Enhanced ADC linkers

Most approved antibody-drug conjugates use valine-citrulline (Val-Cit) linkers that are cleaved by lysosomal cathepsins. The problem: these proteases also exist in healthy tissues, causing premature payload release and off-target toxicity. Better linker selectivity requires chemistry beyond the standard amino acid toolkit.

Using non-canonical amino acid residues in the linker peptide, researchers identified sequences with high selectivity for cancer-associated proteases over normal-tissue enzymes. The ncAA-containing linkers achieved potent tumour cell killing while non-cleavable controls showed minimal activity, confirming that therapeutic effect depends on selective cleavage, not passive drug leakage (Gorzen et al., 2025).

Linker design is a critical variable in ADC development. Site-specific ncAA conjugation (defining where the drug attaches to the antibody) combined with ncAA-enhanced linkers (controlling when and where the drug releases) gives developers two independent optimisation levers for improving the therapeutic window of antibody-drug conjugates.