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Synthesis and Immunomodulatory Activity of Fluorine‐Containing Bisphosphonates
Journal article   Open access   Peer reviewed

Synthesis and Immunomodulatory Activity of Fluorine‐Containing Bisphosphonates

Satoshi Mizuta, Mohammed S. O Tagod, Masashi Iwasaki, Yoichi Nakamura, Hiroaki Senju, Hiroshi Mukae, Craig T Morita and Yoshimasa Tanaka
ChemMedChem, Vol.14(4), pp.462-468
02/19/2019
DOI: 10.1002/cmdc.201800764
PMCID: PMC6818088
PMID: 30637982
url
https://doi.org/10.1002/cmdc.201800764View
Published (Version of record) Open Access

Abstract

Immune checkpoint blockade using anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, many types of cancer do not respond and for those that do, only a minority of patients achieve durable remissions. Therefore, oncoimmunologists are working to develop adoptive cell therapies for non‐hematopoietic tumors by harnessing immune effector cells such as αβ T cells and γδ T cells. In contrast to conventional αβ T cells that recognize peptides in the context of MHC class I or II molecules, γδ T cells expressing Vγ2Vδ2 T cell receptors (also termed Vγ9Vδ2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin‐3A1‐dependent manner. Vγ2Vδ2 T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine‐containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine‐containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2 T‐cell‐mediated cytotoxicity, and also promoted the expansion of peripheral blood Vγ2Vδ2 T cells. These results demonstrate that a prodrug of a fluorine‐containing zoledronate analogue can sensitize tumor cells for killing as well as expand Vγ2Vδ2 T cells for adoptive cell therapy. Firing up the T cells: Cancer immunotherapy has become a clinically validated intervention. Although much attention is focused on monoclonal antibody (mAb)‐based immunotherapies, the efficacy of immune checkpoint therapy is limited. To develop more effective treatments, we synthesized fluorinated nitrogen‐containing (N‐BPs) and a prodrug 11 for use with Vγ2Vδ2 T‐cell‐based immunotherapies.
 nitrogen-containing bisphosphonates Vγ2Vδ2 γδ T cells cancer immunotherapy non-radioactive cellular cytotoxicity assays fluorine

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