Recent progress in linker technology for antibody-drug conjugates: Methods for connection and release

Abstract

Linkers connect antibodies to payloads in antibody-drug conjugates (ADCs). The choice of linker controls the conjugation-site and antibody-drug ratios as well as the releasing mechanism and the rate of release. In order to optimize the efficacy of ADCs, improvements in linker technology, especially site-selective conjugation methods, are being explored. Site-specific conjugation methods involving non-natural amino acid incorporation, glycan utilization, and enzymatic addition methodologies are discussed in this chapter. In addition to conjugation methodology, payload-releasing strategy is a very important consideration for delivering maximum focused toxicity to the vicinity of the tumor cells. Although protease-cathepsin-cleavable dipeptide Val-Cit sequence is currently the most common choice for an enzymatic cleavable linker, novel approaches for releasing payloads, such as light stimulation and chemical reaction, have been reported. In this chapter, advances in development of linker technology will be reviewed.