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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不成功，对新的免疫疗法的医学需求迫切而未得到满足。适用于所有癌症患者。跨膜蛋白BTN3A1是一个有希望的新免疫治疗靶点，因为它的激动剂结合既能解除对αβT细胞的抑制，又能激活γδT细胞。一种有效的BTN3A1激动剂低毒治疗小鼠卵巢癌模型，提示BTN3A1激动剂的进一步开发是有根据的。然而，目前的小分子BTN3A1激动剂受到PK特性差的限制，包括低稳定性好，膜通透性低，肿瘤选择性有限。我们在这方面的初步数据显示，基于磷酸盐支架的BTN3A1激动剂相对于以磷酸为基础的支架提高了细胞稳定性激动剂，以及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，保留了这些特征，同时还改善了血浆稳定性和动力学细胞摄取，并可能增加肿瘤细胞的特异性。这个项目的总体目标是综合具有改善类药物性质的新型BTN3A1配体并在细胞和小鼠模型中进行评估癌症。我们的中心假设是，基于磷酸盐支架的新型合成激动剂可以参与 BTN3A1通过刺激αβ和γδT细胞来触发抗癌免疫反应。刺激两个T 细胞群是创新的，而且可能是外来的，因为它们以一种不是相关T细胞和γδT细胞的浸润更有利于患者的总体生存。为了实现这些目标，我们将将我们新的芳基-酰氧基烷基膦酸酯保护策略应用于BTN3A1激动剂。我们将合成一个系列芳基-酰氧基烷基膦酸类BTN3A1配体前药，最适合体内应用，以及表征它们的稳定性、新陈代谢、效力和选择性。我们将使用现有的试点化合物来解决 BTN3A1配体如何激活αβ和γδ的抗癌反应的基本悬而未决的问题 T细胞对淋巴瘤细胞的杀伤作用更强，对卵巢癌细胞的免疫力也更强。这将是第一次 BTN3A1配体对αβT细胞检查点抑制作用的SAR研究我们将研究这些组织的活动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。这个最终目标是找到一种安全有效的BTN3A1配体前药，可用于治疗癌症免疫疗法。这些发现将出现在抗癌免疫的生物学理解的时候而BTN3A1的作用还远未完成。因此，这些研究有可能对该领域产生重大影响。癌症免疫疗法的最新进展。