Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells
- RSC Med Chem. 2024 Jun 3;15(7):2462-2473. doi: 10.1039/d4md00208c.
- 1. School of Pharmacy and Pharmaceutical Sciences, Cardiff University Cardiff CF10 3NB UK [email protected].
- 2. Institute of Immunology and Immunotherapy, University of Birmingham Birmingham B15 2TT UK [email protected].
- 3. Cancer Immunology and Immunotherapy Centre, University of Birmingham Birmingham B15 2TT UK.
- 4. School of Chemistry, University of Birmingham Birmingham B15 2TT UK.
- 5. Medicines Discovery Institute, Cardiff University Cardiff CF10 3AT UK.
The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by Carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder Cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel Cancer immunotherapeutic agents.