CHAPTER 4. Auristatin Payloads for Antibody–Drug Conjugates (ADCs)

The auristatins are a synthetic-peptide-based drug class that inhibit tubulin polymerization and can display exceptionally high potency on a broad array of cancer cells. Consequently, a tremendous amount of research has been focused the design and utilization of auristatin family members within antibody–drug conjugates (ADCs) that deliver the drug to antigen-positive tumour cells. Molecules within the drug class are present within nearly half of all ADCs currently in clinical use, and one of them, monomethyl auristatin E (MMAE) is the active payload in the clinically-approved drug, brentuximab vedotin (ADCETRIS™). The history of the auristatins is described, starting from the discovery of the parental natural product dolastatin 10 to the design and validation of novel synthetic auristatins for targeted delivery. Focus is placed on the most well-known family members, MMAE and monomethyl auristatin F (MMAF), both of which have been extensively investigated in clinical settings. Also discussed are the unique features of the auristatins, such as synthetic accessibility and the ability to modify the drug for control of potency, cell permeability, bystander effects, susceptibility to multidrug resistance efflux, pharmacokinetics, activity and tolerability. The auristatins have featured prominently within modern ADC research, and new developments within the drug class indicate that they will continue to do so.