CHAPTER 5: Maytansinoid Payloads for Antibody–Drug Conjugates (ADCs)
Published:11 Jul 2019
The maytansinoids are highly cytotoxic benzoansamacrolides that suppress microtubule dynamics to preferentially kill dividing versus quiescent cells, typically with concentrations that give 50% inhibition (IC50 values) in the sub-nanomolar range. Here, methods are described for preparing maytansinoids for incorporation into antibody–drug conjugates (ADCs) via coupling to antibodies that selectively target antigens on the surface of cancer cells. Maytansinoid ADCs kill antigen-positive cancer cells and, in some instances, release metabolites that can also kill other tumour cells, a mechanism termed “bystander killing”. In vitro and in vivo models comparing maytansinoid ADCs with different linker stabilities as well as those releasing metabolites that induce different degrees of bystander killing are presented. In vivo, non-specific cellular uptake and premature metabolite release are discussed as potential mechanisms leading to ADC systemic toxicity. In addition, the relative tolerance of slowly dividing cells to maytansinoids is presented as a potential tolerability advantage for this payload class compared with payloads that kill cells less discriminately.