Modified MIS Production & Process Development for Preclinical & