Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold

Antibody-drug conjugates (ADCs) are a rapidly growing class of cancer therapeutics. The goal of ADCs is to overcome the low therapeutic index of conventional cytotoxic agents. However, realizing this goal has been a significant challenge. Consisting of an antibody linked to a therapeutic payload, ADCs comprise many components which can be modified, including the target, payload, linker, and bioconjugation method. Many approaches have been developed to improve the physical properties, potency, and selectivity of ADCs. The anti-HER-2 antibody trastuzumab, first approved in 1998, has emerged as an exceptional targeting agent for ADCs, as well as a broadly used platform for testing new technologies, The extensive work in this area enables the comparison of various linker strategies, payloads, drug-to-antibody ratios (DAR), and mode of attachment. In this review, these conjugates, ranging from the first clinically approved trastuzumab ADC, Kadcyla (T-DM1) to the latest variants, are described with the goal of providing a broad overview and comparison of existing and emerging conjugate technologies.