CORE 2 --REAGENT EVALUATION, PRODUCTION AND PERMIT

核心2——试剂评估、生产和许可

• 批准号: 6844181
• 负责人: CAROL J WIKSTRAND
• 金额: $ 17.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844181
• 关键词: antineoplastics; athymic mouse; biomedical facility; brain neoplasms; drug design /synthesis /production; drug screening /evaluation; immunologic substance development /preparation; laboratory rat; monoclonal antibody; neoplasm /cancer chemotherapy

The role of Core 2 is threefold: 1) the preclinical evaluation and analysis of drugs, peptides, MAbs and derived constructs, and activated immune cells for clinical application in terms of toxicity, stability, in vivo localization and therapeutic effect, generated in Projects 1, 2, and 3 of this SPORE and implemented clinically in Core 3; 2) the production of clinical grade MAb reagents; and 3) the preparation and submission of Investigational New Drug (IND) permit applications for all reagents of potential clinical utility. This Core provides a continuum from bench to clinical administration and assures the orderly progression and quality control of reagents in development that have characterized the development and implementation of our currently successful MAb reagents in Phase I and II clinical trials. The Functions/Specific Aims of Core 2 are as follows: Specific Aim 1. Pro-clinical evaluation of intact, engineered, conjugated, and modified constructs of MAbs and immunoreagent batches currently under investigation in Core 3 of this SPORE in terms of in vivo stability, localization, and therapeutic effect in immunocompetent and athymic rodent tumor xenograft models, including subcutaneous and intracranial models. Specific Aim 2. Pro-clinical analysis of derived peptides, drugs, and other moieties in terms of in vivo stabality, localization, and therapeutic effect in animal models as described in Aim 1 for any reagents of promise identified in Projects 1, 2, and 3. Specific Aim 3. Pro-clinical evaluation and quality certification of all reagents (drug, peptide, MAb, and derived constructs) generated in Projects 1, 2, and 3 and under investigation in Core 3 of this SPORE. a. Quality control by performance of, or contract for, all assays for bacterial, fungal, viral, pyrogen, and DNA contamination, and general safety tests in vivo (Core 3 immunoreagents), b. Toxicity testing and analysis of drug, peptide, MAb-toxin conjugates, nuclide-MAb conjugates and their derivatives, and effector cells in animal models (normal and athymlc rodents; Projects 1, 2 and 3; Core 3). c Determination of the maximum tolerated doses (MTD) for all substances showing no toxicity and maximal stability and therapeutic effect in athymic and normal rat and mouse model systems (subcutaneous, intracranial, CNS tumor xenografts: Projects 1 and 2). Specific Aim 4. Production of clinical grade reagents: Production of clinical grade MAb, antibody fragments, constructs, and conjugates in sufficient quantity for clinical trials conducted m Core 3. Small molecule inhibitors from Project 1 will be contracted out to GMP producers or the NCI RAID Program. Specific Aim 5. Preparation and submission of IND permit applications for all proposed therapies developed in Projects 1, 2, and 3. As the pre-clinical development Core, Core 2 has fundamental support functions for Projects 1, 2, and 3, and Cores 1 and 3.

Core 2的作用有三个方面：1）在本SPORE项目1、2和3中产生并在Core 3中临床实施的用于临床应用的药物、肽、单克隆抗体及其衍生构建体和活化免疫细胞的毒性、稳定性、体内定位和治疗效果的临床前评价和分析; 2）生产临床级单克隆抗体试剂;以及3）准备和提交所有具有潜在临床用途的试剂的研究性新药（IND）许可申请。该核心提供了从实验室到临床给药的连续统一体，并确保了开发中试剂的有序进展和质量控制，这些试剂是我们目前在I期和II期临床试验中成功开发和实施的MAb试剂的特征。核心2的功能/具体目标如下：具体目标1。在免疫活性和无胸腺啮齿动物肿瘤异种移植模型（包括皮下和颅内模型）中，对本SPORE核心3中目前正在研究的MAb和免疫试剂批次的完整、工程化、结合和修饰构建体进行体内稳定性、定位和治疗作用的临床前评价。具体目标2。根据目标1中所述的动物模型中的体内稳定性、定位和治疗效果，对衍生肽、药物和其他部分进行临床前分析，用于项目1、2和3中确定的任何有前景的试剂。 具体目标3。所有试剂（药物、肽、单克隆抗体、 和衍生结构），并在本SPORE的核心3中进行研究。a.通过执行或合同进行细菌、真菌、病毒、热原和DNA污染的所有测定以及体内一般安全性试验（核心3免疫试剂）进行质量控制，B。药物、肽、MAb-毒素缀合物、核素-MAb缀合物及其衍生物和效应细胞在动物模型中的毒性测试和分析（正常和无胸腺啮齿动物;项目1、2和3;核心3）。c测定在无胸腺和正常大鼠和小鼠模型系统（皮下、颅内、CNS肿瘤）中显示无毒性和最大稳定性和治疗效果的所有物质的最大耐受剂量（MTD 异种移植物：项目1和2）。具体目标4。临床级试剂的生产：生产临床级单克隆抗体、抗体片段、构建体和偶联物，其数量足以在核心3中进行临床试验。项目1的小分子抑制剂将外包给GMP生产商或NCI RAID计划。具体目标5.为项目1、2和3中开发的所有拟定疗法准备并提交IND许可申请。作为临床前开发核心，核心2对项目1、2和3以及核心1和3具有基本支持功能。