TAS::75 0849::TAS TOPIC 255 DEVELOPMENT OF GB13 AS A NOVEL GLIOBLASTOMA THERAPY

TAS::75 0849::TAS 主题 255 GB13 作为新型胶质母细胞瘤疗法的发展

• 批准号: 8351880
• 负责人: STEPHEN ABRAMSON
• 金额: $ 19.98万
• 依托单位: TARGEPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8351880
• 关键词: Affinity; Animals; Astrocytoma; Binding; Biochemical; Biological Assay; Canis familiaris; Cell Culture Techniques; Cells; Central Nervous System Neoplasms; Chimeric Proteins; Circular Dichroism Spectroscopy; Clinical Trials; Contracts; Cultured Tumor Cells; Cyclic GMP; DNA; Data; Development; Endotoxins; Enzyme-Linked Immunosorbent Assay; Funding; Glioblastoma; Glioma; High Pressure Liquid Chromatography; Human; In Vitro; Interleukin-13; Investigation; Isoelectric Focusing; Label; Life; Link; Liquid Chromatography; Manufacturer Name; Measures; Methods; Peptide Mapping; Phase; Procedures; Process; Production; Property; Proteins; Pseudomonas; Qualifying; Receptor Cell; Recombinants; Records; Recurrence; Reproducibility; Residual state; Small Business Innovation Research Grant; Sodium Dodecyl Sulfate-PAGE; Testing; Tissues; Toxic effect; Western Blotting; Work; animal efficacy; base; culture plates; cytotoxic; experience; forest; glioma cell line; killings; manufacturing process; medical schools; mutant; novel; overexpression; pre-clinical; receptor; scale up; standard of care; tandem mass spectrometry; ultraviolet

This Phase I SBIR contract is to (1) produce multiple lots of GB13 to establish the quality and reproducibility of the manufacturing process, (2) characterize biochemical properties of GB13, including affinity to target cells, (3) qualify a live cell-based bioassay with multiple product lots, (4) develop a plan for Phase II SBIR preclinical development activities, including anmial efficacy and toxicity investigations to support the filing of an IND for human clinical trials. High-Grade astrocytomas (HGAs) are aggressive CNS tumor with median survival:::::: 14 months using the current standard of care. About 80% of HGAs overexpress an IL-13 receptor subunit [GB-13Ra(2)] that is virtually absent in healthy CNS tissue. GB 13 is a recombinant targeted cytotoxic fusion protein being developed to treat recurrent HGAs. Its targeting moiety, a single mutant human IL-13.E13K [Glu(13)-+Lys] binds GB-13Ra{2) with 50-fold higher affinity than native IL-13 and has low affinity for IL-13 receptor s of healthy tissue. It is linked to a mutant Pseudomonas endotoxin (PE4E), that is unable to bind its normal target cell receptor and can kill only cells that recognize IL 13.E13K. GB13 is a potent killer of cultured animal GBM cells in vitro. Targepeutics seeks funds to (1) produce multiple lots of GB13 to establish the quality and reproducibility of the manufacturing process, (2) characterize biochemical properties of GB13, including affinity to target cells, (3) qualify a live cell-based bioassay with multiple product lots, (4) develop a plan for Phase" SBIR preclinical development activities, including animal efficacy and toxicity investigations to support the filing of an IND for human clinical trials.

该 I 期 SBIR 合同旨在 (1) 生产多个批次的 GB13，以确定制造工艺的质量和可重复性，(2) 表征 GB13 的生化特性，包括对靶细胞的亲和力，(3) 验证多个产品批次的基于活细胞的生物测定，(4) 制定 II 期 SBIR 临床前开发活动计划，包括动物功效和毒性研究，以支持 IND 的提交 人体临床试验。 高级别星形细胞瘤 (HGA) 是一种侵袭性 CNS 肿瘤，中位生存期:::::: 14 个月 目前的护理标准。大约 80% 的 HGA 过表达 IL-13 受体亚基 [GB-13Ra(2)]，即 健康的中枢神经系统组织中几乎不存在。 GB 13是一种重组靶向细胞毒性融合蛋白 开发用于治疗复发性 HGA。其靶向部分是单突变型人 IL-13.E13K [Glu(13)-+Lys] 与 GB-13Ra{2) 的结合亲和力比天然 IL-13 高 50 倍，并且对 IL-13 受体的亲和力低 健康的组织。它与突变型假单胞菌内毒素 (PE4E) 有关，无法结合其正常的内毒素。 靶细胞受体，只能杀死识别 IL 13.E13K 的细胞。 GB13是文化的有力杀手 体外动物 GBM 细胞。 Targepeutics 寻求资金 (1) 生产多批 GB13，以建立 制造过程的质量和再现性，（2）表征GB13的生化特性， 包括对靶细胞的亲和力，(3) 对多个产品批次进行基于活细胞的生物测定进行鉴定，(4) 开发 计划“阶段”SBIR 临床前开发活动，包括动物功效和毒性研究 支持人体临床试验 IND 的备案。