasing the drug in the endosomal/lysosomal environment. This chapter aims to review the field of acid-sensitive cleavable linker technologies relevant to ADCs.