Objective

Antibody Drug Conjugates (ADCs) typically contain a small molecule highly potent cytototoxic payload that is attached to a monoclonal antibody via a chemical linker, and utilises the targeting ability of the antibody to deliver the cytotoxin to its intended target. The architecture of the chemical linker comprises a conjugating functionality suitable for attachment to the antibody, a spacer unit that typically incorporates a hydrophilic element and a trigger which releases the potent cytototoxic payload. The design of the chemical linker must take into account the desirable features for ADCs of high stability in systemic circulation but efficient payload release once the ADC reaches its intended target. Understanding these conflicting requirements is critical to designing an effective linker. This ADC linker design has been approached in a variety of different ways, with increasingly elegant solutions continuing to be reported as the understanding of the intricate design complexities increases. This presentation will focus on the synthetic approaches used in ADC linkers, and the impact of linker design on antibody conjugation, ADC pharmacokinetics and payload release. Linker approaches utilized in commercial ADCs as well as ADCs currently in clinical, pre-clinical and early stage development are discussed, as well as the presentation of suitable case studies demonstrating that optimal linker design drives the success of ADC drug development.