Expression System and Process Development for MIS Scale Up

MIS 放大的表达系统和工艺开发

基本信息

批准号：
8781225
负责人：
Timothy P Coleman
金额：
$ 22.49万
依托单位：
NEMUCORE MEDICAL INNOVATIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8781225
关键词：
Address Amino Acids Binding Binding Sites Biological Biological Response Modifier Therapy Biomanufacturing Biomedical Engineering C-terminal Cancer Center Cancer Patient Cattle Cell Density Cessation of life Chemistry Chinese Hamster Ovary Cell Clinical Clinical Trials Complement Conditioned Culture Media Core Facility Data Development Diagnosis Disulfides Duct (organ) structure Economics Embryo Equipment Experimental Designs Family Female Fermentation General Hospitals Genes Genetic Glycoproteins Goals Half-Life Harvest Hormones Human Human Cloning Investigation Isomerase Knowledge Laboratories Ligands Link Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Massachusetts Medical Medicine Methods Molecular Biology Molecular Chaperones Multi-Drug Resistance N-terminal Nanotechnology National Cancer Institute Newly Diagnosed Patients Peptide Hydrolases Pharmacologic Substance Phenotype Plasmids Population Preparation Procedures Process Production Protein-Serine-Threonine Kinases Proteins Pseudomonas fluorescens Receptor Signaling Recombinants Recurrence Resistance Resources Ribosomes Serum Solutions Specificity System Technology Testing Therapeutic Therapeutic Agents Tissues Toxic effect Transforming Growth Factor beta Translating Universities Woman Work cancer cell chemotherapeutic agent combinatorial conventional therapy cost dimer disulfide bond exhaust in vivo innovation male member microbial monomer mutant novel overexpression promoter prospective protein folding public health relevance receptor reproductive research study scale up screening therapeutic protein tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is a highly lethal gynecologic cancer with an estimated 21,860 new cases and approximately 13,850 deaths in the USA per year. A large majority of the patients, cancer reoccurs after initial treatment and manifest resistance to conventional and novel chemotherapeutic agents representing a formidable clinical challenge, which could be mitigated by the production of novel, targeted therapies. Recently, Drs. Donahoe, MacLaughlin and Teixeira from Massachusetts General Hospital (MGH) showed that recombinant human M?llerian Inhibiting Substance (rhMIS) specifically targets ovarian cancer cell populations that respond poorly to the currently used chemotherapeutic agents and could be an innovative, targeted medicine to address recurrent multidrug resistant ovarian cancer. In vivo when MIS was tested as a single agent it was found to inhibit tumor growth in experiments lasting 80 to 100 days. Additionally since the MIS receptor is poorly expressed in endogenous tissue systemic toxicity of rhMIS is expected to be low. A significant unmet need hindering the progress of an rhMIS treatment for ovarian cancer is the development of scaled production of the protein with reasonable economics. This R43 proposal describes the parallel molecular biology processing methods to create >1000 strain and plasmid combination to successfully express rhMIS in Pseudomonas fluorescens and the investigative process development procedures required to scale production of rhMIS in P. fluorescens. The team from Nemucore Medical Innovations (NMI), Pfenex, and MGH propose as the subject of this R43 application to fully develop and characterize the methods and processes required to produce rhMIS using single use disposable biomanufacturing equipment. NMI is establishing a modular biomanufacturing facility compliant with the FDA's pharmaceutical quality system guidance to enable the production of novel biotherapeutics for clinical investigation, such as rhMIS.

描述（由申请人提供）：卵巢癌是一种高度致命的妇科癌症，每年美国估计有21,860例新病例，大约13,850例死亡。绝大多数患者，初次治疗后的癌症再次出现，并表现出对常规和新型化学治疗剂的抵抗力，代表了强大的临床挑战，可以通过产生新颖的靶向疗法来缓解这种临床挑战。最近，博士。来自马萨诸塞州综合医院（MGH）的Donahoe，Maclaughlin和Teixeira表明，重组的人类M？llerian抑制物质（RHMIS）专门针对卵巢癌细胞群体，这些细胞群体对当前使用的化学治疗剂反应较差，并且可能是一种创新的，可以作为一种创新的，可寻求的，可寻求的，可再生的多种耐药性卵巢卵巢癌。当MIS测试为单一药物时，发现在持续80至100天的实验中会抑制肿瘤的生长。此外，由于MIS受体在内源性组织全身毒性中的表达不佳，预计将很低。巨大的未满足需要阻碍了RHMI治疗对卵巢癌的进步的是，具有合理的经济学的蛋白质生产的发展。该R43提案描述了平行的分子生物学处理方法，以创建> 1000应变和质粒组合，以成功地表达荧光症中的rhmis以及在荧光p.荧光菌中缩放RHMI所需的研究过程开发程序。 Nemucore Medical Innovations（NMI），PFENEX和MGH的团队提议作为R43应用程序的主题充分开发和表征使用一次性的可装配生物制造设备生产RHMI所需的方法和过程。 NMI正在建立一个符合FDA的药物质量系统指导的模块化生物制造设施，以实现新型的生物治疗剂进行临床研究，例如RHMIS。