In contrast to traditional cancer treatment modalities, targeted therapy acts specifically on tumor-associated molecular targets, thereby reducing toxicities to normal tissues. Although mechanistically diverse, “smart drugs” invariably rely on the identification of surface-presented biomarkers to achieve specific targeting. Unfortunately, extracellular antigens are rarely restricted to cancer cells, thus presenting a critical barrier to the development of safer, more potent therapeutics. In lieu of tumor-exclusive surface-bound targets, we present a novel strategy to design targeted therapeutics that can sense and respond to intracellular disease signatures to provide an additional layer of targeting specificity. An example of an intracellular disease profile is sentrin-specific protease 1 (SENP1), which is frequently overexpressed in prostate, pancreatic, and oncocytic thyroid tumors. We developed a cytotoxic protein switch architecture by re-designing granzyme B (GrB) to act as a synthetic zymogen that requires SENP1-mediated cleavage to trigger apoptosis. We demonstrate that this synthetic GrB molecule is activated by SENP1 in a dose-dependent manner and can achieve SENP1-selective target-cell killing. Furthermore, we demonstrate that this protein architecture can be modularly reconfigured for alternative ligand inputs and is compatible with other technologies for targeted therapy, including immunotoxins and cell-based immunotherapy.

Designing targeted therapeutics to interrogate intracellular tumor antigens

253rd National Meeting (2017)

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