Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent V9/Vδ2 T cell activation and eradication of cancer cells

• Published in: RSC medicinal chemistry Vol. 15; no. 7; pp. 2462 - 2473
• Main Authors: Xu, Qin, Sharif, Maria, James, Edward, Dismorr, Jack O, Tucker, James H. R, Willcox, Benjamin E, Mehellou, Youcef
• Format: Journal Article
• Published: 17.07.2024
• ISSN: 2632-8682
• DOI: 10.1039/d4md00208c

The phosphoantigen ( E )-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of V9/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 V9/Vδ2 T cells, which translated into efficient V9/V2 T cell-mediated eradication of bladder cancer cells in vitro . Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as V9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents. Phosphonodiamidate prodrugs of the monophosphonate derivatives of HMBPP, a natural phosphoantigen, exhibit potent activation of V9V2 T cells resulting in the lysis of bladder cancer cells in vitro .