SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme

描述（由申请人提供）：我们的目标是开发一种新的分子实体，具有新的作用机制，用于靶向和消除多形性胶质母细胞瘤（GBM，高级别胶质瘤），这是一种致命的侵袭性脑肿瘤，没有有效的治疗方法。预计今年将有1.2万名患者被诊断为GBM，其中大多数人将在一年内死亡。迫切需要一种有效的抗胶质瘤药物。我们正在开发一种新的治疗性蛋白脂纳米囊泡，它可以靶向并摧毁胶质瘤肿瘤。由小溶酶体鞘脂激活蛋白皂苷C （SapC, 80 aa）和磷脂二油基磷脂酰丝氨酸（DOPS）组成；稳定的200纳米SapC-DOPS纳米囊泡（临床配方称为BXQ-350）对广泛存在于多种肿瘤细胞和肿瘤新生血管中的富含磷脂酰丝氨酸的膜表面具有异常高的亲和力。与鞘脂激活剂的功能一致，BXQ-350似乎选择性地诱导肿瘤细胞经历神经酰胺介导的细胞死亡，显然不影响非肿瘤细胞。在该方案的I期研究中，我们证明了使用SapC-DOPS靶向和杀死颅内胶质瘤的可行性。静脉给药SapC-DOPS的小鼠原位植入胶质瘤导致剂量依赖性的生存改善。在II期，开发了符合GMP的SapC-DOPS配方（即BXQ-350），并在其他原位临床前GBM模型中证实了效力。支持自主研发的研究正在进行中。到目前为止，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。在这个为期三年的IIB期申请中，BXQ-350的主要目标是提交IND，完成i期临床试验，并为ii期做准备。认识到胶质瘤是高度异质性的，另一个目标是确定生化因素（如细胞表面PS水平；遗传标记）与BXQ-350的杀瘤活性程度之间的联系。了解这些因素将改善给药策略，减少治疗反应变化的风险。具体目标是：(1)BXQ-350的GMP规模化生产；(2)提交IND并完成i期临床试验；(3)将BXQ-350的杀伤敏感性与胶质瘤细胞株的分子和细胞特性联系起来（来自肿瘤库）。BXQ-350为减缓肿瘤生长和消除深层脑肿瘤提供了一种创新的、潜在的强大方法。最终，我们将把这项技术用于治疗其他肿瘤和开发肿瘤靶向成像诊断。

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.