Immunotherapy for gliomas with monoclonal antibodies targeting MCSP

描述(申请人提供)：恶性胶质瘤导致严重的神经功能障碍，包括语言障碍、记忆和认知丧失、运动障碍、视力障碍、癫痫发作和进行性残疾。最常见的胶质瘤(多形性胶质母细胞瘤)患者的中位生存期只有12-24个月。虽然神经症状可能会通过手术得到缓解，但恶性胶质瘤通常会因为残留的显微镜下病变的持续生长而复发。因此，需要更有效的辅助治疗来治疗术后残留的肿瘤。我们观察到，70%的人脑胶质瘤表达高分子量黑色素瘤相关抗原(HMW-MAA)，这是一种与细胞外基质(ECM)相互作用的大细胞表面蛋白多糖(PG)。针对HMW-MAA产生的单抗能够抑制肿瘤细胞的生长。我们希望在这项提案中解决的总体假设是，在临床相关的动物脑瘤模型中，用HMW-MAA特异性单抗进行被动免疫治疗可以抑制胶质瘤的生长并延长生存期。这与使用针对EGFR(Erbitux)和HER2/neu(Herceptin)的阻断单抗的类似发现是一致的，这是专门针对胶质瘤报道的。这一提议的具体目的是验证以下假设：1.HMW-MAA特异性mAb在脑胶质瘤中以较高的浓度在体内积累和保留。使用一种高灵敏度的技术(MicroPET)，我们将测量全身给药后HMW-MAA特异性单抗在GL261小鼠脑胶质瘤中的积累和滞留。2.HMW-MAA特异性单抗可在体内抑制脑胶质瘤的生长，延长荷瘤小鼠的生存时间。我们将检测HMW-MAA特异性单抗对同基因GL261脑胶质瘤C57BL/6小鼠肿瘤生长和存活的影响。3.HMW-MAA特异性单抗抑制HMW-MAA介导的信号转导和肿瘤细胞生长。我们将检测HMW-MAA特异性mAb对培养的GL261细胞生长、存活和细胞内信号转导的影响，并将这些结果与mAb在体内对GL261胶质瘤的作用相关联。这些研究将被用来开发专注于单一HMW-MAA特异性单抗的理论基础，以人性化并开发针对人脑胶质瘤的I期临床试验。这一建议符合我们研究计划的总体目标，该计划的中心是开发有针对性的免疫治疗策略来治疗恶性胶质瘤。

DESCRIPTION (provided by applicant): Malignant gliomas cause severe neurologic dysfunction, including language disorders, memory and cognitive loss, motor deficits, visual impairment, seizures and progressive disability. Patients with the most common type of glioma (glioblastoma multiforme) have a median survival of only 12-24 months. While neurological symptoms may be alleviated with surgery, malignant gliomas commonly recur due to continued growth of residual microscopic disease. Therefore, more effective adjuvant therapies are required for treatment of residual tumor present after surgery. We have observed that 70% of human gliomas express high molecular weight melanoma-associated antigen (HMW-MAA), a large cell-surface proteoglycan (PG) that interacts with the extracellular matrix (ECM). Monoclonal antibodies (mAb) raised against HMW-MAA are capable of inhibiting the growth of tumor cells. The overall hypothesis that we wish to address in this proposal is that passive immunotherapy with HMW-MAA-specific mAbs inhibit glioma growth and prolong survival in a clinically relevant animal brain tumor model. This is consistent with similar findings using blocking mAbs against EGFR (Erbitux) and HER2/neu (Herceptin) as reported specifically for gliomas. The specific aims of this proposal are to test the hypotheses that: 1. HMW-MAA-specific mAb accumulates and is retained in cerebral gliomas at high concentrations in vivo. Using a highly sensitive technique (MicroPET), we will measure the accumulation and retention of HMW- MAA-specific mAb in GL261 murine cerebral gliomas following systemic administration. 2. HMW-MAA-specific mAb inhibits the growth of cerebral gliomas in vivo and prolongs the survival of mice with intracranial gliomas. We will measure the effect of HMW-MAA-specific mAb on tumor growth and survival in C57BL/6 mice with syngeneic GL261 cerebral gliomas. 3. HMW-MAA-specific mAb inhibits HMW-MAA-mediated signal transduction and tumor cell growth. We will measure the effect of HMW-MAA-specific mAb on tumor cell growth, survival and intracellular signaling in cultured GL261 cells and correlate these results with the effects of mAb on GL261 gliomas in vivo. These studies will be used to develop a rationale for focusing on a single HMW-MAA-specific mAb to humanize and develop for a Phase I clinical trial against human gliomas. This proposal fits with the overall goal of our research program which is centered on the development of targeted immunotherapeutic strategies to treat malignant gliomas.