Synthesis and evaluation of BTN3A1 ligands for cancer immunotherapy

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Abstract There is a compelling and unmet medical need for new immunotherapies as current agents are not successful for all cancer patients. The transmembrane protein BTN3A1 is a promising new immunotherapy target because its agonist binding both removes inhibition of αβ T cells and activates γδ T cells. A BTN3A1 agonist effectively treated a mouse model of ovarian cancer with low toxicity, suggesting further development of BTN3A1 agonists is warranted. However, current small molecule BTN3A1 agonists are limited by poor PK properties, including low stability, low membrane permeability, and limited tumor selectivity. Our preliminary data in this area shows that BTN3A1 agonists based on a phosphonate scaffold have improved cellular stability relative to phosphate-based agonists, and prodrug forms of these agonists have better potency. We have recently discovered a novel aryl- acyloxyalkyl prodrug strategy that retains these features while also improving plasma stability and kinetics of cellular uptake, and may increase tumor cell specificity. The overall objective of this program is to synthesize novel BTN3A1 ligands with improved drug-like properties and evaluate them in cellular and mouse models of cancer. Our central hypothesis is that novel synthetic agonists based on a phosphonate scaffold can engage BTN3A1 to trigger an anti-cancer immune response by stimulating both αβ and γδ T cells. Stimulating both T cell populations is innovative and potentially adventitious because they infiltrate tumors in a pattern that is not correlated and γδ T cell infiltration can be more favorable to overall survival. To achieve these goals, we will apply our novel aryl-acyloxyalkyl phosphonate protecting strategy to BTN3A1 agonists. We will synthesize a series of aryl-acyloxyalkyl phosphonate BTN3A1 ligand prodrugs optimized for in vivo application, and characterize their stability, metabolism, potency and selectivity. We will use existing pilot compounds to address fundamental unanswered questions of how BTN3A1 ligands activate the anti-cancer response of both αβ and γδ T cells against lymphoma cells, but also more immunologically cold ovarian cancer cells. This would be the first SAR study of BTN3A1 ligands on checkpoint inhibition of αβ T cells. We will examine the activity of these compounds in animal models of lymphoma and ovarian cancer, and assess the safety of the compounds. The ultimate goal is to identify a safe and effective BTN3A1 ligand prodrug that can be used for cancer immunotherapy. These findings will come at a time when the biological understanding of anti-cancer immunity and the role of BTN3A1 is far from complete. Thus, these studies have the potential for high impact on the field of cancer immunotherapy.