Engineering Protein Modulators of Notch Activation for T-cell immunotherapy
用于 T 细胞免疫治疗的 Notch 激活的工程蛋白质调节剂
基本信息
- 批准号:10612995
- 负责人:
- 金额:$ 38.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffinityAllogenicAntibodiesAutoimmune DiseasesBackBacteriophagesBenchmarkingBindingBinding ProteinsBiochemicalBiochemistryBiological AssayBlocking AntibodiesCationsCell Differentiation InductionCell LineCell NucleusCell Surface ReceptorsCellsCellular biologyClinicalClinical TrialsClosure by clampCoculture TechniquesCollecting CellCommunicable DiseasesCultured CellsCyclic GMPDevelopmentDiseaseDisulfidesDoseEngineeringExposure toExtracellular DomainFDA approvedFamilyFreezingGenerationsGoalsHealth Services AccessibilityHematologic NeoplasmsHomologous GeneImmuneImmune System DiseasesImmunoglobulin FragmentsImmunotherapeutic agentImmunotherapyIndustry StandardLigand BindingLigandsLinkMalignant NeoplasmsMeasuresMinnesotaMolecular ConformationMonitorMutationNOTCH3 geneOncologyPatientsPeptide HydrolasesPerformancePhage DisplayPhysiologicalPopulationProtein EngineeringProteinsProteolysisReagentReporterReportingResearchResearch PersonnelSignal TransductionSiteSourceStandardizationStructureSurfaceSystemT cell differentiationT cell therapyT-Cell ActivationT-LymphocyteTechnologyTestingTherapeuticTimeTranscription CoactivatorTranscription InitiationUniversitiesYeastsarmcancer cellcancer therapycell killingcell typechelationchimeric antigen receptorchimeric antigen receptor T cellscostcost effectivedesignengineered T cellsexperimental studygraft vs host diseasehealth disparityimprovedindividual patientinduced pluripotent stem cellinnovationmanufacturing processmimeticsnanobodiesnext generationnotch proteinnovelorgan transplant rejectionprecursor cellprogramsprotein phosphatase inhibitor-2receptorstructural biologysurface coatingtherapeutic developmenttool
项目摘要
Summary
Investigators at the University of Minnesota have teamed up to engineer novel protein activators of the Notch
family of cell surface receptors, which are master regulators of T-cell differentiation from induced pluripotent
stem cells. This technology will accelerate the development of engineered T cell therapies for treating cancer as
well as a range of diseases including auto-immune disorders, infectious disease, immune-deficiencies, graft vs.
host disease, and organ transplant rejection. Existing FDA approved engineered T cells are powerful
therapeutics yet major challenges remain, including difficulty in differentiating T cells from precursor cell types
and difficulty in editing and validating precursor cells prior to differentiation. To overcome these limitations and
to enable a transformative jump in T cell engineering approaches, the research team is developing reagents that
target and trigger conformational opening of the proteolytic switch NRR domain of Notch1. The Notch NRR
buries a cryptic protease site that is normally only exposed to its protease physiologically by tugging forces
generated during binding of its ligand on a neighboring cell. The project aims to develop soluble nanobody
reagents that functionally pry open the domain and remove the requirement for co-culture with Notch ligands
during T cell differentiation. In Aim 1 of the project, phage-display protein engineering is used to identify and
optimize nanobodies that selectively bind structurally distinct states of the Notch1 NRR. In Aim 2, these
nanobodies are strategically linked together in arrays for creating potent Notch1 activators by inducing
conformational “opening” of the NRR. In Aim 3, iPSC cell lines that report Notch1 signaling and T cell commitment
will be developed, characterized, and then used in assays monitoring differentiation of iPSCs into T cells under
induction by engineered Notch1 activators. In the final stage of the project, the reporter cell lines will be used in
benchmarking experiments comparing the performance of Notch1 activators developed in Aim 1 and 2, to
industry standard technologies. The milestones of this project are: (a) generating a tool set of molecules that
bind selectively to the Notch1 NRR; (b) developing a panel of iPSC reporter systems that monitor commitment
and differentiation of iPSCs to T cells that have normal physiologic function including cell killing potential; (c)
creating potent and selective Notch1 activators that induce iPSCs to differentiate into T cells with a marked
improvement in the efficiency differentiation and expansion over current approaches. This will enable
development of improved cancer treatments, and improve health disparities by increasing access to treatment
with a standardized iPSC-based cell source that can be frozen and banked for multiple doses while significantly
bringing down cost per product.
