New binding-to-release chemistry enables tumor drug delivery without internalization
Scientists unveiled a binding-to-release (BTR) platform using PhoPEx chemistry that releases drug payloads at tumor sites without needing receptor-mediated endocytosis, showing higher tumor exposure and safety in preclinical models.
A novel binding-to-release (BTR) strategy was developed by engineering a phosphorus(V)-phenol exchange (PhoPEx) linker that undergoes proximity-induced cleavage by nucleophilic residues within a target’s binding site, thereby uncoupling payload release from receptor-mediated endocytosis. In vitro and in vivo experiments using fibroblast activation protein (FAP) showed that BTR-small-molecule-drug conjugates (SMDCs) achieved a 5.9-fold increase in tumor monomethyl auristatin E exposure and tumor-to-blood ratios up to 14.7-fold higher than internalization-to-release (ITR) SMDCs, while reducing off-target release and raising the maximum tolerated dose by 7.5-fold.
The platform enabled accurate fluorescence-based detection of FAP in clinical lymph-node specimens and was extended to PD-L1 and peptide-based conjugates, demonstrating versatility across targets. Toxicology studies and multiple xenograft models confirmed enhanced efficacy and safety, suggesting a widened therapeutic window. These findings indicate that BTR could expand the range of druggable cancer antigens beyond those that internalize efficiently.
Why it matters
It provides a way to target many cancer proteins previously unsuitable for drug conjugates, potentially improving treatment options.
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