CORE--INVESTIGATIONAL NEW DRUG AND MONOCLONAL ANTIBODY PERMIT APPLICATION

核心--研究性新药和单克隆抗体许可证申请

• 批准号: 6243549
• 负责人: CAROL J WIKSTRAND
• 金额: $ 19.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243549
• 关键词: antineoplastics; antitumor antibody; athymic mouse; biomedical facility; combination cancer therapy; dosage; drug screening /evaluation; glioma; hybrid antibody; immunoconjugates; laboratory mouse; laboratory rat; melphalan; meningioma; meningitis; molecular cloning; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; polymerase chain reaction; recombinant DNA; site directed mutagenesis

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提供：1)药物和单抗的临床前评估 用于制备研究性新药(IND)应用的试剂 2)新事物的不断产生和发展，以及 猪传染性支气管炎转基因抗体的建立及鉴定 临床应用。IND申请的准备工作包括 建立生物特异性，执行FDA规定的所有 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 许可BBIND 2692和BBIND 3344；这些试验正在评估疗效 鞘内和囊内给药无毒性 胶质瘤、转移性恶性肿瘤患者的单抗81C6和MEL-14；或 其他脑瘤。核心1的第二个角色是提供连续的 IND应用和第一阶段试验的试剂来源。三个领域是 正在进行的研究：1)抗胶质瘤单抗的嵌合化；2)临床前 药物和单抗结合物在无瘤大鼠异种移植模型中的评价 允许动脉内和鞘内给药模式的系统；以及 3)开发和重新生产治疗胶质瘤的新试剂和 髓母细胞瘤。单抗嵌合。小鼠单抗进入I期试验，81C6 和Mel-14已通过基因组克隆嵌合化，并转染到 SP2/0表达系统，纯化，证明保留了特异性和 亲和力等于或大于亲本鼠分子，以及 在裸鼠皮下异种移植模型中定位。增强等离子体 半衰期和更大的剂量/gm百分比定位和定位 观察了各项指标，以及减少的脱卤化。替代方法 正在为这些和所有其他候选者探索嵌合化 试剂，关于所需的人体骨架，最多产细胞 表达系统和定点突变。的模型系统 试剂开发。我们已经开发并应用了两个模型系统 无菌大鼠对动脉或鞘内血管的评价 隔室疗法。肿瘤移植模型包括胶质瘤(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 马法兰对胶质瘤和髓母细胞瘤移植瘤的作用 单抗-假单胞菌毒素结合物鞘内治疗肿瘤；以及 放射性核素-单抗结合物(~(211)AT)的治疗效果 颅内肿瘤和软脑膜疾病。新技术的发展 抗胶质瘤和抗髓母细胞瘤试剂。其他候选人 用于诊断、成像或治疗靶向的分子已经被 确认身份。目前，唯一被证明有价值的单抗在 髓母细胞瘤的分区治疗是抗L1单抗UJ181.4， 它的持续使用因其固有的低分泌量而受到影响 费率。我们正在通过嵌合化来优化这一单抗用于I期研究。我们 建议多表位L1分子试剂的生产 髓母细胞瘤的治疗应用及其作用的确定 细胞与软脑膜基质的聚集和黏附。