Improving therapy of glioblastoma multiforme by enhancing therapeutic drug delive

描述(由申请人提供)：可以设计和实施新的抗体药物结构来治疗恶性多形性胶质母细胞瘤(GBM)。基底节细胞瘤是一种恶性星形细胞瘤，是最常见的神经胶质瘤之一。基底细胞瘤是一种迅速致命且无法治愈的癌症，需要新的治疗方法。新诊断的GBM的标准治疗方案是三管齐下的治疗方案：(I)手术切除肿瘤，(Ii)全脑或立体定向外照射治疗残留病，(Iii)化疗，再次治疗残留病。然而，尽管技术越来越复杂，但这三种方式在切除造成的不良损害和影响健康脑组织的放射毒性方面都有局限性，复发的可能性几乎是普遍的。本申请中描述的方法可能提供临床方法来特异性地靶向GBM中血管生成和异常的血管内皮细胞；用细胞毒性α颗粒局部照射这些血管和邻近的血管周围的癌症干细胞巢；有利于血管内皮细胞的重建和改进后续的化疗。此外，这种药物将被静脉注射并快速进入肿瘤血管，但它不一定要通过血脑屏障 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。应用这种药物治疗GBM的意义在于通过使用靶向放射治疗构建物在GBM动物模型中特异性地治疗这种疾病，从而填补当前治疗方案中的医学和科学空白。所建议的药物旨在(I)靶向GBM血管网络并结合到血管内皮细胞表面表达的单体形式的血管内皮-钙粘素(VE-CADHM)，利用α粒子发射抗体构建；(Ii)通过225Ac放射性核素的衰变，向这些表达VE-CADHM的细胞及其局部微环境传递短距离、高能的α粒子发射的细胞毒性剂量；以及(Iii)有利地重建GBM VE以改进后续的化疗。生物分布研究将被用来确定递送的药剂的量、其停留时间和在GBM内的准确位置。这些生物分布数据也将被分析以计算剂量量值。将进行联合时间表依赖治疗研究，以调查疗效。将使用已建立的方法进行机制研究，以确定阿尔法治疗成分对GBM VE的形态、成熟和通透性的影响。我们已经建立了有效翻译其他靶向阿尔法粒子发射抗体构建体的跟踪记录 (抗CD33)从板凳到临床治疗白血病。这种建议的血管靶向剂的临床前研究产生的数据将用于支持MSKCC的GBM患者的临床应用

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