Phosphonamidate prodrugs of a butyrophilin ligand

The use of T cell immunotherapy may have clinical potential for the treatment of bacterial infections or certain cancers including myeloid leukemia, because T cells are able to mediate their destruction. While the type of human T cells responsible for mediating this process account for only a small percentage of circulating immune cells, their population is capable of rapid expansion when stimulated with an active drug such as a phosphoantigen. Although the precise mechanism of this response remains unclear, experimental evidence shows that once inside the cell a phosphoantigen binds to the protein called butyrophilin 3A1 and this step is required for activation of an immune response. Because the most potent natural phosphoantigen is too biologically unstable for potential clinical use, we have explored and developed phosphoantigen analogs that provide a more balanced stability and potency profile. These analogs would function like a Trojan horse, in the sense that we strategically mask our analogs such that the active drug remains unrecognized as a substrate to various biological processes that would otherwise result in its identification and subsequent transformation into non-active components prior to reaching its target. Conceptually similar to a Trojan horse, the intention when designing these analogs is to hide the active drug until it is ready to reveal itself once permitted to enter the target cell. Once within the cell, this Trojan horse undergoes biochemical conversion and eventually reveals the active drug. Once revealed, our active drug functions to raise the flag of the castle, through binding to butyrophilin 3A1, to signal the T cells to help combat bacterial infections and certain cancers. This work provides evidence of novel phosphoantigen analogs with improved stability and potency relative to the most potent natural phosphoantigen. The combination of stability and potency resulted in evaluation of an analog in mice, which proved to sensitize tumors within minutes.