SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme

SapC-DOPS 纳米囊泡用于治疗多形性胶质母细胞瘤

• 批准号: 8737800
• 负责人: XIAOYANG QI
• 金额: $ 94.85万
• 依托单位: BEXION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737800
• 关键词: Activator Appliances; Affinity; Animal Model; Animals; Antineoplastic Agents; Behavioral; Biochemical; Biological Assay; Biological Markers; Brain Neoplasms; Catabolism; Cell Death; Cell surface; Cells; Ceramides; Characteristics; Chemistry; Clinical; Clinical Trials; Data; Diagnosis; Diagnostic Imaging; Dose; Drug Formulations; Drug Kinetics; Genetic; Genetic Markers; Glioblastoma; Glioma; Glucosylceramides; Goals; Grant; Growth; Heterogeneity; Human; Implant; Investigational Drugs; Investigational New Drug Application; Link; Mediating; Membrane; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Normal Cell; Nude Mice; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphatidylserines; Phospholipids; Plasmids; Predisposition; Primates; Procedures; Production; Property; Proteins; Proteolipids; Protocols documentation; Qualifying; Radiosurgery; Research; Risk; Rodent; Safety; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipid Activator Proteins; Sphingolipids; Surface; Techniques; Technology; Testing; Therapeutic; Toxic effect; Tumor Bank; Tumor-Derived; Xenograft Model; analytical method; annexin A5; beta-Glucosidase Stimulating Protein; cancer cell; cell bank; chemotherapy; drug candidate; effective therapy; efficacy trial; expression vector; glioma cell line; improved; in vivo; innovation; intravenous administration; killings; lysosomal proteins; meetings; nanovesicle; neoplastic cell; neovasculature; nonhuman primate; novel; oncology; phase 1 study; pre-clinical; preclinical study; public health relevance; response; scale up; success; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): Our goal is to develop a new molecular entity with a novel mechanism of action for targeting and eliminating glioblastoma multiforme (GBM, high grade glioma), a deadly and invasive brain tumor with no effective treatment. Of the 12,000 patients expected to be diagnosed with GBM this year, most will succumb within a year. There is an urgent demand for an efficacious anti-glioma drug. We are developing a new class of therapeutic proteolipid nanovesicle that can target and destroy glioma tumors. Composed of the small lysosomal sphingolipid activator protein saposin C (SapC, 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles (clinical formulation is called BXQ-350) have unusually high affinity for phosphatidylserine-enriched membrane surfaces that occur widely in many types of tumor cells and tumor neovasculature. Consistent with sphingolipid activator function, BXQ-350 appear to selectively induce tumor cells to undergo ceramide-mediated cell death, apparently sparing non-tumor cells. In Phase I of this proposal, we demonstrated the feasibility of using SapC-DOPS to target and kill intracranial gliomas. Intravenous administration of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. In Phase II, a GMP compliant formulation of SapC-DOPS (i.e., BXQ-350) was developed, and potency was confirmed in additional orthotopic preclinical GBM models. IND-enabling studies are in progress. Pharmacokinetics and toxicity studies thus far indicate favorable distribution and safety profiles in rodent and non-rodent studies. In this three-year Phase IIB proposal, the key objectives are to file the IND for BXQ-350, complete a Phase 1 clinical trial, and prepare for Phase 2. Recognizing that gliomas are highly heterogeneous, another objective is to identify and link biochemical factors (e.g., cell surface PS levels; genetic markers) to the degree of BXQ-350 tumoricidal activity. Understanding of these factors will improve dosing strategies and reduce the risk of variable therapeutic response. Specific Aims are: (1) Scale- up GMP production of BXQ-350; (2) File the IND and complete the Phase 1 clinical trial; and (3) Correlate susceptibility to killing by BXQ-350 with molecular and cellular characteristics of glioma cell lins (from a tumor bank). BXQ-350 offers an innovative and potentially powerful approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately, we will progress this technology for treating other tumors and for developing tumor-targeted imaging diagnostics.

描述（由申请人提供）：我们的目标是开发一种具有新颖作用机制的新分子实体，用于靶向和消除多形性胶质母细胞瘤（GBM，高级神经胶质瘤），这是一种致命的侵袭性脑肿瘤，没有有效的治疗方法。今年预计将有 12,000 名 GBM 患者被诊断出，其中大多数将在一年内死亡。迫切需要一种有效的抗神经胶质瘤药物。我们正在开发一种新型治疗性蛋白脂质纳米囊泡，可以靶向并破坏神经胶质瘤。由小溶酶体鞘脂激活蛋白 saposin C（SapC，80 个氨基酸）和磷脂二油酰磷脂酰丝氨酸（DOPS）组成；稳定的 200 nm SapC-DOPS 纳米囊泡（临床制剂称为 BXQ-350）对富含磷脂酰丝氨酸的膜表面具有异常高的亲和力，这种膜表面广泛存在于多种类型的肿瘤细胞和肿瘤新血管系统中。与鞘脂激活剂功能一致，BXQ-350 似乎选择性诱导肿瘤细胞经历神经酰胺介导的细胞死亡，显然不会伤害非肿瘤细胞。在该提案的第一阶段，我们展示了使用 SapC-DOPS 靶向和杀死颅内神经胶质瘤的可行性。对原位植入神经胶质瘤的小鼠静脉注射 SapC-DOPS 导致存活率呈剂量依赖性改善。在第二阶段，开发了符合 GMP 的 SapC-DOPS 配方（即 BXQ-350），并在其他原位临床前 GBM 模型中证实了其效力。支持 IND 的研究正在进行中。迄今为止的药代动力学和毒性研究表明，在啮齿动物和非啮齿动物研究中具有良好的分布和安全性。在这项为期三年的 IIB 期提案中，主要目标是提交 BXQ-350 的 IND，完成 1 期临床试验，并为 2 期做好准备。认识到神经胶质瘤具有高度异质性，另一个目标是识别生化因素（例如细胞表面 PS 水平；遗传标记）并将其与 BXQ-350 杀肿瘤活性程度联系起来。了解这些因素将改善给药策略并降低治疗反应变化的风险。具体目标是：（1）扩大BXQ-350的GMP生产； （2）提交IND并完成1期临床试验； (3) 将 BXQ-350 杀伤的敏感性与神经胶质瘤细胞 lins（来自肿瘤库）的分子和细胞特征相关联。 BXQ-350 提供了一种创新且潜在强大的方法来减缓肿瘤生长和消除深部脑肿瘤。最终，我们将推进这项技术用于治疗其他肿瘤和开发肿瘤靶向成像诊断。