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
项目成果
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ANDREW J WIEMER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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