Multi-receptor Targeting of Glioblastoma

胶质母细胞瘤的多受体靶向

基本信息

批准号：
10313101
负责人：
Waldemar Debinski
金额：
$ 64.28万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10313101
关键词：
Abnormal Cell Address Animals Antitumor Response Bacterial Toxins Binding Brain Canis familiaris Catheters Cells Clinical Protocols Complement Convection Cyclophosphamide Cytotoxic agent Cytotoxin Development Disease Management Dose Dose-Limiting Drug Delivery Systems Drug Monitoring EPHA3 gene Engineering Environment EphA2 Receptor EphB2 Receptor Ephrins Excision Glioblastoma Glioma Grant Growth Heterogeneity Human IL13RA1 gene IgG1 Immune response Immune system Immunologics Infusion procedures Interleukin-13 Interleukin-13 Overexpression Investigational Drugs Ligands Magnetic Resonance Imaging Medicine Molecular Molecular Target Monitor Patients Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Play Primary Brain Neoplasms Progression-Free Survivals Property Recurrence Reflux Research Resistance Role Safety Site System Testing Therapeutic Therapeutic Agents Time Toxic effect Tumor-associated macrophages Variant assault base brain parenchyma catalyst cell killing cell transformation cytotoxic drug action drug candidate drug distribution exhaustion experimental study first-in-human good laboratory practice human disease human model immunogenic improved in situ vaccination meetings mutant neoplastic cell neovasculature novel overexpression pre-clinical real time monitoring receptor response safety and feasibility scaffold stem-like cell therapy resistant translational model tumor tumor heterogeneity tumor microenvironment tumor progression

项目摘要

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.

胶质母细胞瘤（GBM）的治疗代表了医学上未满足的需求。使用对流增强递送来递送有效的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 α 2 (IL-13RA2)， EphA2、EphA3 和 EphB2 受体这些受体存在于各种病理生理区室中。 GBM 和所有四种蛋白均在肿瘤核心的肿瘤细胞和局部浸润的肿瘤细胞中表达，而 EphA2 也存在于肿瘤新血管系统中。此外，IL-13RA2、EphA2 和 EphA3 与和相关。 EphA3 受体在神经胶质瘤干细胞样细胞 (GSC) 的病理学中发挥着至关重要的作用。很容易在 M2 肿瘤相关巨噬细胞 (TMA) 中检测到，因此，IL-13RA2、EphA2、EphA3 统称为“IL-13RA2”。和 EphB2 在主要 GBM 区室中过度表达，显示参与肿瘤进展 Eph 受体配体之一 ephrinA5 (eA5) 结合 EphA2、EphA3 和在当前的项目中，我们将追求用一种受体靶向所有四种受体的新想法。我们已经设计了一种使用受监控且有效的 CED 交付的药物化合物。基于 eA5 和 IL-13 突变体的药物，使用 IgG1 支架靶向所有四种受体，并将其与修饰细菌毒素形成 QUAD 3.0-PE38QQR，该缀合物对 GBM 肿瘤安全有效。将通过三个具体目标继续这一令人兴奋的研究，在具体目标 1 中，我们将进行评估。 QUAD 3.0-PE38QQR 治疗犬高级别胶质瘤的分布、安全性和抗肿瘤活性，代表最接近的人类疾病模型。在特定目标 2 中，我们将开发 QUAD 3.0-PE38QQR。我们将在复发性 GBM 患者中进行首次人体 I 期临床试验。 QUAD-CTX 将在良好生产规范 (GMP) 条件下进行临床前动物研究。基于与 FDA 的 IND 前讨论，研究将根据良好实验室规范 (GLP) 进行。在第三个具体目标中，我们将执行获得研究性新药 (IND) 的条件。 QUAD 3.0-PE38QQR 在复发性 GBM 患者中的 I 期临床试验重点是获得。 CED 给药药物的最佳分布容积、其安全性、初始疗效和诱导证据因此，通过一种治疗剂和改进的递送系统，我们将能够消除肿瘤细胞和促进其生长的肿瘤微环境的异常细胞。该方法还解决了肿瘤间和肿瘤内异质性的关键问题，并有望引起人们的关注。我们设想这种全面攻击，即原位疫苗接种或所谓的“肿瘤炎症”效应。 “分子切除”将使 GBM 得到更有效的治疗。