CORE--BASIC, PRECLINICAL, AND CLINICAL SUPPORT

核心——基础、临床前和临床支持

• 批准号: 6593429
• 负责人: CAROL J WIKSTRAND
• 金额: $ 31.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6593429
• 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1：1）药物和单克隆抗体的临床前评价 用于准备研究性新药（IND）申请的试剂 2）新的不断产生和发展， 转基因抗体的建立和鉴定 临床应用 IND申请的准备包括 建立生物特异性，执行所有FDA规定的 细菌、真菌、病毒、热原和DNA污染的检测，以及 一般安全测试。 两项I期临床研究正在进行中， 允许BBIND 2692和BBIND 3344;这些试验正在评估疗效 并且没有鞘内和囊内施用的毒性 在患有神经胶质瘤、转移性恶性肿瘤的患者中的MAb 81 C6和Mel-14;或 其他脑肿瘤 核心1的第二个作用是提供持续的 IND申请和I期试验的试剂来源。 三个领域 正在进行：1）抗胶质瘤单克隆抗体的嵌合; 2）临床前 在无胸腺大鼠异种移植模型中评价药物和MAb缀合物 允许动脉内和鞘内给药模式的系统;以及 3)开发和从头生产用于神经胶质瘤的新试剂， 髓母细胞瘤 MAb嵌合。 I期试验中的鼠单克隆抗体，81 C6 和Mel-14，已经通过基因组克隆嵌合，转染到 纯化的SP2/0表达系统显示出保留特异性， 亲和力等于或大于亲本鼠分子， 定位于无胸腺小鼠皮下异种移植模型中。 增强等离子体 半衰期和更大的定位（剂量/gm百分比）和定位 观察到指数，以及降低的脱卤作用。 替代方法 嵌合体化的可能性正在探索中， 试剂，对于所需的人类框架，最大生产力的细胞 表达系统和定点诱变。 模型系统 试剂开发 我们开发并应用了两个模型系统， 无胸腺大鼠用于评价动脉内或鞘内 隔室疗法 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，我们正在评估动脉内和鞘内 向神经胶质瘤和成神经管细胞瘤异种移植物施用美法仑; 用MAb-假单胞菌毒素缀合物鞘内治疗癌;和 α-发射核素-MAb缀合物（211 AT）对 颅内肿瘤和软脑膜疾病。 开发新 抗神经胶质瘤和抗髓母细胞瘤试剂。 额外候选者 用于诊断、成像或治疗靶向的分子已经 鉴定 目前，唯一一种被证明在临床上有价值的MAb 髓母细胞瘤的隔室治疗是抗L1单抗UJ181.4， 由于其固有的低分泌， 率 我们正在通过嵌合优化这种mAb用于I期研究。 我们 建议生产多表位L1分子的试剂， 在髓母细胞瘤中的治疗应用及其作用的确定 细胞聚集和粘附于软脑膜基质。