CORE--Basic, Preclinical, and Clinical Support Core

核心1规定：1)对最终临床试验所需的药物和克隆试剂进行临床前评估和分析；2)继续开发针对基因挖掘方法确定的目标的新试剂，在单独资助的赠款中，并建立和表征用于临床应用的转基因抗体试剂；以及3)为本SRC产生的所有试剂或在单独资助的赠款中产生的所有试剂准备IND申请。临床前评估包括对SRC中产生的所有试剂(药物、单抗、嵌合单抗分子、构建物和连接物)进行所有必要的认证分析，目前支持项目4中阐述的I/II阶段试验。核心1的开发作用是产生用于临床应用的新的或改进的试剂，如目标1所述。正在进行三个领域：1)嵌合化、片段工程和生化 2)对药物和抗体结合物(皮下、颅内和鞘内；肿瘤性脑膜炎)模型的评价；以及3)临床前的特征和由其他资助赠款产生的试剂的发展，用于间隔治疗。MAB工程学。除了在I/II期试验中成功地嵌合单抗(81C6及其衍生物)外，我们现在已经有了必要的方法学来产生糖尿病、微体和CH2结构域缺失的F(ab‘)2单抗，以改善穿透、血液清除和/或不存在肾小球捕获，用于直接治疗应用和细胞介导的诱导 反应性。中枢神经系统肿瘤治疗的体内模型。试剂开发的核心是在模拟人类中枢神经系统疾病的模型中对稳定性、定位能力和肿瘤稳定或杀瘤效应进行一致的临床前评估。我们通过新的疾病模型(室管膜瘤)和新的给药途径，不断完善我们的大型可用模型库(sc，ic，ith)，用于临床前评估特异性、有效性和无毒性。这一计划最独特的是无菌大鼠软脑膜脑膜炎模型，该模型不仅允许建立蛛网膜下腔扩散的中枢神经系统肿瘤，而且还允许首次给药。由单独资助的赠款产生的胶质瘤靶向试剂的开发。单抗 试剂VS GPNMB、MRP3、SSTR2A和胶质瘤相关神经节苷脂3‘-isLM1和3’，6‘-isLD1，由单独的资金产生，将在该核心的支持下进行临床前评估。

Core 1 provides : 1) preclinical evaluation and analysis of drugs and monoclonal reagents requisite for eventual clinical trial, 2) continued development of new reagents directed against targets identified by gene mining approaches in separately funded grants, and establishment and characterization of genetically modified antibody reagents for clinical application; and 3) preparation of IND applications for all reagents generated in this SRC or in separately funded grants. Preclinical evaluation includes the performance of all requisite certification assays for all reagents (drug, MAb, chimeric MAb molecules, constructs and conjugates) generated in the SRC, and currently supports Phase I/II trials elaborated in Project 4. The developmental role of Core 1 is to generate new or modified reagents for clinical application as described in Aim 1. Three areas are being pursued: 1) chimerization, fragment engineering, and biochemical and genomic production of MAb conjugates/constructs; 2) evaluation of drugs and antibody conjugates in athymic rodent models (subcutaneous (sc), intracranial (ic), and intrathecal (ith); neoplastic meningitis); and 3) preclinical characterization and development of reagents generated in other funded grants for compartmental therapy. MAb engineering. In addition to the successful chimerization of the MAbs in Phase I/II trials (81C6 and derivatives), we now have available the requisite methodology for the generation of diabodies, minibodies, and CH2 domain-deleted F(ab')2 MAbs for improved penetration, blood clearance, and/or lack of glomerular trapping for both direct therapeutic application and elicitation of cell mediated reactivity. In vivo models for CNS neoplasia therapy. Central to development of reagents is the consistent preclinical evaluation of stability, localizing ability, and tumoristatic or tumoricidal effect in models mimicking human CNS disease. We constantly refine our large repertoire (sc, ic, ith) of available models in athymic rats with new disease models (ependymoma) and new administration routes; e.g. it and ic with convection enhanced delivery methods, for preclinical assessment of specificity, efficacy, and lack of toxicity. Most unique to this program is the leptomeningeal meningitis model in athymic rats which allows not only establishment of CNS tumors with subarachnoid spread, but the ith administration of therapeutic reagents. Development of glioma-targeting reagents generated in separately funded grants. MAb reagents vs GPNMB, MRP3, SSTR2A, and glioma-associated gangliosides 3'-isoLM1 and 3',6'-isoLD1, generated under separate funding, will undergo preclinical evaluation under the auspices of this core.