Cathepsin B in the lysosome cleaves the peptide bond between Cit-PAB of dipeptide linkers containing valine (Val)-citrulline (Cit) and p-aminobenzylalcohol (PAB). When PAB and a drug are binded covalently with carbamate bonds, the drug can be released by hydrolysis after cleavage of the peptide bond between Cit-PAB. Antibody-drug conjugates (ADCs) has been developed using this mechanism.
- Contain Val-Cit sequence degradable by a lysosome enzyme
- Have superior plasma stability comparable to that of non-cleavable linkers
- Available for manufacturing with several tens gram scale
- 1) Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity.
- 2) A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy
- 3) Effect of Attachment Site on Stability of Cleavable Antibody Drug Conjugates