The valine-citrulline-p-aminobenzyloxycarbonyl (Val-Cit-PAB) linker is a cleavable linker system specifically designed for the controlled intracellular release of a therapeutic agent. Antibody-drug conjugates (ADC) can maximize therapeutic benefit while simultaneously reducing systemic toxicity in surrounding healthy tissue.

The linker system consists of several components:
1) Valine-citrulline (Val-Cit) dipeptide: This peptide sequence serves as a recognition site for lysosomal proteases. Cathepsin B, which is frequently overexpressed in tumor cells, plays a central role in this process.
2) p-Aminobenzyloxycarbonyl (PABC) spacer: This spacer connects the dipeptide to the cytotoxic drug and releases the drug via a cascade mechanism following cleavage of the dipeptide.

-> high stability and target specificity of Val-Cit linker conjugates:
linkers must be stable in the bloodstream and in healthy tissue while simultaneously delivering active agents efficiently to the tumor (specific enzymatic cleavage in tumor tissue).


Literature:
Exo-Cleavable Linkers: Enhanced Stability and Therapeutic Efficacy in Antibody−Drug Conjugates. Watanabe et al.; J. Med. Chem. 2024, 67, 18124−18138.
https://doi.org/10.1021/acs.jmedchem.4c01251