Sharif, Maria, Pinna, Claudia M. A., Rakhimova, Kamila, Taher, Taher E., Beggs, Andrew D., Mehellou, Youcef  ORCID: https://orcid.org/0000-0001-5720-8513 and Willcox, Benjamin E.
2026.
Insights into the
mechanism of action of phosphoantigen
prodrugs on Vγ9Vδ2 T cell activation.
ACS pharmacology & translational science
10.1021/acsptsci.6c00264
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Abstract
The activation of Vγ9Vδ2 T cells has emerged as a promising modality in cancer immunotherapy. Phosphate and phosphonate prodrugs of Vγ9Vδ2 T cell phosphoantigens have been developed as potent activators of Vγ9Vδ2 T cells that are capable of effectively facilitating lysis of a range of cancer cells in vitro. In this work, we show that phosphonate prodrugs of the phosphoantigen derivative, HMBP, enter cells in an energy-independent manner and produce their pharmacological activity independently of the mevalonate pathway, a target of the widely used bisphosphonate and Vγ9Vδ2 T cell activator, zoledronate. Interestingly, these prodrugs, termed HMBP ProPAgens, induced an enhanced and more universal Vγ9Vδ2 T cell cytotoxicity against diverse cancer cell lines in vitro compared to zoledronate, an effect also observed in patient-derived colorectal cancer organoids. Together, the data presented in this work further support the development of HMBP ProPAgens as a novel class of cancer immunotherapeutic agents.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Pharmacy |
| Publisher: | American Chemical Society |
| ISSN: | 2575-9108 |
| Date of First Compliant Deposit: | 4 September 2026 |
| Date of Acceptance: | 27 July 2026 |
| Last Modified: | 04 Sep 2026 14:12 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/189398 |
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