Glycosidase Cleavable Linker

Glycosidase cleavable linkers use enzyme-triggered hydrolysis to connect targeted ligands or prodrugs with cytotoxic payloads, supporting selective release at tumor cells or defined biological sites^[1][2]. Mechanistically, β-glucuronide linkers can be cleaved by lysosomal β-glucuronidase, and this design enabled CS5001 to release a DNA-crosslinking PBD dimer in ROR1-expressing malignancy models^[3]. In antibody-enzyme prodrug therapy, a monoclonal antibody-β-glucuronidase conjugate activated epirubicin-glucuronide at antigen-positive tumor cells, restoring cytotoxicity after prodrug hydrolysis^[4]. Compared with non-cleavable or nonspecifically labile linkers, ideal ADC linkers should remain stable in circulation and release payload specifically in tumors, because nonspecific release contributes to off-target toxicity^[2]. Glycosylated paclitaxel prodrugs also showed improved solubility, serum release behavior, and β-glucuronidase-mediated parent-drug release, supporting glycosylation as a practical prodrug modification strategy^[5]. Therefore, glycosidase cleavable linkers provide research value for ADCs, prodrugs, and targeted drug conjugates when linker stability, enzyme access, tumor selectivity, and payload release must be experimentally balanced^[1][2][5].