Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

人 EGFRvIII 特异性 BiTE 用于治疗胶质母细胞瘤

• 批准号: 8803629
• 负责人: JOHN H. SAMPSON
• 金额: $ 56.98万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803629
• 关键词: Accounting; Acute; Affect; Animal Model; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Autoimmune Process; Binding; Brain; Brain Neoplasms; CD3 Antigens; Cancer Etiology; Cell Line; Cell physiology; Cells; Certification; Cessation of life; Child; Clinical; Clinical Trials; Common Neoplasm; Complex; Data; Dose; Dose-Limiting; Drug Kinetics; Drug Stability; Drug or chemical Tissue Distribution; Epidermal Growth Factor Receptor; Evaluation; Glioblastoma; Goals; Human; Human Anti-Mouse Antibody; Immunity; Immunocompetent; Immunoglobulin Fragments; Immunosuppressive Agents; Immunotherapy; In Vitro; Influenza; Investigational Drugs; Investigational New Drug Application; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Modeling; Mus; Mutation; Normal tissue morphology; Oncogenic; Patients; Pharmaceutical Preparations; Positioning Attribute; Pre-Clinical Model; Primary Brain Neoplasms; Primates; Production; Protein Tyrosine Kinase; Protocols documentation; Public Health; Quality of life; Recurrence; Resistance; Safety; Serum; Specificity; Sum; Surface; Syndrome; System; T-Lymphocyte; Testing; Therapeutic; TimeLine; Tissues; Toxic effect; Toxicity Tests; Toxicology; Transgenic Model; Transgenic Organisms; Translating; Translations; United States Food and Drug Administration; Vaccines; Viral; Xenograft Model; Xenograft procedure; base; cell bank; cell growth; clinical efficacy; cytokine; epidermal growth factor receptor VIII; immunogenicity; improved; in vivo; man; meetings; model design; neoplastic cell; novel; paracrine; phase I trial; pre-clinical; programs; public health relevance; reconstitution; research study; response; stability testing; tumor; tumor microenvironment; young adult

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.

描述（由申请人提供）：胶质母细胞瘤（GBM）保持统一致命。它也是原发性恶性脑肿瘤中最常见的，这是儿童和年轻人癌症死亡的最常见原因。与当前疗法受到脱靶毒性的限制相反，免疫疗法有望精确的方法，并且大量证据表明，如果适当地重定向，则T细胞可以消除大型，良好 已建立的肿瘤。 我们已经开发了一种新型的双特异性T细胞参与者（BITE），该TETH3+ T细胞有效地将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咬合消除了具有人类T细胞重构的异种移植模型中良好成熟的Egfrviiipos人GBM，而没有自身免疫性毒性的证据。基于这些数据，我们开发了一种从完全人类抗体段的EGFRVIII-CD3咬合，通过大大降低免疫原性的潜力来提高临床安全性。由于对人CD3的所有可用抗体都不会与包括灵长类动物在内的任何其他物种进行反应，因此我们重新修复了独特的，药理响应式，免疫能力的，人类CD3转基因的鼠模型，该模型将允许直接评估人性化的叮咬剂进行临床试验，从而极大地提高了预先限制和临床效率的效率和毒性的效率和毒性的效率。 我们的总体目标是将EGFRVIII-Expressing GBM患者的安全有效免疫疗法的咬合治疗平台转换。在该提案中，我们寻求进行研究新药（IND）需要实验，因为食品药品监督管理局（FDA）在正式的IND会议上概述了我们。在AIM 1中将验证铅人类构建体的体外细胞毒性和体内疗效。AIM 2将完成对当前良好制造实践（CGMP）生产的必要方案的优化，并产生足够数量的索引研究。 AIM 3将记录CGMP药物的活性和药代动力学，从而产生确定第一剂剂量的重要信息。正式的毒理学和稳定性测试将在AIM 4中完成，以评估任何潜在的非目标活动，并分别指导制造时间表进行临床试验。数据总和 根据FDA在我们的IND会议期间的要求，本提案中生成的将用于组装必要的文件，并在AIM 5中向FDA提交IND申请。