Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

描述(申请人提供)：胶质母细胞瘤(GBM)仍然是致命的。它也是最常见的原发恶性脑瘤，是导致儿童和年轻人癌症死亡的最常见原因。与目前受到靶外毒性限制的治疗方法不同，免疫疗法承诺了一种精确的方法，大量证据表明，如果适当地重新定向，T细胞可以很好地根除大的 已确诊的肿瘤。我们已经开发出一种新型的双特异性T细胞结合蛋白(BITE)，它能有效地将CD3T细胞捆绑在表达肿瘤特异性表皮生长因子受体突变EGFRvIII的肿瘤细胞表面。我们的第一个EGFRvIII-CD3片段在没有自身免疫毒性证据的情况下，在由人类T细胞重建的异种移植模型中根除了良好建立的EGFRvIIIPOS人GBM。基于这些数据，我们开发了一种利用全人抗体片段开发的EGFRvIII-CD3片段，通过大幅降低免疫原性的可能性提高了临床安全性。由于所有可用的针对人类CD3的抗体不会与包括灵长类动物在内的任何其他物种发生交叉反应，我们重新获得了一种独特的、药理上有反应的、具有免疫活性的人CD3转基因小鼠模型，该模型将允许直接评估用于临床试验的人源化咬合，大大提高了临床前疗效和毒性研究的有效性和可译性。我们的总体目标是将BITE治疗平台转化为对表达EGFRvIII的GBM患者进行安全、有效的免疫治疗。在这项提案中，我们寻求进行研究新药(IND)所需的实验，正如食品和药物管理局(FDA)在我们的正式IND前会议上向我们概述的那样。与这两个靶点结合的铅人类构建体的体外细胞毒性和体内有效性将在目标1中得到验证。目标2将完成当前良好制造规范(CGMP)生产铅人类构建体的必要优化方案，并将产生足够数量的IND使能研究。目标3将记录cGMP药物产品的活性和药代动力学，提供对确定第一人剂量至关重要的信息。正式的毒理学和稳定性测试将在目标4中完成，允许评估任何潜在的非目标活动，并分别指导临床试验的制造时间表。数据总和 根据FDA在IND前会议上的要求，在本建议书中生成的IND将用于汇编必要的文件，并在AIM 5向FDA提交IND申请。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) remains uniformly lethal. It is also the most common of the primary malignant brain tumors, which are the most frequent cause of cancer death in children and young adults. In contrast to current therapy which is limited by off-target toxicity, immunotherapy promises an exquisitely precise approach, and substantial evidence indicates that, if appropriately redirected, T cells can eradicate large, well established tumors. We have developed a novel bispecific T cell engager (BiTE) that effectively tethers CD3+ T cells to the surface of tumor cells that express the tumor-specific epidermal growth factor receptor mutation, EGFRvIII. Our first EGFRvIII-CD3 BiTE eradicated well-established EGFRvIIIPOS human GBM in a xenograft model reconstituted with human T cells without evidence of autoimmune toxicity. Based on these data, we developed a developed a EGFRvIII-CD3 BiTE from fully-human antibody segments, increasing clinical safety by drastically reducing the potential for immunogenicity. Because all available antibodies specific for human CD3 do not cross-react with any other species including primates, we have rederived a unique, pharmacologically responsive, immunocompetent, human CD3 transgenic murine model that will allow for direct assessment of the humanized BiTE destine for clinical trial, drastically increasing the validity and translatability of pre-clinical efficacy and toxicity studis. Our overall goal is to translate the BiTE therapeutic platform for safe, effective immunotherapy in patients with EGFRvIII-expressing GBM. In this proposal, we seek to perform Investigational New Drug (IND) required experiments, as the Food and Drug Administration (FDA) has outlined to us in our formal Pre-IND meeting. The in vitro cytoxicity and in vivo efficacy of the lead human construct, shown to bind to both targets, will be validated in Aim 1. Aim 2 will complete the necessary optimization of protocols for current good manufacturing practice (cGMP) production of the lead human construct and will yield a sufficient quantity for IND-enabling studies. Aim 3 will document the activity and pharmacokinetics of the cGMP drug product, producing information critical in determining the first-in-man dose. Formal toxicology and stability testing will be completed in Aim 4, allowing for assessment of any potential off-target activity and guiding manufacturing timelines for clinical trial respectively. The sum total of data generated in this proposal, as requested by the FDA during our Pre-IND meeting, will be used to assemble the necessary documents and file an IND application with the FDA in Aim 5.