Mark Frigerio* and Andrew F. Kyle Pages 3393 - 3424 ( 32 )
Antibody Drug Conjugates (ADCs) use targeting ability of monoclonal antibodies to deliver potent cytototoxic payloads to their intended target. The linker encompasses 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 warhead. Understanding the conflicting requirements of ADC design, providing stability in systemic circulation but efficient payload release once the ADC reaches its intended target, is crucial to effective linker development. ADC linker design has been approached in a variety of different ways, with increasingly elegant solutions continuing to be reported as understanding of the intricate design complexities increases. This review focuses 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.
Antibody Drug Conjugate, Linker Design, Conjugation Technologies, Disulfide Rebridging, Release Mechanism, Toxin Specific Linkers.
Abzena, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, Abzena, Babraham Research Campus, Babraham, Cambridge, CB22 3AT