NOVEL TUMOR ANTIGEN FOR ANTIBODY TARGETING

描述：单克隆抗体（MoAb）具有临床潜力， 诊断和治疗人类癌症。使用MoAb 3F 8， 神经节苷脂GD 2和人神经母细胞瘤作为肿瘤模型，研究者 在过去的13年里，已经证明MoAb可以成功地 纳入多模式治疗战略。MoAb可以同时针对 辐射和免疫效应器功能有效， 疾病使用单一单克隆抗体-抗原系统，超过50%的患者 转移性神经母细胞瘤的患者有望长期存活， 二十年前没有人幸存下来。3年后的晚期复发现在很罕见，而且晚期复发 抗体治疗的影响最小。类似于联合化疗， 研究者希望MoAb方法的有效性进一步增强 如果有一组临床上有用的单克隆抗体的话。相对缺乏 儿科胚胎、间叶和脑肿瘤中的合适靶点， 极大地限制了基于抗体的策略的发展。这些肿瘤 包括横纹肌肉瘤（RMS）、骨肉瘤（OS）、尤文氏/PNET（ES） 促结缔组织增生性小圆细胞瘤（DSRT），脑肿瘤和其他肉瘤， 儿童/青少年年龄组。在对他们的 神经母细胞瘤MoAb清单，研究人员已经确定了一种新的MoAb 对人神经外胚层具有广谱反应性的8H 9， 间充质和上皮肿瘤。该单克隆抗体与 正常血液或骨髓细胞、脑、脑干、脊髓、正常器官 除了肾上腺皮质、胰腺和 肝脏抗原表达在阳性肿瘤中是同质的， 在MoAb结合后在37 ℃下未调节。8H 9是有效的清洗 从血液或骨髓干细胞中提取肿瘤。当放射性标记时，8H 9保留 免疫反应性，有效靶向人神经母细胞瘤， 横纹肌肉瘤异种移植物静脉内和鞘内注射8H 9， 对食蟹猴无副作用。在这份资助申请中， 研究者建议确定131-I-8H 9在患者中的生物分布 RMS、OS、ES、DSRT、脑肿瘤和其他软组织肉瘤。他们将 测试这种抗体在检测肿瘤时的灵敏度和特异性， 与传统的放射学研究相比。这种药物的药代动力学 当静脉内给药时的抗体和沉积在肿瘤中的8H 9的量 与正常器官的对比将被仔细定义。这一信息至关重要 用于放射免疫治疗以及未来的基于抗体的靶向治疗。

DESCRIPTION: Monoclonal antibodies (MoAb) have clinical potentials for the diagnosis and therapy of human cancers. Using the MoAb 3F8 directed at ganglioside GD2, and human neuroblastoma as the tumor model, the investigator has demonstrated over the last 13 years that MoAb can be successfully integrated into multimodality curative strategies. MoAb can target both radiation and immune effector functions effectively at minimal residual disease. With a single MoAb - antigen system, more than 50 percent of patients with metastatic neuroblastoma are expected to be long term survivors whereas none survived 2 decades ago. Late relapses after 3 years are now rare, and late effects from antibody treatment minimal. Analogous to combination chemotherapy, the investigator expects the efficacy of MoAb approach to be further amplified if a panel of clinically useful MoAbs is available. The relative lack of appropriate targets among pediatric embryonal, mesenchymal and brain tumors has greatly limited the development of antibody-based strategies. These tumors include rhabdomyosarcoma (RMS), osteosarcoma (OS), Ewing's/PNET (ES), desmoplastic small round cell tumor (DSRT), brain tumors and other sarcomas in the pediatric/adolescent age group. Following an extensive screening of their neuroblastoma MoAb inventory, the investigators have identified a novel MoAb 8H9 with a broad spectrum of reactivity against human neuroectodermal, mesenchymal, and epithelial tumors. This MoAb has no cross reactivity with normal blood or marrow cells, brain, brainstem, spinal cord, normal organs except for faint staining of the cytoplasm of adrenal cortex, pancreas and liver. Antigen expression is homogenous among positive tumors and remains unmodulated at 37 degrees C following MoAb binding. 8H9 is effective in purging tumors from blood or marrow stem cells. When radiolabeled, 8H9 retains immunoreactivity and targets effectively to human neuroblastoma and rhabdomyosarcoma xenografts. Intravenous and intrathecal injections of 8H9 has no side effects in cynomolgus monkeys. In this grant application the investigator proposes to define the biodistribution of 131-I-8H9 in patients with RMS, OS, ES, DSRT, brain tumors and other soft tissue sarcomas. They will test the sensitivity and specificity of this antibody in detecting tumors when compared to conventional radiographic studies. The pharmacokinetics of this antibody when given intravenously and the amount of 8H9 deposited in tumors versus normal organs will be carefully defined. This information is critical for radioimmunotherapy as well as future antibody-based targeted therapies.