DIVERSIFYING MICA TO CREATE TARGETED ADAPTERS TO RECRUIT AND ACTIVATE NK CELLS TO
使云母多样化以创建有针对性的适配器来招募和激活 NK 细胞
基本信息
- 批准号:8455819
- 负责人:
- 金额:$ 31.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-15 至 2014-09-14
- 项目状态:已结题
- 来源:
- 关键词:AccountingAchievementAffinityAntibodiesAttentionAvidityBindingBispecific AntibodiesCD94 AntigenCancer EtiologyCancerousCell surfaceCell-Mediated CytolysisCellsCleaved cellClinical TrialsCytolysisDistressEffector CellEngineeringEnzymesFc domainGrantHealthHumanImmuneImmune systemImmunoglobulin FragmentsImmunologicsImmunotherapyIn VitroKiller CellsLigandsLiquid substanceMICA proteinMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of urinary bladderMammalsMediatingMembraneMicaMonoclonal AntibodiesMultiple MyelomaNatural ImmunityNatural Killer CellsNatureOncogenicOncolyticPeptide HydrolasesPhage DisplayPharmaceutical PreparationsPhaseProtein EngineeringProteinsPublishingRecruitment ActivitySalesSignal TransductionSmall Business Innovation Research GrantStagingStressSurfaceSurface AntigensSynapsesSystemT-LymphocyteTechnologyTherapeuticTherapeutic antibodiesTumor AntigensVirusarmbasecancer cellcell killingclinical efficacyfibroblast growth factor receptor 3innovationkillingsleukemia/lymphomaneoplastic cellnovelnovel strategiesoncolysispublic health relevancereceptorscaffoldtumor
项目摘要
DESCRIPTION (provided by applicant): Monoclonal antibodies targeting tumor associated antigens (TAA's) have since 1997, provided safe and efficacious human cancer therapeutics. More recently, bispecific antibodies or bispecific antibody fragments that promote immunologic synapses between cells of the innate immune system and malignant cells have shown in clinical trials remarkable efficacy and potency against several leukemias and lymphomas. We propose in this Phase I SBIR study to determine whether it is feasible to develop a platform based on engineering a novel human scaffold, MICA, to target and promote killing of specific cancer cells by generating specific immunologic synapses. NK cells and certain T-cells of the innate immune system protect the host from the malignant enemy within by constant surveillance for cells expressing surface MICA or MICB, indicators that the cell is a threat to the health of the host. Once such effector cells of the innate immunity detect a cell decorated by a membrane-bound MIC protein, they attack and destroy the decorated, threatening cell. Such threats include malignancies; but many cancerous cells do not express a level of MICA sufficient to recruit the effector cells. Many high grade malignant cells trap MIC protein intracellularly or secrete proteases that cleave the MIC protein from their surface, clearing the distress signal and enabling escape from innate immunity. Thus, in spite of being dangerous and threatening host survival, cancer cells can break through the surveillance by manipulating surface expression of MIC proteins. We propose to overcome this escape of malignant cells by decorating their surfaces with MICA from outside. Soluble MICA targeted specifically to TAA's expressed uniquely on the malignant cell surface would be administered parenterally. Such a novel approach enables an adaptive use of Nature's potent innate immunity to override the evolved, nefarious mechanism of cancer escape---"innate immunotherapy". The innovation lies in the conversion of this human MICA scaffold naturally deployed by the innate immune system into an immune "adaptor" that specifically binds malignant cells and thereby recruits and activates innate immunity effector cells expressing the receptor for MICA, NKG2D, to promptly kill the targeted cell. We propose herein to focus these platform technologies and concepts on a prototypic and important TAA, Fibroblast Growth Factor Receptor-3 (FGFR3), an oncogenic protein over expressed on most human bladder cancers and many multiple myeloma cells. We intend to demonstrate in vitro specific killing of human cells expressing FGFR3.
