Chimeric Anti-Fibulin-3 Reagents For Targeted Therapy Of Glioblastoma
用于胶质母细胞瘤靶向治疗的嵌合抗 Fibulin-3 试剂
基本信息
- 批准号:8871977
- 负责人:
- 金额:$ 42.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAngiogenesis InhibitorsAntibodiesApoptosisBasal laminaBindingBiodistributionBiologicalBiological ProductsBiologyBlocking AntibodiesBlood VesselsBlood capillariesBrainBrain NeoplasmsCD8B1 geneCellsClinicalConnective TissueCytotoxic agentEngineeringExotoxinsExtracellular MatrixExtracellular Matrix ProteinsFamilyFutureGenesGeneticGlioblastomaGliomaGoalsGrowthGuidelinesHeterogeneityImmune responseImmunoglobulin Variable RegionImmunotherapeutic agentImmunotoxinsImprove AccessInvestigational DrugsKnowledgeLaboratoriesLeadLigand Binding DomainMalignant neoplasm of brainMaximum Tolerated DoseModelingMolecularMonoclonal AntibodiesPathway interactionsPeripheralPrimary Brain NeoplasmsProteinsPseudomonasReagentRecombinantsRecurrenceResistanceRiskS1-5 proteinSafetySignal TransductionSpecificityT cell responseT-Cell ReceptorT-LymphocyteTestingThe Cancer Genome AtlasTherapeuticTimeToxic effectToxinTumor Cell InvasionTumor Stem CellsValidationVascular Endothelial Growth Factor ReceptorVascularizationantiangiogenesis therapyantitumor effectautocrinebevacizumabbrain tissuecancer typecapillarychimeric antigen receptorconventional therapycross reactivitycytotoxiccytotoxicityexperiencefibulinhigh rewardhigh riskmeetingsmemberneoplastic cellnervous system disordernotch proteinnovelnovel therapeuticsoutcome forecastparacrinepre-clinicalpublic health relevancereceptorrelating to nervous systemresponsescaffoldtargeted treatmenttumortumor growthtumor microenvironmenttumor progression
项目摘要
DESCRIPTION (provided by applicant): The goal of this project is to develop and validate novel biological reagents against glioblastomas (GBMs), which are one of the most common and the most aggressive kind of brain tumors. GBMs are highly invasive in brain tissue and their dispersion is exacerbated by cytotoxic and antiangiogenic therapies, resulting in a much worse clinical picture when the tumor recurs. Novel therapeutics addressing the biology of GBM should be able to disrupt invasion or vascularization and sensitize tumor cells, thus causing tumor disruption in multiple fronts when combined with conventional therapies. This project will focus on the protein fibulin-3 identified by our group, which is secreted by GBM cells and has unique localization and mechanisms in GBM but is absent from normal brain. Fibulin-3 is a novel activator of the Notch pathway and genetic targeting of this protein disrupts Notch signaling in the tumor and reduces GBM growth and resistance. We have produced a function-blocking antibody against fibulin-3 ("mAb428.2") and in this project we will use it as a starting point to generate and validate a family of anti-fibulin-3 recombinant reagents. In Specific Aim 1, we propose to validate safety and efficacy of mAb428.2 against intracranial GBMs to advance it towards investigational new drug status. We hypothesize that anti-fibulin-3 will reduce tumor growth and vascularization with no significant peripheral toxicity or local off-target effects. We will study mAb428.2 specificity, cross-reactivity, biodistribution, safety and anti-tumor efficacy following FDA guidelines, aiming at completing pre-IND validation. In Specific Aim 2, we propose to develop and validate an anti-fibulin-3 single-chain immunotoxin as cytotoxic agent for GBM. We have already generated a single-chain variable fragment (scFv) derived from mAb428.2 and hypothesize that the smaller size of this fragment will improve access and toxicity against GBM. We will conjugate the scFv with Pseudomonas exotoxin and will validate this novel immunotoxin for specificity, safety and efficacy against intracranial GBM. Finally, using fibulin-3 scFv, in Specific Aim 3 we propose to generate and test a chimeric antigen receptor (CAR) against fibulin-3. We hypothesize that a fibulin-3-binding CAR expressed in T lymphocytes will be robustly activated in the tumor microenvironment and will result in strong anti-tumor response even in presence of tumor cell heterogeneity. This is a high-risk/high-reward concept for future immunotargeting of the tumor stroma, and the goal of this aim will be to establish a proof of feasibility and demonstrate that such CAR can be generated and specifically activated by fibulin-3. Successful completion of this project will result in a family f lead biological agents targeting the GBM microenvironment, with different levels of preclinical validation. These results will be used to advance the most promising candidate(s) for submission as investigational new drug(s) for GBM.
