Enhancing the Safety and Efficacy of PSMA-Based Small-Molecule Drug Conjugates by Linker Stabilization and Conjugation to Transthyretin Binding Ligand

This work describes the enhancement of a novel antitumor
therapeutic
platform that combines advantages from small-molecule drug conjugates
(SMDCs) and antibody drug conjugates (ADCs). Valine–citrulline
(VCit) dipeptide linkers are commonly used cathepsin B cleavable linkers
for ADCs. However, the instability of these linkers in mouse serum
makes translating efficacy data from mouse to human more challenging.
Replacing the VCit linker with glutamic acid–valine–citrulline
(EVCit) has been reported to enhance the stability of ADCs in mouse
serum. However, the effect of EVCit linker on the stability of SMDCs
has not been reported. Here, we report that incorporating the EVCit
linker in prostate-specific membrane antigen-targeting SMDCs, equipped
with the transthyretin ligand AG10, resulted in conjugates with lower
toxicity, an extended half-life, and superior therapeutic efficacy
to docetaxel in a xenograft mouse model of prostate cancer. This should
make SMDCs’ preclinical toxicity and efficacy data from mice
more reliable for predicting human results.