总结
明尼苏达大学的研究人员合作设计了Notch的新型蛋白质激活剂,
细胞表面受体家族,其是T细胞从诱导的多能分化的主要调节剂。
干细胞这项技术将加速用于治疗癌症的工程T细胞疗法的发展,
以及一系列疾病,包括自身免疫性疾病、传染病、免疫缺陷、移植物抗宿主病(graft vs.
宿主疾病和器官移植排斥现有的FDA批准的工程T细胞是强大的
然而,主要的挑战仍然存在,包括难以将T细胞与前体细胞类型区分开来
以及在分化之前编辑和验证前体细胞的困难。为了克服这些局限性,
为了实现T细胞工程方法的变革性飞跃,研究小组正在开发试剂,
靶向并触发Notch 1的蛋白水解开关NRR结构域的构象打开。Notch NRR
掩埋了一个隐蔽的蛋白酶位点,该位点通常仅在生理上通过牵引力暴露于其蛋白酶
在其配体与邻近细胞结合期间产生。该项目旨在开发可溶性纳米抗体
功能性地撬开结构域并消除与Notch配体共培养的需要的试剂
在T细胞分化过程中。在该项目的目标1中,噬菌体展示蛋白工程用于识别和
优化选择性结合Notch 1 NRR的结构不同状态的纳米抗体。在Aim 2中,
纳米抗体在阵列中策略性地连接在一起,用于通过诱导
NRR的构象“开放”。在目标3中,报告Notch 1信号传导和T细胞定型的iPSC细胞系
将被开发、表征,然后用于监测iPSC分化为T细胞的测定,
通过工程化Notch 1激活剂诱导。在项目的最后阶段,报告细胞系将用于
比较目标1和目标2中开发的Notch 1激活剂的性能的基准测试实验,
行业标准技术。该项目的里程碑是:(a)生成一套分子工具,
选择性地结合Notch 1 NRR;(B)开发一组iPSC报告系统,
以及iPSC向具有正常生理功能(包括细胞杀伤潜力)的T细胞的分化;(c)
创造有效的和选择性的Notch 1激活剂,诱导iPSC分化为T细胞,
与目前的方法相比,效率差异和扩展方面的改进。这将使
开发更好的癌症治疗方法,并通过增加治疗机会来改善健康差距
使用标准化的基于iPSC的细胞来源,可以冷冻并储存多个剂量,
降低每件产品的成本。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WENDY RYAN GORDON其他文献
WENDY RYAN GORDON的其他文献
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{{ truncateString('WENDY RYAN GORDON', 18)}}的其他基金
Decoding mechanotransduction mechanisms of cell-surface receptors
解码细胞表面受体的机械转导机制
- 批准号:
10330300 - 财政年份:2016
- 资助金额:
$ 38.48万 - 项目类别:
Decoding mechanotransduction mechanisms of cell-surface receptors
解码细胞表面受体的机械转导机制
- 批准号:
9897757 - 财政年份:2016
- 资助金额:
$ 38.48万 - 项目类别:
Decoding mechanotransduction mechanisms of cell-surface receptors
解码细胞表面受体的机械转导机制
- 批准号:
10542757 - 财政年份:2016
- 资助金额:
$ 38.48万 - 项目类别:
Decoding mechanotransduction mechanisms of cell-surface receptors
解码细胞表面受体的机械转导机制
- 批准号:
9319295 - 财政年份:2016
- 资助金额:
$ 38.48万 - 项目类别:
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