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: 9750830
• 负责人: JOHN H. SAMPSON
• 金额: $ 87.11万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750830
• 关键词: Acute; Affect; Animal Model; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Autoimmune Process; Binding; Brain; Brain Neoplasms; CD3 Antigens; Cancer Etiology; Cell Line; Cells; Certification; 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; Pharmacology; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Primary Brain Neoplasms; Primates; Process; Production; Protein Tyrosine Kinase; Protocols documentation; Public Health; Quality of life; Recurrence; Resistance; Safety; Serum; Specificity; Sum; Surface; Syndrome; System; T cell therapy; T-Lymphocyte; Testing; Therapeutic; TimeLine; Tissues; Toxic effect; Toxicity Tests; Toxicology; Transgenic Model; Transgenic Organisms; Translating; United States Food and Drug Administration; Vaccines; Viral; Xenograft Model; Xenograft procedure; base; bi-specific T cell engager; cell bank; cell growth; childhood cancer mortality; clinical translation; clinically translatable; cytokine; efficacy study; epidermal growth factor receptor VIII; experimental study; first-in-human; immunogenicity; improved; in vivo; meetings; model design; mouse model; murine antibody; neoplastic cell; novel; paracrine; phase I trial; preclinical efficacy; programs; public health relevance; reconstitution; 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）仍然是致命的。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。与目前受到脱靶毒性限制的疗法相比，免疫疗法有望提供一种极其精确的方法，并且大量证据表明，如果适当地重新定向，T 细胞可以根除大量的、良好的细胞。 已形成的肿瘤。 我们开发了一种新型双特异性 T 细胞接合器 (BiTE)，可有效地将 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 的肿瘤细胞表面。我们的第一个 EGFRvIII-CD3 BiTE 在用人类 T 细胞重建的异种移植模型中根除了成熟的 EGFRvIIIPOS 人类 GBM，没有自身免疫毒性的证据。基于这些数据，我们利用全人抗体片段开发了 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。由于所有可用的人类 CD3 特异性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，因此我们重新获得了一种独特的、具有药理反应性、免疫活性的人类 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 目的地，大大提高了临床前疗效和毒性研究的有效性和可转化性。 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。在本提案中，我们寻求进行研究性新药 (IND) 所需的实验，正如美国食品和药物管理局 (FDA) 在我们正式的 IND 前会议中向我们概述的那样。主要人类构建体的体外细胞毒性和体内功效（显示与两个靶标结合）将在目标 1 中得到验证。目标 2 将完成对主要人类当前良好生产规范 (cGMP) 生产的协议的必要优化。构建并将产生足够数量的 IND 支持研究。目标 3 将记录 cGMP 药品的活性和药代动力学，提供对于确定首次人体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，以便评估任何潜在的脱靶活性并分别指导临床试验的生产时间表。数据总和 根据 FDA 在我们的 IND 前会议期间提出的要求，该提案中生成的信息将用于收集必要的文件并向 FDA 提交目标 5 中的 IND 申请。