Acid-labile hydrazone (AcBut)

aka acid-cleavable linker

The hydrazone linker is acid-sensitive and breaks in the lysosome's low pH. It was used in the calicheamicin ADCs, but is too leaky for most modern designs.

Hydrazone linkers hydrolyse at pH 4 to 5 and are relatively unstable in plasma, contributing to the off-target toxicity of first-generation ADCs. Gemtuzumab ozogamicin and inotuzumab ozogamicin use a hydrazone combined with a disulfide.