Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

描述（由申请方提供）：胶质母细胞瘤（GBM）仍然具有一致的致死性。它也是最常见的原发性恶性脑肿瘤，是儿童和年轻人癌症死亡的最常见原因。与受脱靶毒性限制的当前疗法相比，免疫疗法有望提供一种非常精确的方法，并且大量证据表明，如果适当地重新定向，T细胞可以根除大的、良好的免疫缺陷。 建立肿瘤。 我们已经开发了一种新的双特异性T细胞粘附剂（BiTE），其有效地将CD3 + T细胞束缚到表达肿瘤特异性表皮生长因子受体突变EGFRvIII的肿瘤细胞的表面。我们的第一个EGFRvIII-CD3 BiTE在用人T细胞重建的异种移植模型中根除了良好建立的EGFRvIIIPOS人GBM，而没有自身免疫毒性的证据。基于这些数据，我们从全人抗体片段开发了一种EGFRvIII-CD3 BiTE，通过大幅降低免疫原性的可能性来提高临床安全性。由于所有可用的人CD3特异性抗体不与任何其他物种（包括灵长类动物）发生交叉反应，我们重新推导了一种独特的、免疫应答的、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BiTE，大大提高了临床前疗效和毒性研究的有效性和可翻译性。 我们的总体目标是将BiTE治疗平台转化为表达EGFRvIII的GBM患者的安全，有效的免疫治疗。在本提案中，我们寻求进行研究性新药（IND）要求的实验，正如食品药品监督管理局（FDA）在我们的正式IND前会议上向我们概述的那样。将在目标1中验证与两种靶标结合的人体先导构建体的体外细胞毒性和体内疗效。目标2将完成对主要人体构建体的现行药品生产质量管理规范（cGMP）生产方案的必要优化，并将产生足够的数量用于IND使能研究。目标3将记录cGMP制剂的活性和药代动力学，产生确定首次人体剂量的关键信息。将在目标4中完成正式的毒理学和稳定性试验，以便分别评估任何潜在的脱靶活性和指导临床试验的生产时间表。数据的总和 根据FDA在IND前会议期间的要求，本提案中生成的信息将用于收集必要的文件，并在目标5中向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.