CORE--PRECLINICAL THERAPEUTIC REAGENT EVALUATION, PRODUCTION AND NEW DRUG PERMIT

核心--临床前治疗试剂评价、生产及新药许可

• 批准号: 7495672
• 负责人: CAROL J WIKSTRAND
• 金额: $ 28.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7495672
• 关键词: Animal Model; Biological Assay; Biological Models; Cells; Central Nervous System Neoplasms; Certification; Clinical; Clinical Trials; Conduct Clinical Trials; Contracts; DNA; Development; Effector Cell; Engineering; Evaluation; Guanosine Monophosphate; Immune; Immunocompetent; Immunoglobulin Fragments; Investigation; Investigational Drugs; Maximum Tolerated Dose; Modeling; Peptides; Performance; Pharmaceutical Preparations; Phase; Preparation; Production; Pyrogens; Quality Control; Rapid Access to Intervention Development; Rattus; Reagent; Reproduction spores; Rodent; Role; Safety; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Toxicity Tests; Toxin Conjugates; Viral; Xenograft Model; clinical application; in vivo; inhibitor/antagonist; mouse model; pre-clinical; programs; research clinical testing; small molecule; subcutaneous; tumor xenograft

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.

核心2的作用有三重：1）对项目1中产生的药物、肽、单克隆抗体和衍生构建体以及用于临床应用的活化免疫细胞的毒性、稳定性、体内定位和治疗效果进行临床前评估和分析该 SPORE 的 、 2 和 3 并在 Core 3 中进行了临床实施； 2）临床级MAb试剂的生产； 3) 准备并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管理的连续统一体，并确保正在开发的试剂的有序进展和质量控制，这是我们目前在 I 期和 II 期临床试验中成功开发和实施 MAb 试剂的特征。核心 2 的功能/具体目标如下： 具体目标 1. 目前在该 SPORE 的核心 3 中正在研究的单克隆抗体和免疫试剂批次的完整、工程、缀合和修饰构建体的体内稳定性的临床前评估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）中的定位和治疗效果。具体目标 2. 对于项目 1、2 和 2 中确定的任何有希望的试剂，按照目标 1 中所述，对动物模型中的衍生肽、药物和其他部分进行体内稳定性、定位和治疗效果的临床前分析。 3. 具体目标 3. 所有试剂（药物、肽、MAb、 和派生结构）在项目 1、2 和 3 中生成，并在该 SPORE 的核心 3 中进行调查。一个。通过执行或签订合同进行质量控制，所有细菌、真菌、病毒、热原和 DNA 污染检测以及一般体内安全测试（核心 3 免疫试剂），b．动物模型（正常和无胸腺啮齿动物；项目 1、2 和 3；核心 3）中药物、肽、MAb-毒素缀合物、核素-MAb 缀合物及其衍生物以及效应细胞的毒性测试和分析。 c 确定在无胸腺和正常大鼠和小鼠模型系统（皮下、颅内、中枢神经系统肿瘤）中显示无毒性和最大稳定性以及治疗效果的所有物质的最大耐受剂量（MTD） 异种移植：项目 1 和 2)。具体目标 4. 生产临床级试剂：生产足够数量的临床级 MAb、抗体片段、构建体和缀合物，用于核心 3 中进行的临床试验。项目 1 的小分子抑制剂将外包给 GMP 生产商或 NCI RAID 程序。具体目标 5. 为项目 1、2 和 3 中开发的所有拟议疗法准备和提交 IND 许可申请。作为临床前开发核心，核心 2 对项目 1、2 和 3 以及核心具有基本支持功能1 和 3。