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: 8517053
• 负责人: Michael R. McDevitt
• 金额: $ 32.11万
• 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/8517053
• 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以治疗恶性多形性胶质母细胞瘤（GBM）。胶质母细胞瘤是一种恶性星形细胞瘤，也是最常见的神经胶质肿瘤之一。GBM是一种快速致命且不可治愈的癌症，需要新的治疗方法。新诊断GBM的标准治疗是一种三管齐下的治疗方案：（i）手术切除肿瘤，（ii）全脑或立体定向外射束放疗治疗残留疾病，（iii）化疗，再次解决残留疾病。然而，尽管技术越来越先进，但所有这三种方式都有局限性，因为切除和放射毒性会对健康脑组织造成不良损伤，复发的可能性几乎是普遍的。本申请中描述的方法可以潜在地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;用细胞毒性α粒子局部照射那些血管和邻近的血管周围癌症干细胞龛;并有利地重塑血管内皮并改善后续化疗。此外，该药剂将静脉内施用并快速进入肿瘤脉管系统，但其不必穿过血脑屏障以被肿瘤细胞吸收。 有效这种药物可以有效地根除肿瘤，同时保留正常组织，并可能影响恶性星形细胞瘤的治疗方式。应用该药剂对抗GBM的重要性需要通过使用靶向放射治疗构建体在GBM动物模型中特异性治疗该疾病来填补当前治疗方案中的医学和科学空白。所提出的药剂被设计为（i）靶向GBM血管网络并结合血管内皮钙粘蛋白的单体形式（VE-cadhm），在肿瘤血管内皮细胞表面上表达的表位，使用α-颗粒发射抗体构建体;（ii）递送细胞毒性剂量的短程，通过225 Ac放射性核素的衰变向这些表达VE-cadhm的细胞以及它们的局部微环境发射高能α粒子;和（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递送的药剂量、其在GBM内的停留时间和精确位置。还将分析这些生物分布数据，以计算剂量测定值。将进行联合方案依赖性治疗研究，以研究疗效。将使用已建立的方法进行机制研究，以确定α治疗组分导致的GBM VE的形态学、成熟和渗透性变化。我们已经建立了有效翻译其他靶向α粒子发射抗体构建体的跟踪记录 （抗CD 33）从实验室到临床治疗白血病。该拟定血管靶向药物的临床前研究生成的数据将用于支持MSKCC GBM患者的临床应用