DCTD Biopharmaceutical Development

DCTD生物制药开发

• 批准号: 8844958
• 负责人: DAVID HEIMBROOK
• 金额: $ 533.3万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2018-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8844958
• 关键词: Adenovirus Vector; Adjuvant; Advisory Committees; Amyloid; Amyloidosis; Antibodies; Antigens; Area; Biological; Biological Assay; Biological Products; Biological Response Modifiers; Budgets; CCR; Cancer Therapy Evaluation Program; Cancer Vaccines; Certification; Childhood; Chimeric Proteins; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Collaborations; Communities; Country; Cyclic GMP; DNA Vaccines; Data; Dendritic Cells; Deposition; Development; Developmental Therapeutics Program; Disease; Documentation; Drug Discovery Groups; Drug Formulations; Educational workshop; Endotoxins; Escherichia coli; Evaluation; Extramural Activities; Facility Designs; Faculty; Familiarity; Fermentation; Funding; Gene-Modified; Glioma; Government; Government Agencies; Government Programs; Head and Neck Cancer; Herpesviridae; Human Resources; IL2 gene; Image; Immune; Immunologic Adjuvants; Immunotherapy; Immunotoxins; In Vitro; Institutes; Institution; Insulin-Dependent Diabetes Mellitus; Intellectual Property; Interleukin-12; Interleukin-15; Interleukin-2; International; Intravenous; Investigation; Licensing; Liquid substance; Lymphoma; Malaria Vaccines; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammalian Cell; Manufacturer Name; Measles; Metastatic Neoplasm to the Liver; Mission; Monoclonal Antibodies; Multiple Myeloma; Mus; National Cancer Institute; National Institute of Allergy and Infectious Disease; Neuroblastoma; New Agents; Non-Hodgkin' s Lymphoma; Oligonucleotides; Oncolytic viruses; Pathway interactions; Patients; Peptide Vaccines; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Plasmids; Plastics; Primary carcinoma of the liver cells; Process; Production; Program Development; Program Evaluation; Proteins; Protocols documentation; Qualifying; Recombinant Proteins; Recombinants; Recommendation; Regulation; Research; Research Contracts; Research Personnel; Research Project Grants; Residual Neoplasm; Resources; STAT3 gene; Safety; Schedule; Shipping; Ships; Source; System; Technology; Technology Transfer; Testing; Therapeutic; Time; Training; Translating; Tropism; Vaccines; Vial device; Viral; Virus; Work; aluminum sulfate; amyloid imaging; antiangiogenesis therapy; base; cancer diagnosis; cancer immunotherapy; cancer therapy; chaperonin; chemokine; chimeric antibody; clinical lot; cost; cytokine; experience; flexibility; gene therapy; humanized monoclonal antibodies; improved; innovation; interest; large scale production; lot production; manufacturing facility; manufacturing process; meetings; melanoma; member; novel vaccines; oncology; programs; response; scale up; technology development; working group

The Biopharmaceutical Development Program (BDP) supports development, manufacturing, and testing of new concepts in cancer therapeutics based on biological agents and biological response modifiers. Located at the NCI-Frederick campus, the BDP uses leading-edge technologies for development of monoclonal antibodies, cytokines, immunotoxins and other recombinant proteins, peptide and DNA vaccines, virus vaccines and targeted cytolytic viruses, gene therapy products, and other biological agents. The BDP maintains Current Good Manufacturing Practices (CGMP)-compliant facilities that provide complete support from evaluation of manufacturing feasibility through process development and clinical manufacturing with all required regulatory documentation for proof of concept clinical studies. BDP is a major component of the research grant and contract program of the Biological Resources Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, of the National Cancer Institute (BRB, DTP, DCTD, NCI). During the 2008 Fiscal Year, the BDP released 22 manufacturing lots to support clinical trials or toxicological studies, and performed QC stability studies to support more than 40 other lots still in use. With a staff of 100 highly trained and experienced personnel, the BDP has undertaken over 100 projects since its inception, and over 60 of these have gone into clinical trials. BDP facilities are designed to be highly flexible, enabling work on multiple projects for a variety of different therapies. An innovative, dynamic program, the BDP mission is to concentrate on products that are in early development, beginning with demonstrating product feasibility, through to production of Phase I/II clinical supplies and complete testing. In support of an NCI Immunotherapy Workshop initiative, BDP established a new cGMP manufacturing process for Interleukin-15. IL-15 from BDP is now in toxicological studies for the first clinical trial that is expected to start in FY09. In FY08, BDP also supported QC re-certification of Interleukin-12 that had been donated by the original manufacturer. IL-12 will be made available through a CTEP mechanism