ANTIBODY TREATMENT OF NEOPLASTIC MENINGEAL XENOGRAFTS

肿瘤性脑膜异种移植物的抗体治疗

• 批准号: 2443022
• 负责人: IRA BERGMAN
• 金额: $ 10.6万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-15 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443022
• 关键词: antineoplastics; clinical trials; combination cancer therapy; cytotoxicity; drug administration routes; human subject; human therapy evaluation; immunoglobulins; laboratory rat; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; xenotransplantation

Spread of cancer into the cerebrospinal fluid (CSF) is painful, debilitating and lethal. It occurs in 20% of childhood and adult brain tumors and an increasing percentage of systemic tumors. There is presently no lasting effective therapy for overt disease and the average life expectancy is 6 months with meningeal spread from a systemic cancer and 12 months with spread from a primary brain tumor. The major objective of this project is to develop new therapies for leptomeningeal (LM) neoplasia that utilize monoclonal antibodies (MoAbs). Specific treatment will include unmodified MoAbs alone or in combination with cytokines or growth factors such as IL-1, IL-2, TNF, and G-CSF. The mechanisms of anti-tumor effect will be studied by standard histologic and immunohistologic analysis of the CSF, leptomeninges and brain; in vitro assays of CSF cytotoxicity, antibody dependent cytotoxicity and complement dependent cytotoxicity; variation of MoAb immunoglobulin class, fractions (e.g. F(Ab')2) and scheduling; and depletion of host cellular and complement inflammatory response. A xenograft model with human tumors will be utilized to explore various strategies and agents for treatment. The initial experiments will evaluate the pharmacokinetics, toxicity, anti-tumor effects, and mechanisms of action of intrathecal (IT) and intravenous (IV) 3F8 and R24 MoAbs in athymic rats with LM xenografts of human melanoma, medulloblastoma or neuroblastoma. These MoAbs are in clinical trials for the treatment of human neuroblastoma and melanoma and have produced some promising results for the treatment of systemic disease. Our major hypothesis is that IT MoAb will be therapeutic against LM tumors which express the target antigen. Specific predictions are that IT-administered MoAb will distribute rapidly throughout the accessible CSF space and penetrate several mm into nervous tissue parenchyma; the specific binding of MoAb to tumor cells that express its target antigen will be 10 fold higher than non-specific binding to other tissues; IT MoAb will not be toxic to normal nervous system tissue; and sufficient complement and effector cells will enter the meningeal space to act with the MoAbs to eliminate tumor cells. The value of our anticipated results would be translation of the finding to clinical trials with these MoAbs for the treatment of LM disease in humans.

将癌症传播到脑脊液（CSF）中很痛苦， 衰弱和致命。 它发生在20％的童年和成人大脑中 肿瘤和全身性肿瘤百分比增加。 有 目前尚无对明显疾病和平均水平的持久疗法 预期寿命为6个月，脑膜因系统性癌症传播 从原发性脑肿瘤中扩散了12个月。 该项目的主要目的是开发新的疗法 利用单克隆抗体（MOABS）的嗜血症（LM）肿瘤。 具体处理将包括单独或组合未修饰的摩押 具有IL-1，IL-2，TNF和G-CSF等细胞因子或生长因子。 这 抗肿瘤效应的机制将通过标准组织学和 CSF，瘦素和大脑的免疫组织学分析；体外 CSF细胞毒性，抗体依赖性细胞毒性和补体的测定 依赖性细胞毒性；摩押免疫球蛋白类别的变化，分数 （例如f（ab'）2）和计划；宿主细胞和 补充炎症反应。 具有人类肿瘤的异种移植模型将用于探索各种 治疗策略和药物。 最初的实验将 评估药代动力学，毒性，抗肿瘤作用和 鞘内（IT）和静脉内（IV）3F8和R24的作用机制 与人类黑色素瘤LM异种移植的无性大鼠中的摩押， 髓母细胞瘤或神经母细胞瘤。这些摩押在临床试验中 人类神经母细胞瘤和黑色素瘤的治疗，并产生了一些 治疗全身性疾病的有希望的结果。 我们的专业 假设MOAB将对LM肿瘤具有治疗性 表达靶抗原。 具体的预测是IT管理 摩押将在可访问的CSF空间中迅速分发 将几毫米渗入神经组织实质中；特定的结合 摩押到表达其靶抗原的肿瘤细胞将为10倍 高于非特异性与其他组织的结合；摩押不会 对正常神经系统组织有毒；足够补充和 效应细胞将进入脑膜空间，与摩押行动 消除肿瘤细胞。 我们预期结果的价值将是 将发现与这些摩押的临床试验翻译成临床试验 治疗人类LM疾病。

项目成果

A rat model of leptomeningeal human neoplastic xenografts.

人类软脑膜肿瘤异种移植物的大鼠模型。

• DOI: 10.1023/a:1005709708928
• 发表时间: 1997
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Bergman,I;Ahdab-Barmada,M;Kemp,SS;Griffin,JA;Cheung,NK
• 通讯作者: Cheung,NK

Pharmacokinetics of IgG and IgM anti-ganglioside antibodies in rats and monkeys after intrathecal administration.

鞘内给药后 IgG 和 IgM 抗神经节苷脂抗体在大鼠和猴体内的药代动力学。

• 发表时间: 1998
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Bergman,I;Burckart,GJ;Pohl,CR;Venkataramanan,R;Barmada,MA;Griffin,JA;Cheung,NK
• 通讯作者: Cheung,NK

Adeno-associated viral vector gene transfer into leptomeningeal xenografts.

腺相关病毒载体基因转移至软脑膜异种移植物中。

• DOI: 10.1023/a:1005702228721
• 发表时间: 1997
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Rosenfeld,MR;Bergman,I;Schramm,L;Griffin,JA;Kaplitt,MG;Meneses,PI
• 通讯作者: Meneses,PI

Intrathecal administration of an anti-ganglioside antibody results in specific accumulation within meningeal neoplastic xenografts in nude rats.

鞘内注射抗神经节苷脂抗体会导致裸鼠脑膜肿瘤异种移植物中的特异性积累。

• DOI: 10.1097/00002371-199903000-00003
• 发表时间: 1999
• 期刊: Journal of immunotherapy (Hagerstown, Md. : 1997)
• 作者: Bergman,I;Pohl,CR;Venkataramanan,R;Burckart,GJ;Stabin,M;Barmada,MA;Griffin,JA;Cheung,NK
• 通讯作者: Cheung,NK