Improving therapy of glioblastoma multiforme by enhancing therapeutic drug delive

描述（由申请人提供）：新型抗体药物结构可以设计和实施用于治疗多形性恶性胶质母细胞瘤（GBM）。GBM是一种恶性星形细胞瘤，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）全脑或立体定向外束放疗治疗残留疾病，以及（iii）化疗，再次治疗残留疾病。然而，尽管技术越来越先进，但这三种方式在切除和影响健康脑组织的放射性毒性造成的不良损害方面都有局限性，而且复发的可能性几乎是普遍的。本应用中描述的方法可能为特异性靶向GBM中的血管生成和异常血管内皮提供临床方法；用细胞毒性α粒子局部照射这些血管和邻近的血管周围肿瘤干细胞壁龛；有利于血管内皮重塑，改善后续化疗。此外，这种药物可以静脉注射，并迅速进入肿瘤血管，但它不需要通过血脑屏障

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 PUBLIC HEALTH RELEVANCE: Cancer therapy can be advanced through strategic improvements in the agents employed to treat the disease. Translating this agent into the clinic to treat GBM would meet the unmet treatment needs for this disease. A broader use of this agent could be envisioned in the treatment of any type of vascularized cancer, since the antibody component specifically targets only the angiogenic and aberrant vascular endothelium of any tumor. Therefore, the drug would not have to be re-engineered with diverse targeting platforms to recognize unique tumor-specific markers. This system may also be of utility in treating aberrant vessel growth in retinopathy or arthritis. Therefore, in addition to serving the medical needs of a specific population affected with GBM, a much larger population, exhibiting a wide range of diseases, might benefit from this particular agent. The application of this agent to a larger patient population could have a potentially broad and significant impact in health care.