Multi-receptor Targeting of Glioblastoma

胶质母细胞瘤(GBM)的治疗在医学上是一个未得到满足的需求。我们一直在追求一个 对流增强递送有效靶向和特异性细胞毒素的治疗方法 (CED)。我们和其他人发现，GBM患者过度表达白细胞介素13受体α2(IL-13RA2)， EphA2、EphA3和EphB2受体。这些受体存在于不同的病理生理隔间。 在肿瘤中心的肿瘤细胞和局部浸润性肿瘤细胞中均有表达，而 EphA2也存在于肿瘤新生血管中。此外，IL-13RA2、EphA2和EphA3与 在胶质瘤干细胞(GSC)的病理生物学中发挥重要作用。最后，EphA3受体可以 容易在M2肿瘤相关巨噬细胞(TMA)中检测到。因此，IL-13RA2、EphA2、EphA3 和EphB2在参与肿瘤进展的主要GBM间隔区过度表达 和/或抵抗治疗。Eph受体的一种配体ephinA5(EA5)与EphA2、EphA3和EphA2结合。 EphB2受体。在当前的项目中，我们将追求以四个受体为靶点的新想法。 使用监测和有效的CED提供的药物化合物。我们已经设计了一个 基于eA5和IL-13突变体的试剂，靶向所有四种受体，使用IgG1支架并将其连接到 修饰细菌毒素，形成QUAD 3.0-PE38QQR。该结合物治疗GBM肿瘤安全有效。我们 将通过三个具体目标继续这一令人兴奋的研究路线。在具体目标1中，我们将评估 QUAD 3.0-PE38QQR在犬高级别胶质瘤治疗中的分布、安全性和抗肿瘤活性 代表了最接近的人类疾病模型。在具体目标2中，我们将为以下目标开发Quad 3.0-PE38QQR 复发性基底膜患者的首例人类I期临床试验。我们将在Quad 3.0-PE38QQR下 良好制造规范(GMP)条件。Quad-CTX将进行临床前动物研究， 基于IND前与FDA的讨论。研究将在良好实验室操作规范(GLP)下进行 获得研究用新药(IND)的条件。在第三个具体目标中，我们将履行 QUAD 3.0-PE38QQR治疗复发基底膜患者的I期临床试验。重点将放在获得 CED给药的最佳分配量、安全性、初效及诱导证据 免疫反应。因此，有了一种治疗剂和改进的递送系统，我们将 清除肿瘤细胞和肿瘤微环境中的异常细胞，促进其生长。这 该方法还解决了肿瘤间和瘤内异质性的关键问题，并有望引起 一种原位接种或所谓的“肿瘤发炎”效应。我们设想这次我们所称的全面进攻 “分子切除”，将导致更有效的治疗基底膜。

Treatment of glioblastoma (GBM) represents an unmet need in medicine. We have been pursuing a therapeutic approach of delivering potent targeted and specific cytotoxins using convection-enhanced delivery (CED). We and others found that patients with GBM over-express interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors. These receptors are present in various pathophysiological compartments of GBM and all four are expressed in tumor cells of the core of tumor and in locally-infiltrating tumor cells, while EphA2 is also found in tumor neovasculature. Further, IL-13RA2, EphA2, and EphA3 are associated with, and play crucial roles in, the pathobiology of glioma stem-like cells (GSC). Finally, the EphA3 receptor can be readily detected in M2 tumor-associated macrophages (TMA). Thus, collectively, IL-13RA2, EphA2, EphA3 and EphB2 are over-expressed in principal GBM compartments shown to be involved in tumor progression and/or resistance to therapies. One of the Eph receptor ligands, ephrinA5 (eA5), binds EphA2, EphA3 and EphB2 receptors. In the current project, we will pursue the novel idea of targeting all four receptors with one pharmaceutical compound delivered using monitored and effective CED. We have already engineered an agent based on eA5 and IL-13 mutants targeting all four receptors using an IgG1 scaffold and conjugated it to a modified bacterial toxin to form QUAD 3.0-PE38QQR. The conjugate is safe and effective in GBM tumors. We will continue this exciting line of research through three Specific Aims. In Specific Aim 1, we will evaluate QUAD 3.0-PE38QQR distribution, safety and anti-tumor activity in treating canine high-grade gliomas, which represents the closest model of human disease. In Specific Aim 2, we will develop QUAD 3.0-PE38QQR for first-in-human Phase I clinical trial in patients with recurrent GBM. We will make QUAD 3.0-PE38QQR under Good Manufacturing Practices (GMP) conditions. The QUAD-CTX will undergo pre-clinical animal studies, based on pre-IND discussions with the FDA. Studies will be perfromed under Good Laboratory Practices (GLP) conditions in order to obtain an Investigational New Drug (IND). In the third Specific Aim, we will perform Phase I clinical trial with QUAD 3.0-PE38QQR in patients with recurrent GBM. The focus will be on obtaining optimal volume of distribution of the CED-administered drug, its safety, initial efficacy and evidence of inducing immune responses. Thus, with one therapeutic agent and improved delivery system, we will be eliminating tumor cells and abnormal cells of the tumor microenvironment promoting its growth. This approach also addresses crucial issues of inter- and intra-tumoral heterogeneity and is also expected to evoke an in situ vaccination or so called “tumor inflaming” effect. We envision that this all-out assault, termed by us “molecular resection”, will result in a more effective management of GBM.