Lipophilic Pyridinium Bisphosphonates: Potent gd T Cell Stimulators**

Bisphosphonates such as risedronate and ibandronate are widely used to treat a variety of bone resorption diseases, preventing protein prenylation and disrupting osteoclast function. Bisphosphonates also activate human gd T cells (expressing the Vg2Vd2 T cell receptor), and these activated gd T cells kill tumor cells. 3] There has thus been interest in using bisphosphonates in cancer immunotherapy, with promising results against B-cell malignancies and hormone refractory prostate cancer. In a very recent clinical trial, it was shown that zoledronate offered a significant anticancer benefit when added to hormone therapy, reducing the risk of cancer returning by 36%. The bisphosphonates used in these trials are, however, extremely polar and are rapidly removed from circulation by binding to bone. We reasoned that it might be possible to develop more lipophilic bisphosphonates as gd T cell stimulators that would have improved cell uptake properties as well as decreased bone binding affinity. Herein, we report that novel lipophilic pyridinium bisphosphonates are approximately 250 times more effective in gd T cell activation than any other bisphosphonate drugs. Current nitrogen-containing bisphosphonates are thought to act primarily by blocking farnesyl diphosphate (FPP) formation in the isoprene biosynthesis pathway (Figure 1),