DCTD Biopharmaceutical Development

DCTD生物制药开发

• 批准号: 9004429
• 负责人: DAVID HEIMBROOK
• 金额: $ 637.35万
• 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/9004429
• 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; phase I trial; programs; response; scale up; technology development; vaccine trial; 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）支持基于生物学剂和生物反应修饰剂的癌症治疗中新概念的开发，制造和测试。 BDP位于NCI-Frederick校园，使用领先的技术来开发单克隆抗体，细胞因子，免疫毒素和其他重组蛋白，胡椒和DNA疫苗，病毒疫苗，靶向细胞溶剂疫苗，基因治疗产物，基因治疗产物以及其他生物学型。 BDP维护当前的良好制造实践（CGMP） - 计划的设施，这些设施通过流程开发和临床制造评估生产可行性提供了完整的支持，并提供了所有必需的监管文件，以证明概念临床研究证明。 BDP是国家癌症研究所（BRB，DTP，DCTD，NCI）的生物资源分支，发育治疗和诊断部发育治疗计划的研究赠款和合同计划的主要组成部分。 在2008财政年度，BDP发布了22批制造批次，以支持临床试验或毒理学研究，并进行了质量控制稳定性研究，以支持仍在使用的其他40多种批次。自成立以来，BDP拥有100名训练有素且经验丰富的人员，其中有100多个项目，其中60多个已经进行了临床试验。 BDP设施的设计非常灵活，为多种不同疗法的多个项目提供了工作。 BDP的创新，动态的计划是将重点放在早期开发中的产品上，从证明产品可行性到生产I/II期临床供应和完整的测试。 为了支持NCI免疫疗法研讨会计划，BDP建立了用于白介素15的新CGMP制造过程。 BDP的IL-15现在正在进行第一次临床试验的毒理学研究，预计将于2009财年开始。在08财年，BDP还支持原始制造商捐赠的白介素12的QC重新认证。 IL-12将通过CTEP机制提供给合格的研究人员，以进行许多新的癌症免疫疗法和疫苗试验。 AD-CCL-21是由BDP生产的另一种免疫疗法，使用趋化因子基因改性的树突状细胞在晚期非小肺癌和恶性黑色素瘤中使用趋化因子基因改性的树突状细胞运送到两个机构进行疫苗试验。在08财年，BDP发布了AD5-STR/TK.RGD的临床很多临床，对卵巢癌患者的初步临床试验，对腺病毒载体进行了修改。 RRP450（一种重组疱疹病毒）完成了制造和测试，并将为IDS申请以治疗肝转移患者。 AD-DELTA-24-RGD现在正在接受卵巢癌患者的临床试验和神经胶质瘤的另一项试验。神经胶质瘤的第二次试验是在调节申请的过程中。在08财年之前发行的BDP产品是MR1-1，这是一种靶向神经胶质瘤的免疫毒素。前两名患者在08财年接受了MR1-1治疗。 ADAFP和两个靶向α-FETO蛋白（AFP）的质粒进入了肝细胞癌的I期临床试验，第二次试验正在另一个机构待解决。释放AD5/3DELTA-24，毒理学研究正在进行I期卵巢癌临床试验。在08财年期间，针对头颈癌的STAT3途径的寡核苷酸STAT3诱饵进入了零期临床试验。先前释放的基于麻疹的溶瘤病毒MV-NIS已经在用于多发性骨髓瘤的I期试验中，进入了卵巢癌的一项新的I期临床试验。 11-1F4项目是较早的突袭项目，用于开发靶向淀粉样蛋白沉积物的嵌合抗体。在08财年，在使用Murine-11-1f4进行成像研究的初始患者中实现了淀粉样蛋白沉积的有趣成像。这项挑战疾病中的潜在客户正在遵循这项研究的持续结果。 08财年的其他BDP活动支持许多其他新药物用于前列腺癌，卵巢癌，神经胶质瘤，宫颈癌和淋巴瘤患者的临床试验的开发。根据《政府经济法》，BDP还为其他机构进行了偿还制造活动，以支持I型糖尿病和疟疾疫苗中的临床试验。在这些项目中，BDP开发了新的专业知识，该专业知识将直接适用于BDP癌症管道中的项目。 BDP看到了一些早期的产品达到了I/II早期研究以外的08财年临床里程碑。在08财年期间，BDP在非霍奇金斯淋巴瘤的临床试验中发布了多个HA-22，这是一种免疫毒素。一家商业公司已获得该代理商的许可，并将在其设施中进行进一步的制造。 HU14.18-IL2，一种针对恶性黑色素瘤和小儿神经母细胞瘤的GD-2抗原的细胞因子抗体融合蛋白是一个传统的BDP项目，为其制造了多个临床批次。在08财年期间，HU14.14-IL-2在具有最小残留疾病的黑色素瘤患者中与抗血管生成剂进行了临床试验。 BDP正在支持持有知识产权的商业公司进一步发展的技术转移。另一个传统的BDP项目是一种特定于患者的ID疫苗，用于淋巴瘤，该疫苗在BDP生产了100多种特定于患者的产品以进行多项早期研究后被一家商业公司许可并接管。在08财年，该疫苗在非霍奇金淋巴瘤中完成了III期临床试验，该公司宣布了与FDA讨论结果的计划。 FDA需要测试以在计划的许多BDP代理计划期间证明产品稳定性，因为在与各种烟道的相互作用中，甚至塑料静脉输液管，生物制剂可能会随着时间的推移而降解。在08财年，BDP对包括单克隆抗体和病毒在内的各种产品进行了越来越多的使用点研究。这些研究需要许多测试，以验证给药过程中产品质量的这些关键评估的准确性。此外，BDP QC工作人员正在直接与FDA研究人员合作，以改善对溶瘤病毒的体外高级病毒评估，这是该领域的挑战安全问题。 在08财年，BDP建立了其已建立的系统和经验丰富的人员，可以为其他学术和政府计划提供帮助。 BDP接待了来自美国机构，其他政府机构和国外的访客，提供了有关建立与BDP类似计划的其他计划的培训。在BDP制造设施的游览和培训课程中，概述了外部调查人员的概述，概述了BDP质量系统如何将良好的制造实践（GMP）法规转化为I/II期产品的实践。 BDP科学工作人员继续在校外社区中活跃，以学术能力和咨询承诺服务，并在国家和国际会议上提出科学发现。