Enzymatically cleavable peptide linkers have gained significant attention in ADC development. They offer superior plasma stability and target specific release mechanism.
Val-Cit and Phe-Lys are optimized peptide-based linkers that can be cleaved by lysosomal extracts and human cathepsin B. Val-Cit (vc) has been successfully implemented in ADCs with payloads such as MMAE/MMAF. Bifunctional p-aminobenzyl alcohol group (PAB) has been used to separate drugs from the site of enzymatic cleavage and minimize the influence of the drug structure and cytotoxic activity. Glutamic acid–valine–citrulline linkers have been reported to ensure in vivo stability and efficacy of antibody–drug conjugates.