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:
- 金额:$ 35.44万
- 依托单位:
- 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:
- 关键词:AddressAffectAgonistAmericanAnimal Cancer ModelAnimal ModelAntigensAreaBindingBiologicalBiological AssayCTAG1 geneCancer ModelCancer PatientCell LineCell Membrane PermeabilityCell ProliferationCell modelCellsClinicalCoculture TechniquesCytolysisDataDevelopmentDiphosphatesDiseaseDoseDrug TargetingEvaluationFailureGoalsHumanImmuneImmune checkpoint inhibitorImmune responseImmune systemImmunologicsImmunotherapeutic agentImmunotherapyIn VitroInfiltrationIntegral Membrane ProteinKineticsLigand BindingLigandsLymphomaLymphoma cellMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMedicalMetabolismModelingMusNormal CellOutcomePatientsPatternPeripheral Blood Mononuclear CellPermeabilityPharmaceutical PreparationsPhosphorusPlasmaPopulationProdrugsProductionPropertyProteinsPublic HealthResearchRoleSafetySeriesSpecificityT cell infiltrationT-Cell ActivationT-Cell ProliferationT-LymphocyteTestingTherapeuticTimeToxic effectTransplantationTumor AntigensTumor ImmunityWorkanti-canceranticancer activitybutyrophilincancer cellcancer immunotherapycheckpoint inhibitionchemotherapycytokineefficacy evaluationfightingimmune checkpointimmunotoxicityimprovedin vivoinnovationinorganic phosphateleukemia/lymphomamouse modelneoplastic cellnoveloverexpressionphosphonatepreventprogramspublic health relevancereceptorresponseretention ratesafety assessmentscaffoldsmall moleculestability testingtumortumor growthtumor progressionuptakeγδ 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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANDREW J WIEMER其他文献
ANDREW J WIEMER的其他文献
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{{ truncateString('ANDREW J WIEMER', 18)}}的其他基金
Regulation of gamma delta T cell immunoediting by novel phosphoantigens
新型磷酸抗原对 γδT 细胞免疫编辑的调节
- 批准号:
9215652 - 财政年份:2015
- 资助金额:
$ 35.44万 - 项目类别:
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