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Synthesis and evaluation of BTN3A1 ligands for cancer immunotherapy

用于癌症免疫治疗的 BTN3A1 配体的合成和评估

基本信息

批准号：
10613486
负责人：
ANDREW J WIEMER
金额：
$ 35.44万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613486
关键词：
Address Affect Agonist American Animal Cancer Model Animal Model Antigens Area Binding Biological Biological Assay CTAG1 gene Cancer Model Cancer Patient Cell Line Cell Membrane Permeability Cell Proliferation Cell model Cells Clinical Coculture Techniques Cytolysis Data Development Diphosphates Disease Dose Drug Targeting Evaluation Failure Goals Human Immune Immune checkpoint inhibitor Immune response Immune system Immunologics Immunotherapeutic agent Immunotherapy In Vitro Infiltration Integral Membrane Protein Kinetics Ligand Binding Ligands Lymphoma Lymphoma cell Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mediating Medical Metabolism Modeling Mus Normal Cell Outcome Patients Pattern Peripheral Blood Mononuclear Cell Permeability Pharmaceutical Preparations Phosphorus Plasma Population Prodrugs Production Property Proteins Public Health Research Role Safety Series Specificity T cell infiltration T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Time Toxic effect Transplantation Tumor Antigens Tumor Immunity Work anti-cancer anticancer activity butyrophilin cancer cell cancer immunotherapy checkpoint inhibition chemotherapy cytokine efficacy evaluation fighting immune checkpoint immunotoxicity improved in vivo innovation inorganic phosphate leukemia/lymphoma mouse model neoplastic cell novel overexpression phosphonate prevent programs public health relevance receptor response retention rate safety assessment scaffold small molecule stability testing tumor tumor growth tumor progression uptake γδ T cells

项目摘要

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.

摘要由于目前的药物并不成功，因此对新的免疫疗法存在迫切且未满足的医疗需求所有癌症患者。跨膜蛋白BTN 3A 1是一个有前途的新免疫治疗靶点，因为它的激动剂结合既消除了αβ T细胞的抑制又激活了γδ T细胞。BTN 3A 1激动剂有效地以低毒性治疗卵巢癌小鼠模型，提示BTN 3A 1激动剂的进一步开发是有根据的然而，目前的小分子BTN 3A 1激动剂受限于差的PK性质，包括低的稳定性、低膜渗透性和有限的肿瘤选择性。我们在这方面的初步数据显示，基于膦酸酯支架的BTN 3A 1激动剂相对于基于磷酸酯的BTN 3A 1激动剂具有改善的细胞稳定性。激动剂和这些激动剂的前药形式具有更好的效力。我们最近发现了一种新的芳基- 酰氧基烷基前药策略，其保留了这些特征，同时还改善了血浆稳定性和药物动力学。细胞摄取，并可增加肿瘤细胞特异性。该计划的总体目标是综合具有改善的药物样性质的新型BTN 3A 1配体，并在细胞和小鼠模型中评估它们。癌我们的中心假设是，基于膦酸盐支架的新型合成激动剂可以参与 BTN 3A 1通过刺激αβ和γδ T细胞来触发抗癌免疫应答。同时刺激T 细胞群是创新的，可能是外来的，因为它们以一种模式浸润肿瘤，相关和γδ T细胞浸润可能更有利于总生存。为了实现这些目标，我们将将我们的新型芳基-酰氧基烷基膦酸酯保护策略应用于BTN 3A 1激动剂。我们将合成一个一系列优化用于体内应用的芳基-酰氧基烷基膦酸酯BTN 3A 1配体前药，和表征其稳定性、代谢、效力和选择性。我们将使用现有的试验化合物来解决 BTN 3A 1配体如何激活αβ和γδ的抗癌反应的基本未回答的问题 T细胞对抗淋巴瘤细胞，也对卵巢癌细胞免疫更冷。这将是第一 BTN 3A 1配体对αβ T细胞的检查点抑制的SAR研究。我们将研究这些活动本发明的目的是在淋巴瘤和卵巢癌的动物模型中研究化合物，并评估化合物的安全性。的最终目标是鉴定可用于癌症的安全有效的BTN 3A 1配体前药免疫疗法这些发现将在生物学对抗癌免疫的理解 BTN 3A 1的作用远未完成。因此，这些研究有可能对该领域产生重大影响癌症免疫疗法的一部分