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: 9095464
• 负责人: JOHN H. SAMPSON
• 金额: $ 102.44万
• 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/9095464
• 关键词: Accounting; Acute; Affect; Animal Model; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Autoimmune Process; Binding; Brain; Brain Neoplasms; CD3 Antigens; Cell Line; Cell physiology; 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; Health; 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; childhood cancer mortality; clinical efficacy; cytokine; epidermal growth factor receptor VIII; immunogenicity; improved; in vivo; man; meetings; model design; mouse model; murine antibody; neoplastic cell; novel; paracrine; phase I trial; pre-clinical; programs; 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）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。与目前受脱靶毒性限制的治疗方法相比，免疫治疗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细胞可以很好地根除大的、严重的肿瘤