Improving therapy of glioblastoma multiforme by enhancing therapeutic drug delive

通过增强治疗药物的输送来改善多形性胶质母细胞瘤的治疗

• 批准号: 8677818
• 负责人: Michael R. McDevitt
• 金额: $ 33.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677818
• 关键词: Address; Affect; Alpha Particles; Anaplastic astrocytoma; Animal Model; Antibodies; Arthritis; Autoradiography; Binding; Biodistribution; Blood - brain barrier anatomy; Blood Vessels; Brain; Caring; Cell surface; Cells; Clinic; Clinical; Combined Modality Therapy; Data; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Endothelial Cells; Endothelium; Engineering; Epitopes; Event; Excision; Exhibits; Genetic Engineering; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Healthcare; Image; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Location; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Medical; Memorial Sloan-Kettering Cancer Center; Methods; Microscopic; Microscopic Autoradiography; Microscopy; Modality; Modeling; Monoclonal Antibodies; Newly Diagnosed; Normal tissue morphology; Operative Surgical Procedures; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Population; Probability; Radiation; Radiation therapy; Radio; Radioisotopes; Recurrence; Regimen; Residual Tumors; Retinal Diseases; Schedule; Stem cells; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Treatment Protocols; Tumor Tissue; Vascular Endothelium; Vascular remodeling; brain tissue; cadherin 5; cancer stem cell; cancer therapy; chemotherapy; chromophore; cytotoxic; design; dosimetry; fluorescence imaging; improved; in vivo; insight; irradiation; leukemia; meetings; mouse model; neoplastic cell; neovasculature; novel; novel therapeutic intervention; particle; patient population; preclinical study; residence; stem cell niche; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Novel antibody drug constructs can be designed and implemented to treat malignant glioblastoma multiforme (GBM). GBM is a malignant astrocytoma and one of the most common glial tumors. GBM is a rapidly fatal and incurable cancer, for which novel therapeutic approaches are needed. The standard-of-care for newly diagnosed GBM is a three-pronged regimen to treat the disease: (i) surgical resection to remove the tumor, (ii) whole-brain or stereotactic external-beam radiotherapy to treat residual disease, and (iii) chemotherapy, again to address residual disease. However, despite increasingly more sophisticated technology, all three of these modalities have limitations regarding untoward damage from excision and radio-toxicity affecting healthy brain tissue and the probability of recurrence is nearly universal. The approach described in this application may potentially afford clinical methods to specifically target the angiogenic and aberrant vascular endothelium in GBM; locally irradiate those vessels and the adjacent perivascular cancer stem cell niche with cytotoxic alpha particles; and favorably remodel the vascular endothelium and improve subsequent chemotherapy. Furthermore, this agent will be administered intravenously and rapidly access the tumor vasculature, but it does not have to transit the Blood Brain Barrier to be effective. Such an agent could potently eradicate tumor while sparing normal tissue and could impact the way malignant astrocytomas are treated. The significance of the application of this agent against GBM entails filling the medical and scientific gap in the current treatment regimen by using a targeting radio-therapeutic construct to specifically treat this disease in an animal model of GBM. The proposed agent is designed to (i) target the GBM vascular network and bind to the monomeric form of vascular endothelium-cadherin (VE-cadhm), an epitope expressed on the tumor vessel endothelial cell surface, employing an alpha-particle emitting antibody construct; (ii) deliver a cytotoxic dose of short-ranged, high energy alpha-particle emissions to these VE-cadhm-expressing cells and also to their local microenvironment via the decay of the 225Ac radionuclide; and (iii) favorably remodel the GBM VE to improve subsequent chemotherapy. Biodistribution studies will be employed to determine the amount of agent delivered, its residence time and precise location within the GBM. These biodistribution data will also be analyzed to calculate dosimetric values. Combined schedule-dependent therapy studies will be undertaken to investigate efficacy. Mechanistic studies will be performed using established methods to determine the morphological, maturational, and permeability changes in the GBM VE as a consequence of the alpha- therapeutic component. We have an established track record of effectively translating other targeted alpha- particle emitting antibody constructs (anti-CD33) from the bench to the clinic to treat leukemia. The data generated by the preclinical study of this proposed vascular targeting agent will be used to support the application for clinica use in patients with GBM at MSKCC

描述（由申请人提供）：可以设计和实施新型抗体药物构建体来治疗恶性胶质母细胞瘤多形制剂（GBM）。 GBM是一种恶性星形胶质细胞瘤，也是最常见的神经胶质肿瘤之一。 GBM是一种迅速致命且无法治愈的癌症，需要采用新颖的治疗方法。新诊断的GBM的护理标准是一种治疗该疾病的三方面治疗方案：（i）手术切除以切除肿瘤，（ii）全脑或立体定向的外束放射疗法治疗残留疾病，以及（iii）化学疗法，再次解决残留疾病。然而，尽管技术越来越复杂，但这三种方式对影响健康脑组织的不良损害和无线电毒性都有局限性，并且复发的可能性几乎是普遍的。本应用中描述的方法可能有可能提供临床方法，以特异性靶向GBM中的血管生成和异常血管内皮；局部照射这些血管和邻近的血管周围癌干细胞壁ne，具有细胞毒性α颗粒；并可以很好地重塑血管内皮并改善随后的化学疗法。此外，该试剂将静脉注射和迅速访问肿瘤脉管系统，但不必将血液脑屏障传播到 有效的。这样的药物可以在保留正常组织的同时有效地消除肿瘤，并可能影响恶性星形胶质细胞瘤的治疗方式。该药物对GBM的应用的重要性需要通过使用靶向放射性治疗构建体来填补当前治疗方案中的医学和科学差距，以在GBM动物模型中特异性治疗该疾病。所提出的剂旨在（i）靶向GBM血管网络，并与血管内皮核蛋白（VE-CADHM）的单体形式结合，这是一种在肿瘤血管内皮细胞表面表达的表位，采用α-粒子发射抗体构建体； （ii）通过225Ac ractionalclide的衰减，向这些表达VE-CADHM的细胞以及其局部微环境的细胞毒性剂量向这些表达VE-CADHM的细胞以及其局部微环境传递了细胞毒性剂量； （iii）有利地重塑GBM VE，以改善随后的化疗。将采用生物分布研究来确定所输送的代理，其停留时间和GBM内的精确位置。这些生物分布数据还将进行分析以计算剂量计值。将进行共同依赖于计划的治疗研究以研究疗效。机械研究将使用已建立的方法来确定GBM VE的形态，成熟和渗透性变化，这是由于字母治疗成分而导致的。我们拥有有效翻译其他靶向颗粒发射抗体构建体的既定记录 （抗CD33）从长凳到诊所以治疗白血病。该提出的血管靶向剂的临床前研究产生的数据将用于支持在MSKCC的GBM患者中使用临床的应用