to qualified investigators for a number of new cancer immunotherapy and vaccine trials. Ad-CCL-21, another Immunotherapy agent manufactured by BDP, was shipped to two institutions for vaccine trials using chemokine gene-modified dendritic cells in advanced non-small lung cancer and malignant melanoma. In FY08, BDP released a clinical lot of Ad5-SSTR/TK.RGD a tropism modified adenovirus vector for an initial clinical trial in patients with ovarian cancer. Manufacturing and testing were completed for rRp450, a recombinant herpes virus, and an IND will be filed for treatment of patients with liver metastases. Ad-Delta-24-RGD is now in a clinical trial in patients with ovarian cancer and another trial in glioma. A second trial in glioma is in the process of regulatory filing. A BDP product that was released before FY08 is MR1-1, an immunotoxin that targets glioma. The first two patients were treated with MR1-1 during FY08. AdAFP and two plasmids targeting alpha-feto protein (AFP) entered a phase I clinical trial in hepatocellular carcinoma, and a second trial is pending at another institution. Ad5/3delta-24 was released and toxicological studies are underway for a Phase I clinical trial in ovarian cancer. During FY08, STAT3 decoy, an oligonucleotide targeting the STAT3 pathway of head and neck cancer entered a Phase¿zero clinical trial. A previously released measles-based oncolytic virus, MV-NIS, that is already in a Phase I trial for multiple myeloma, entered a new Phase I clinical trial in ovarian cancer. The 11-1F4 project is an earlier RAID project for development of a chimeric antibody targeting amyloid deposits. In FY08, interesting imaging of amyloid deposits was achieved in initial patients entered on an imaging study using murine-11-1F4. The continued results in this study are being followed for leads in this challenging disease. Other BDP activities in FY08 supported development of many other new agents for clinical trials in patients with prostate cancer, ovarian cancer, glioma, cervical cancer, and lymphoma, among other cancer indications. Under the Economy in Government Act, BDP also performed reimbursed manufacturing activities for other institutes in support of clinical trials in Type I Diabetes and Malaria Vaccines. In these projects, BDP developed new expertise that will be directly applicable to projects coming into the BDP cancer ¿pipeline.¿ BDP saw some of its earlier products reaching FY08 clinical milestones beyond early Phase I/II studies. During FY08, BDP released several lots of HA-22, an immunotoxin in clinical trials in non-Hodgkins lymphoma. A commercial company has licensed this agent and will perform further manufacturing at their facilities. Hu14.18-IL2, a cytokine¿antibody fusion protein that targets the GD-2 antigen on malignant melanoma and pediatric neuroblastoma is a ¿legacy¿ BDP project for which multiple clinical lots have been manufactured. During FY08, Hu14.18-IL-2 entered combination clinical trials with an anti-angiogenesis agent, in melanoma patients with minimal residual disease. BDP is supporting technology transfer for further development at the commercial company holding the intellectual property. Another ¿legacy¿ BDP project is a patient-specific Id vaccine for lymphoma that was licensed and taken over by a commercial company after BDP made over 100 patient-specific products for several early studies. In FY08, this vaccine completed a Phase III clinical trial in non-Hodgkin's lymphoma, and the company announced plans to discuss results with FDA. FDA requires testing to demonstrate product stability during the planned administration of many BDP agents, because biologicals can be susceptible to degradation over time in interactions with various fluids, even plastic intravenous tubing. In FY08, BDP performed an increasing number of point-of-use studies for a variety of products, including monoclonal antibodies and viruses. These studies require a number of tests to validate the accuracy of these critical assessments of product quality during administration. In addition, BDP QC staff are collaborating directly with FDA investigators to improve in vitro adventitious virus assays for oncolytic viruses, a challenging safety issue in this field. In FY 08, BDP made its established systems and experienced personnel available to provide assistance to other academic and government programs. BDP hosted visitors from outside U.S. institutions, other government agencies, and foreign countries, providing training on establishing other programs similar to the BDP. In tours and training sessions of BDP manufacturing facilities, outside investigators were presented an overview of how BDP Quality Systems translate Good Manufacturing Practice (GMP) regulations into practice for a Phase I/II product. The BDP scientific staff members continued to be active within the extramural community, serving on academic faculties and advisory committees, and presenting scientific findings at national and international meetings.

