The Chemical Design and Synthesis of Linkers Used in Antibody Drug Conjugates.
Curr Top Med Chem. 2018 Jan 18;:
Authors: Frigerio M, Kyle AF
Abstract
Antibody Drug Conjugates (ADCs) use the 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.
PMID: 29357801 [PubMed - as supplied by publisher]
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ΑπάντησηΔιαγραφήThe linker that connects the cytotoxic drug to the mAb is a key determinant of ADC activity. These linkers covalently couple the cytotoxic drug to the antibody, producing an ADC that should be relatively stable in circulation. Stability of the linker is important because it prevents damage to nontarget tissue through spontaneous release of the cytotoxic drug while maximizing tumor drug exposure. ADC Linker
ΑπάντησηΔιαγραφή