描述(由申请人提供):自1997年以来,靶向肿瘤相关抗原(TAA)的单克隆抗体提供了安全有效的人类癌症治疗方法。最近,促进先天免疫系统的细胞和恶性细胞之间的免疫突触的双特异性抗体或双特异性抗体片段在临床试验中显示出针对几种白血病和淋巴瘤的显著功效和效力。我们建议在这项I期SBIR研究中,确定是否可以开发一个基于工程设计的新型人类支架云母的平台,通过产生特异性免疫突触来靶向和促进杀死特定癌细胞。 天然免疫系统的NK细胞和某些T细胞通过持续监测表达表面云母或MICB的细胞(细胞对宿主健康构成威胁的指标)来保护宿主免受内部恶性敌人的侵害。一旦这种先天免疫的效应细胞检测到被膜结合MIC蛋白修饰的细胞,它们就会攻击并摧毁被修饰的威胁细胞。这些威胁包括恶性肿瘤;但许多癌细胞不表达足以招募效应细胞的云母水平。许多高度恶性细胞在细胞内捕获MIC蛋白或分泌蛋白酶,这些蛋白酶从其表面切割MIC蛋白,清除遇险信号并使其能够逃避先天免疫。因此,尽管是危险的和威胁宿主的生存,癌细胞可以通过操纵MIC蛋白的表面表达突破监视。 我们建议通过从外部用云母装饰它们的表面来克服恶性细胞的这种逃逸。特异性靶向在恶性细胞表面上独特表达的TAA的可溶性MICA将肠胃外施用。这种新的方法使自然界强大的先天免疫的适应性使用能够克服癌症逃逸的进化的邪恶机制-“先天免疫疗法”。 创新在于将这种由先天免疫系统自然部署的人云母支架转化为特异性结合恶性细胞的免疫“适配器”,从而招募和激活表达云母受体NKG 2D的先天免疫效应细胞,以迅速杀死靶细胞。我们在本文中提出将这些平台技术和概念集中在原型和重要的TAA,成纤维细胞生长因子受体-3(FGFR 3),一种在大多数人膀胱癌和许多多发性骨髓瘤细胞上过表达的致癌蛋白。我们打算证明表达FGFR 3的人细胞的体外特异性杀伤。
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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David William Martin其他文献
David William Martin的其他文献
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{{ truncateString('David William Martin', 18)}}的其他基金
TARGETABLE BACTERICIDAL PROTEINS TO SPECIFICALLY KILL CLOSTRIDIUM DIFFICILE BACTE
特异性杀死艰难梭菌的靶向杀菌蛋白
- 批准号:
8549942 - 财政年份:2012
- 资助金额:
$ 31.61万 - 项目类别:
TARGETABLE BACTERICIDAL PROTEINS TO SPECIFICALLY KILL CLOSTRIDIUM DIFFICILE BACTE
特异性杀死艰难梭菌的靶向杀菌蛋白
- 批准号:
8250243 - 财政年份:2012
- 资助金额:
$ 31.61万 - 项目类别:
Create, evaluate and develop pre-clinically an engineered R-type pyocin to specif
创建、评估和开发临床前工程 R 型脓毒素,以指定
- 批准号:
7908557 - 财政年份:2010
- 资助金额:
$ 31.61万 - 项目类别:
Create, evaluate and develop pre-clinically an engineered R-type pyocin to specif
创建、评估和开发临床前工程 R 型脓毒素,以指定
- 批准号:
8071633 - 财政年份:2010
- 资助金额:
$ 31.61万 - 项目类别:
Targeted soluble MICA molecules to recruit innate immunity cells to kill specific
靶向可溶性 MICA 分子招募先天免疫细胞来杀死特定的
- 批准号:
8043656 - 财政年份:2010
- 资助金额:
$ 31.61万 - 项目类别:
Targeted soluble MICA molecules to recruit innate immunity cells to kill specific
靶向可溶性 MICA 分子招募先天免疫细胞来杀死特定的
- 批准号:
7907360 - 财政年份:2010
- 资助金额:
$ 31.61万 - 项目类别:
HOST RANGE DIVERSITY OF BACTERIOPHAGE FOR Y. PESTIS
鼠疫杆菌噬菌体的宿主范围多样性
- 批准号:
7107657 - 财政年份:2006
- 资助金额:
$ 31.61万 - 项目类别:
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