Modified MIS Production & Process Development for Preclinical & Clinical Studies

改进的MIS生产

基本信息

批准号：
8833972
负责人：
Timothy P Coleman
金额：
$ 22.5万
依托单位：
NEMUCORE MEDICAL INNOVATIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8833972
关键词：
Address Amino Acids Binding Biological Biological Assay Biological Response Modifier Therapy Biomanufacturing Biomedical Engineering C-terminal CD44 gene Cancer Patient Cattle Cell Line Cell surface Cessation of life Characteristics Chemistry Chinese Hamster Ovary Cell Chromatography Cleaved cell Clinical Clinical Research Clinical Trials Cloning Vectors Complement Conditioned Culture Media Consensus DHFR gene Data Development Diagnosis Disulfides E-Cadherin Economics Embryo Equipment Family Female Foundations General Hospitals Genes Genomics Glycoproteins Grant Growth Half-Life Health Human Human Cloning In Vitro Investigation Laboratories Lead Ligands Link Liquid Chromatography Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Massachusetts Medical Medicine Methods Modification Molecular Biology Mullerian-inhibiting substance receptor Multi-Drug Resistance Mus N-terminal Patients Pharmacologic Substance Phase I Clinical Trials Population Preparation Procedures Process Production Protein-Serine-Threonine Kinases Proteins Rattus Receptor Signaling Recombinants Recurrence Research Resistance Serum Serum Albumin Site Solutions Source Specificity Standard Preparations Stem cells Structure of paramesonephric duct System Testing Therapeutic Therapeutic Agents Tissues Toxic effect Transforming Growth Factor beta Translations Urogenital ridge structure Woman Work base cancer cell chemotherapeutic agent clinical investigation conventional therapy design dimer fetal immunoaffinity chromatography in vivo innovation male member monomer mullerian-inhibiting hormone novel pre-clinical preclinical study protein folding receptor receptor expression reproductive research study scale up targeted treatment tumor tumor growth vector vertebrate embryos

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. In a large majority of the patients, cancer reoccurs after initial treatment and manifest resistance to conventional and novel chemotherapeutic agents, thereby representing a formidable clinical challenge which could be mitigated by the production of novel, targeted therapies. Recently, the Donahoe laboratory at the Massachusetts General Hospital (MGH) showed that recombinant human Müllerian Inhibiting Substance (rhMIS) specifically targets ovarian cancer cell populations that respond poorly to the currently used chemotherapeutic agents indicating that MIS could be used as an innovative, targeted medicine to address recurrent multidrug resistant ovarian cancer. In vivo when MIS was tested in mice as a single agent it was found to inhibit tumor growth in experiments lasting 80 to 100 days. Additionally since MIS receptor expression is limited 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 scale production of a new construct that provides for enhanced cleavage, purity, and potency for use as a standard preparation to study in preclinical trials and for subsequent use in phase I clinical trials against human ovarian cancer, the latter of which will be the subject of another grant for which the MIS produced by the present proposal will lay the foundation for the eventual material used. The team from Nemucore Medical Innovations (NMI), Blue Sky BioServices, and MGH propose as the subject of this R43 application to develop and characterize the methods and processes required to produce rhMIS in single use disposable biomanufacturing equipment. NMI is establishing a modular biomanufacturing facility compliant with the FDA's pharmaceutical quality system guidance to enable such novel biotherapeutics as rhMIS for clinical investigation.

描述（由适用提供）：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。在绝大多数患者中，初始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，从而代表了强大的临床挑战，可以通过产生新颖的靶向疗法来减轻这种挑战。最近，马萨诸塞州综合医院（MGH）的Donahoe实验室表明，重组的人类穆勒抑制物质（RHMIS）专门针对卵巢癌细胞种群，这些卵巢癌细胞种群对当前使用的化学治疗剂反应较差，表明MIS可以用作一种创新的，具有创新性的，可将其作为一种创新的，可再生的多发性多发性多发性多发性多发性卵巢癌。当在小鼠中测试MIS作为单一药物时，发现在持续80至100天的实验中抑制肿瘤生长。此外，由于内源性组织中的MIS受体表达受到限制。 RHMI的全身毒性预计将很低。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提案描述了平行分子生物学处理方法，用于扩展新结构的生产，从而增强了清洁，纯度和用作作为在临床前试验中进行研究的标准准备，并随后在I阶段临床试验中使用对人类卵巢癌的临床试验的使用，后者将是其他材料的材料的主题，该材料将构成现有的材料，该材料将误解为误解的基础。来自Nemucore医疗创新（NMI），蓝天生物服务和MGH提案的团队是该R43应用程序的主题，以开发和表征单一使用一次性的生物制造设备中产生RHMI所需的方法和过程。 NMI正在建立一个模块化生物制造设施，符合FDA的药物质量系统指导，以实现此类新型的生物治疗药，例如RHMIS进行临床研究。