描述(申请人提供):该项目的目标是开发和验证针对胶质母细胞瘤(GBM)的新型生物试剂,胶质母细胞瘤是最常见和最具侵袭性的脑肿瘤之一。基底膜在脑组织中具有高度侵袭性,细胞毒性和抗血管生成治疗加剧了它们的扩散,导致肿瘤复发时的临床表现要糟糕得多。针对GBM生物学的新疗法应该能够破坏肿瘤细胞的侵袭或血管形成,并使肿瘤细胞敏感,从而在与传统疗法相结合时在多个方面导致肿瘤破坏。本课题研究的重点是本课题组发现的由基底膜细胞分泌的、在基底膜中具有独特定位和作用机制但在正常脑中缺失的纤毛蛋白-3。纤维蛋白-3是一种新的Notch途径激活剂,该蛋白的基因靶向可以干扰肿瘤中的Notch信号,减少GBM的生长和耐药性。我们已经制备了一种针对纤维蛋白-3的功能阻断抗体(mAb428.2),在本项目中,我们将以此为起点来制备和验证一系列抗纤维蛋白-3的重组试剂。在具体目标1中,我们建议验证mAb428.2对颅内GBM的安全性和有效性,以推动其进入研究新药状态。我们假设,抗纤维蛋白-3将减少肿瘤生长和血管生成,没有明显的外周毒性或局部脱靶效应。我们将遵循FDA的指导方针,研究mAb428.2的特异性、交叉反应性、生物分布、安全性和抗肿瘤有效性,旨在完成IND前的验证。在具体目标2中,我们建议开发并验证一种抗纤维蛋白-3单链免疫毒素作为GBM的细胞毒剂。我们已经从mAb428.2中产生了一个单链可变区(ScFv),并假设该片段的较小尺寸将改善对GBM的获得性和毒性。我们将单链抗体与假单胞菌外毒素偶联,并验证这种新型免疫毒素对颅内GBM的特异性、安全性和有效性。最后,利用纤维蛋白-3单链抗体,在特定目的3中,我们建议制备并测试针对纤维蛋白-3的嵌合抗原受体(CAR)。我们假设,在T淋巴细胞中表达的纤维蛋白-3结合的CAR将在肿瘤微环境中被强有力地激活,并将导致强烈的抗肿瘤反应,即使存在肿瘤细胞的异质性。对于未来的肿瘤基质免疫靶向,这是一个高风险/高回报的概念,这一目标的目标将是建立一个可行性的证据,并证明这种CAR可以产生并被纤维蛋白-3特异性激活。该项目的成功完成将导致针对GBM微环境的一系列领先生物制剂,具有不同水平的临床前验证。这些结果将被用于提名最有希望的候选人(S)作为GBM的研究新药(S)。
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(1)
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Mariano Sebastian Viapiano其他文献
Mariano Sebastian Viapiano的其他文献
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{{ truncateString('Mariano Sebastian Viapiano', 18)}}的其他基金
Targeting the tumor matrix as immune-boosting strategy for malignant gliomas
靶向肿瘤基质作为恶性胶质瘤的免疫增强策略
- 批准号:
10016372 - 财政年份:2019
- 资助金额:
$ 42.39万 - 项目类别:
Chimeric anti-fibulin-3 reagents for targeted therapy of glioblastoma
用于胶质母细胞瘤靶向治疗的嵌合抗fibulin-3试剂
- 批准号:
9334499 - 财政年份:2015
- 资助金额:
$ 42.39万 - 项目类别:
Targeting the Tumor Matrix as Anti-Invasive and Sensitizing Strategy for Glioma
靶向肿瘤基质作为神经胶质瘤的抗侵袭和增敏策略
- 批准号:
8687613 - 财政年份:2010
- 资助金额:
$ 42.39万 - 项目类别:
Targeting the tumor matrix as anti-invasive and sensitizing strategy for glioma
靶向肿瘤基质作为神经胶质瘤的抗侵袭和增敏策略
- 批准号:
8616849 - 财政年份:2010
- 资助金额:
$ 42.39万 - 项目类别:
Targeting the tumor matrix as anti-invasive and sensitizing strategy for glioma
靶向肿瘤基质作为神经胶质瘤的抗侵袭和增敏策略
- 批准号:
8270532 - 财政年份:2010
- 资助金额:
$ 42.39万 - 项目类别:
Targeting the Tumor Matrix as Anti-Invasive and Sensitizing Strategy for Glioma
靶向肿瘤基质作为胶质瘤的抗侵袭和增敏策略
- 批准号:
8473672 - 财政年份:2010
- 资助金额:
$ 42.39万 - 项目类别:
Targeting the tumor matrix as anti-invasive and sensitizing strategy for glioma
靶向肿瘤基质作为神经胶质瘤的抗侵袭和增敏策略
- 批准号:
8120575 - 财政年份:2010
- 资助金额:
$ 42.39万 - 项目类别:
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