An ADC consists of three key components: a drug or payload, a linker, and an antibody. There are two broad categories of ADC linkers, namely cleavable and non-cleavable linkers.The former can be divided into several sub-types including: Acid-labile linkers, Protease cleavable linkers, Disulfide linkers; In contrast, the non-cleavable linkers have higher blood stability and often rely on internalization kinetics, facile lysosomal delivery, and ensuing ADC degradation to yield cancer cell apoptosis. Non-cleavable linkers account for about 20 % of the ADCs in clinical testing. Clearly, there is inter-dependency between the linker and conjugation chemistry. The choice of linker-conjugation chemistry affects ADC’s stability, efficacy, pharmacokinetics, homogeneity, and biophysical integrity. There are several conjugation strategies: Conjugation through lysine amino acids, Conjugation via cysteine residues by reducing ‘inter-chain’ native disulfide bonds, Increasing the homogeneity of the ADC by sitespecific conjugation via genetically engineered amino acid alteration, Enzyme-mediated conjugation and incorporation of an unnatural amino acid.

References:

1.Bakhtiar R. Biotechnol Lett. 2016 Oct;38(10):1655-64.