CORE--BASIC, PRECLINICAL, AND CLINICAL SUPPORT

核心——基础、临床前和临床支持

• 批准号: 6430233
• 负责人: CAROL J WIKSTRAND
• 金额: $ 28.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430233
• 关键词: antineoplastics; antitumor antibody; athymic mouse; biomedical facility; combination cancer therapy; disease /disorder model; dosage; drug screening /evaluation; glioma; hybrid antibody; immunoconjugates; laboratory rat; medulloblastoma; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; nonhuman therapy evaluation

Core 1 furnishes: 1) the preclinical evaluation of drugs and monoclonal reagents for the preparation of Investigational New Drug (IND) applications and 2) the continued generation and development of new, and the establishment and characterization of genetically modified antibodies for clinical application. The preparation of IND applications includes the establishment of biologic specificity, the performance of all FDA mandated assays for bacterial, fungal, viral, pyrogen, and DNA contamination, and general safety tests. Two Phase I clinical studies are in progress under permits BBIND 2692 and BBIND 3344; these trials are evaluating the efficacy and lack of toxicity of the intrathecal and intracystic administration of the MAbs 81C6 and Mel-14 in patients with gliomas, metastatic malanoma; or other brain tumors. The second role of Core 1 is to provide a continual source of reagents for IND application and Phase I trial. Three areas are being pursued: 1) chimerization of anti-glioma MAbs; 2) preclinical evaluation of drugs and MAb conjugates in athymic rat xenograft model systems to allow intraarterial and intrathecal modes of administration; and 3) development and de novo production of new reagents for glioma and medulloblastoma. MAb chimerization. Murine MAbs in Phase I trial, 81C6 and Mel-14, have been chimerized by genomic cloning, transfected into an SP2/0 expression system, purified, demonstrated to retain specificity and an equal to or greater affinity than the parental murine molecule and localize in athymic mouse subcutaneous xenograft models. Enhanced plasma half-life and greater localization in percent dose/gm and localization indices were observed, as was decreased dehalogenation. Alternate methods of chimerization are being explored for these and all other candidate reagents, with regard to human framework desired, maximally productive cell expression systems, and site-directed mutagenesis. Model systems for reagent development. We have developed and applied two model systems in the athymic rat for the evaluation of intraarterial or intrathecal compartmental therapy. Tumor xenograft models include glioma (D54 MG), medulloblastoma (D341 Med), carcinoma (A431), and rhabdomyosarcoma (TE- 671). Currently, we are evaluating intraarterial and intrathecal administration of melphalan to glioma and medulloblastoma xenografts; the intrathecal therapy of carcinoma with MAb-Pseudomonas toxin conjugates; and the efficacy of alpha-emitting nuclide-MAb conjugates (211AT) to intracranial tumors and leptomeningeal disease. Development of new antiglioma and anti-medulloblastoma reagents. Additional candidate molecules for diagnostic, imaging or therapeutic targeting have been identified. Currently, the only MAb demonstrated to be of value in the compartmental therapy of medulloblastoma is the anti-L1 MAb UJ181.4, the continued use of which has been compromised by its inherent low secretion rate. We are optimizing this mAb for Phase I studies by chimerization. We propose the production of reagents to the multi-epitopic L1 molecule for therapeutic application and determination of its role in medulloblastoma cell aggregation and adhesion to leptomeningeal matrix.

核心1家具：1）药物和单克隆的临床前评估 制备研究新药（IND）应用的试剂 2）新的持续生成和发展，以及 建立和表征转基因的抗体 临床应用。 IND应用程序的准备包括 建立生物学特异性，所有FDA的性能 细菌，真菌，病毒，热原和DNA污染的测定法和 一般安全测试。 两次I期临床研究正在进行中 允许BBIND 2692和BBIND 3344;这些试验正在评估功效 并且缺乏鞘内和内部给药的毒性 神经胶质瘤，转移性肾小球瘤患者的mABS 81C6和MEL-14；或者 其他脑肿瘤。 核心1的第二个角色是提供连续的 IND应用和I期试验的试剂来源。 三个领域 被追捕：1）抗神经瘤mAb的嵌合体； 2）临床前 无胸腺异种移植模型中药物和mAb共轭物的评估 系统允许内部和鞘内给药模式；和 3）从头生产新试剂神经胶质瘤和新试剂 髓母细胞瘤。 mab嵌合。 I期试验中的鼠mabs，81C6 和MEL-14，已通过基因组克隆进行了嵌合，转染了 SP2/0表达系统，纯化，被证明是保留特异性和 比父母鼠分子等于或更大的亲和力 位于无胸腺皮下异种移植模型中。 增强的血浆 半衰期和剂量/gm百分比和本地化的本地化更大 观察到指数，脱核酸减少。 替代方法 这些和所有其他候选人正在探索嵌合 关于人类框架的试剂，最大生产性细胞 表达系统和定向诱变。 模型系统 试剂开发。 我们已经开发并应用了两个模型系统 用于评估胃内或鞘内的无胸腺大鼠 室疗法。 肿瘤异种移植模型包括神经胶质瘤（D54 mg）， 髓母细胞瘤（D341 MED），癌（A431）和横纹肌肉瘤（Te- 671）。 目前，我们正在评估内部和鞘内 给予Melphalan至神经胶质瘤和髓母细胞瘤异种移植物；这 用mAb pexudomonas毒素结合物对癌的鞘内治疗；和 α发射核素-MAB偶联物（211AT）的功效 颅内肿瘤和瘦脑疾病。 新的发展 抗细胞瘤和抗糖母细胞瘤试剂。 其他候选人 用于诊断，成像或治疗靶向的分子已经 确定。 目前，唯一证明在 髓母细胞瘤的分室疗法是抗L1 mAb UJ181.4， 继续使用其固有的低分泌所损害 速度。 我们正在通过嵌合为I期研究优化此mAB。 我们 提出将试剂生产到多pipopic L1分子的 治疗应用和确定其在髓母细胞瘤中的作用 细胞聚集和粘附基质的粘附。