New Non-Peptide Linkers for Antibody-Drug Conjugates Release Cancer Drugs More Selectively

Using structure-guided drug design (including crystal structures of cathepsin B), researchers designed and synthesized novel non-peptide linkers based on a cyclobutane-1,1-dicarboxamide scaffold. They tested protease cleavage specificity in biochemical assays, measured serum stability, evaluated ADC efficacy in animal tumor models, and compared performance head-to-head against the standard valine-citrulline dipeptide linker used in FDA-approved ADCs.

ADCs are one of the fastest-growing areas of cancer drug development, with three FDA-approved and over 60 in clinical trials at the time of this study. A major challenge is the therapeutic index — killing cancer cells while sparing healthy tissue. By making the linker more selective for tumor-specific enzymes, this technology could reduce the side effects of ADC therapies and expand the range of cancers that can be safely treated with these targeted drugs.

This study is part of the broader effort to improve ADC technology — the linker is often called the most underappreciated component of these cancer drugs. Traditional valine-citrulline peptide linkers work but lack protease specificity, contributing to off-target toxicity. By moving beyond peptide chemistry to peptidomimetic structures, this work opens a new design space for ADC linkers. Since 2018, the ADC field has exploded, with drugs like trastuzumab deruxtecan and sacituzumab govitecan becoming blockbusters — making linker innovation even more relevant.

The study demonstrated proof of concept but did not include human clinical trials. While the new linker matched the standard linker's efficacy, the theoretical safety advantage of cathepsin B selectivity was not directly demonstrated through improved therapeutic index in the animal models shown. The long-term stability and immunogenicity of the peptidomimetic linker in humans is unknown.