生物制药开发计划 (BDP) 支持基于生物制剂和生物反应调节剂的癌症治疗新概念的开发、制造和测试。 BDP 位于 NCI-弗雷德里克校区，采用尖端技术开发单克隆抗体、细胞因子、免疫毒素和其他重组蛋白、肽和 DNA 疫苗、病毒疫苗和靶向溶细胞病毒、基因治疗产品和其他生物制剂。 BDP 拥有符合现行良好生产规范 (CGMP) 的设施，提供从生产可行性评估到工艺开发和临床生产的完整支持，并提供概念验证临床研究所需的所有监管文件。 BDP 是国家癌症研究所（BRB、DTP、DCTD、NCI）癌症治疗和诊断部门生物资源分部、发展治疗计划、癌症治疗和诊断部门的研究资助和合同计划的主要组成部分。 2008 财年，BDP 发布了 22 个生产批次以支持临床试验或毒理学研究，并进行了 QC 稳定性研究以支持仍在使用的 40 多个其他批次。 BDP 拥有 100 名训练有素且经验丰富的人员，自成立以来已承担了 100 多个项目，其中 60 多个项目已进入临床试验。 BDP 设施的设计高度灵活，可以针对各种不同的疗法开展多个项目。 BDP 是一项创新、充满活力的计划，其使命是专注于早期开发的产品，从展示产品可行性开始，一直到 I/II 期临床用品的生产和完整测试。 为了支持 NCI 免疫治疗研讨会倡议，BDP 为 Interleukin-15 建立了新的 cGMP 生产工艺。 BDP 的 IL-15 目前正在进行首次临床试验的毒理学研究，预计将于 2009 财年开始。 2008 财年，BDP 还支持对原制造商捐赠的 Interleukin-12 进行 QC 重新认证。 IL-12 将通过 CTEP 机制提供给合格的研究人员，用于许多新的癌症免疫疗法和疫苗试验。 Ad-CCL-21是BDP生产的另一种免疫治疗剂，被运往两家机构，使用趋化因子基因修饰的树突状细胞进行晚期非小细胞肺癌和恶性黑色素瘤的疫苗试验。 2008 财年，BDP 发布了 Ad5-SSTR/TK.RGD 临床批次，这是一种向性修饰的腺病毒载体，用于卵巢癌患者的初步临床试验。重组疱疹病毒rRp450的制造和测试已完成，并将提交用于治疗肝转移患者的IND。 Ad-Delta-24-RGD 目前正在进行一项针对卵巢癌患者的临床试验和另一项针对神经胶质瘤的临床试验。神经胶质瘤的第二项试验正在进行监管备案。 2008 财年之前发布的 BDP 产品是 MR1-1，一种针对神经胶质瘤的免疫毒素。前两名患者在 2008 财年接受了 MR1-1 治疗。 AdAFP 和两个靶向甲胎蛋白 (AFP) 的质粒已进入肝细胞癌的 I 期临床试验，另一家机构正在进行第二项试验。 Ad5/3delta-24 已发布，卵巢癌 I 期临床试验的毒理学研究正在进行中。 2008 财年，STAT3 decoy（一种针对头颈癌 STAT3 通路的寡核苷酸）进入零期临床试验。之前发布的一种基于麻疹的溶瘤病毒 MV-NIS 已处于多发性骨髓瘤的 I 期试验中，现已进入卵巢癌的新 I 期临床试验。 11-1F4项目是一个早期的RAID项目，用于开发针对淀粉样沉积物的嵌合抗体。 2008 财年，使用 murine-11-1F4 进行成像研究的首批患者中获得了有趣的淀粉样蛋白沉积物成像。正在跟踪这项研究的持续结果，以寻找这种具有挑战性的疾病的线索。 2008 财年 BDP 的其他活动支持了许多其他新药的开发，用于前列腺癌、卵巢癌、神经胶质瘤、宫颈癌和淋巴瘤以及其他癌症适应症患者的临床试验。根据《政府经济法》，BDP 还为其他机构开展有偿制造活动，以支持 I 型糖尿病和疟疾疫苗的临床试验。在这些项目中，BDP 开发了新的专业知识，将直接适用于进入 BDP 癌症“管道”的项目。 BDP 的一些早期产品超越了早期 I/II 期研究，达到了 2008 财年的临床里程碑。 2008 财年期间，BDP 发布了多批 HA-22，这是一种正在进行非霍奇金淋巴瘤临床试验的免疫毒素。一家商业公司已获得该代理的许可，并将在其工厂进行进一步的生产。 Hu14.18-IL2 是一种细胞因子抗体融合蛋白，针对恶性黑色素瘤和小儿神经母细胞瘤的 GD-2 抗原，是一个“传统”BDP 项目，已生产多个临床批次。 2008 财年期间，Hu14.18-IL-2 进入了与抗血管生成药物联合治疗具有微小残留病灶的黑色素瘤患者的临床试验。 BDP 正在支持技术转让，以促进拥有知识产权的商业公司的进一步发展。 BDP 的另一个“遗产”项目是针对淋巴瘤的患者特异性 ID 疫苗，在 BDP 为多项早期研究生产了 100 多种患者特异性产品后，该项目获得了许可并由一家商业公司接管。 2008 财年，该疫苗完成了非霍奇金淋巴瘤的 III 期临床试验，该公司宣布计划与 FDA 讨论结果。 FDA 要求进行测试以证明在许多 BDP 药物的计划给药期间产品的稳定性，因为随着时间的推移，生物制品在与各种液体（甚至塑料静脉输液管）相互作用时可能容易降解。 2008 财年，BDP 对各种产品（包括单克隆抗体和病毒）进行了越来越多的使用点研究。这些研究需要进行大量测试来验证给药期间产品质量关键评估的准确性。此外，BDP QC 工作人员正在与 FDA 研究人员直接合作，改进溶瘤病毒的体外外来病毒测定，这是该领域具有挑战性的安全问题。 2008 财年，BDP 利用其既定系统和经验丰富的人员为其他学术和政府项目提供援助。 BDP 接待了来自美国以外机构、其他政府机构和外国的访客，并提供有关建立与 BDP 类似的其他项目的培训。在 BDP 生产设施的参观和培训课程中，外部调查人员大致了解了 BDP 质量体系如何将良好生产规范 (GMP) 法规转化为 I/II 阶段产品的实践。 BDP 的科学工作人员继续活跃在校外社区，在学术院系和咨询委员会任职，并在国内和国际会议上展示科学发现。