CHAPTER 18: Tubulysins as Antibody–Drug Conjugate (ADC) Payloads

The tubulysins are a family of naturally occurring tetrapeptides, originally isolated from a culture broth of strains of myxobacteria (soil bacterial). They are potent inhibitors of microtubule polymerisation, causing rapid disintegration of the cytoskeleton of dividing cells leading to apoptosis, and their potent activity against multidrug-resistant carcinoma cell lines has made them of interest as antibody–drug conjugate (ADC) payloads. As part of ADC development programs, significant work has been completed on increasing potency, structural simplification and molecular stability, as well as developing effective strategies for linking to antibodies. This work has been successful, with a number of antibody–tubulysin conjugates progressing into clinical use.