Immunotherapy for gliomas with monoclonal antibodies targeting MCSP

使用针对 MCSP 的单克隆抗体进行胶质瘤免疫治疗

• 批准号: 7229900
• 负责人: ROBERT A FENSTERMAKER
• 金额: $ 23万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2008-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229900
• 关键词: Address; Adjuvant Therapy; Animals; Antigens; Binding; Blocking Antibodies; Brain Neoplasms; C57BL/6 Mouse; CSPG4 gene; Cell Line; Cell surface; Cells; Cerebrum; Cessation of life; Chondroitin Sulfate Proteoglycan; Cultured Cells; Data; Development; Disease; ERBB2 gene; Epidermal Growth Factor Receptor; Erbitux; Excision; Extracellular Matrix; Glioblastoma; Glioma; Goals; Growth; HMW-MAA; Homologous Gene; Human; Immunologics; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Incidence; Language Disorders; Malignant Glioma; Malignant Neoplasms; Measures; Mediating; Memory; Methods; Microscopic; Modeling; Monoclonal Antibodies; Monoclonal Antibody C225; Mus; Neurologic; Neurologic Dysfunctions; Neurologic Symptoms; Numbers; Operative Surgical Procedures; Passive Immunotherapy; Patients; Performance Status; Phase I Clinical Trials; Proteoglycan; Radiation therapy; Range; Rattus; Reporting; Research; Research Personnel; Residual Tumors; Residual state; Roche brand of trastuzumab; Rodent; Seizures; Sequence Homology; Signal Pathway; Signal Transduction; Specimen; Symptoms; Techniques; Testing; Tumor Antigens; United States; Visual impairment; antigen antibody binding; base; cell growth; chemotherapy; clinically relevant; disability; in vivo; melanoma; melanoma-associated antigen; motor deficit; neoplastic cell; outcome forecast; programs; tumor; tumor growth

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.

描述（由申请方提供）：恶性胶质瘤会导致严重的神经功能障碍，包括语言障碍、记忆和认知丧失、运动缺陷、视力障碍、癫痫发作和进行性残疾。最常见类型的胶质瘤（多形性胶质母细胞瘤）患者的中位生存期仅为12-24个月。虽然神经系统症状可以通过手术缓解，但恶性胶质瘤通常由于残留的显微病变的持续生长而复发。因此，需要更有效的辅助疗法来治疗手术后存在的残留肿瘤。我们已经观察到70%的人胶质瘤表达高分子量黑素瘤相关抗原（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聚糖（PG）。针对HMW-MAA产生的单克隆抗体（mAb）能够抑制肿瘤细胞的生长。我们希望在该提案中解决的总体假设是，在临床相关的动物脑肿瘤模型中，使用HMW-MAA特异性mAb的被动免疫疗法抑制胶质瘤生长并延长存活期。这与使用针对EGFR（爱必妥）和HER 2/neu（赫赛汀）的阻断性mAb的类似结果一致，如针对神经胶质瘤专门报告的。本建议的具体目的是检验以下假设：1。HMW-MAA特异性mAb在体内以高浓度蓄积并保留在脑胶质瘤中。使用高灵敏度技术（MicroPET），我们将测量全身给药后GL 261小鼠脑胶质瘤中HMW-MAA特异性mAb的蓄积和保留。2. HMW-MAA特异性mAb抑制脑胶质瘤的体内生长并延长颅内胶质瘤小鼠的生存期。我们将测量HMW-MAA特异性mAb对患有同基因GL 261脑胶质瘤的C57 BL/6小鼠的肿瘤生长和存活的影响。3. HMW-MAA特异性mAb抑制HMW-MAA介导的信号转导和肿瘤细胞生长。我们将测量HMW-MAA特异性mAb对培养的GL 261细胞中肿瘤细胞生长、存活和细胞内信号传导的影响，并将这些结果与mAb对GL 261胶质瘤的体内影响相关联。这些研究将用于制定关注单一HMW-MAA特异性mAb的基本原理，以进行人源化，并开发针对人神经胶质瘤的I期临床试验。这一建议符合我们研究计划的总体目标，该计划的核心是开发治疗恶性胶质瘤的靶向免疫策略。