Authors
Singh, B., Das, P., Majee, A., Tajdi, A., Devarajan, A., Lomeli, A., Talluri, A., Dutta, R., Thayumanavan, S.
Abstract
Targeted protein degradation (TPD) has been highly effective for intracellular targets, but extending this approach to extracellular and membrane-bound proteins remains difficult because most extracellular TPD (eTPD) strategies depend on ligand-targeting receptors (LTRs) whose expression and recycling vary across tissues. Existing LTR-independent, multivalent platforms expand the scope of eTPDs by eliminating this dependence on LTRs and enabling cancer-selective designs. Layering in an additional degree of selectivity through endogenously activatable triggers, such as overexpressed enzymes, can enhance the tissue tropism of the LTR-independent platforms and widen therapeutic window. Here we report triggerable polymeric lysosome targeting chimeras (tPolyTACs), which combine antibody-defined targeting with locally triggered covalent capture. tPolyTACs conjugate monoclonal antibodies to phosphatase-cleavable substrates that, upon engagement of endogenous cell-surface phosphatases, unmask a reactive quinone methide electrophile, covalently trapping the target complex and driving its clathrin-mediated internalization and autolysosomal degradation. We show tPolyTAC-mediated degradation of the membrane proteins EGFR, PD-L1, and cMET, and demonstrate that para-substituted electrophiles outperform ortho-substituted analogues likely due to more favorable active-site positioning. These results establish tPolyTACs as a modular, covalent, enzyme-responsive platform that resolves the efficiency-selectivity trade-off limitations in extracellular degradation.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 08 Sep 2026.
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