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

这份第一阶段的SBIR合同将：(1)生产多批次的GB13，以确定生产工艺的质量和重复性；(2)表征GB13的生化特性，包括与靶细胞的亲和力；(3)确定具有多个产品批次的活细胞生物测定的资格；(4)为第二阶段SBIR的临床前开发活动制定计划，包括进行动物疗效和毒性研究，以支持IND申请用于人体临床试验。 高级别星形细胞瘤(HGA)是一种侵袭性的中枢神经系统肿瘤，使用 目前的护理标准。大约80%的HGA过度表达IL-13受体亚单位[GB-13ra(2)]，即 在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融合蛋白 开发用于治疗复发的HGA。其靶向部分，单个突变型人IL-13.E13K[Glu(13)-+Lys] 结合Gb-13ra{2比天然IL-13亲和力高50倍，与IL-13受体S亲和力低 健康的组织。它与一种突变的假单胞菌内毒素(PE4E)有关，该突变无法与其正常结合 靶细胞受体，只能杀死识别IL-13.E13K的细胞。GB13是培养物的有力杀手 体外培养动物GBM细胞。Targepeutics寻求资金(1)生产多批GB13以建立 制造方法的质量和重现性，(2)表征GB13的生化特性， 包括对目标细胞的亲和力，(3)用多个产品批次鉴定基于活细胞的生物测定，(4)开发 “SBIR”阶段临床前开发活动计划，包括动物疗效和毒性调查 支持申请IND进行人体临床试验。

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.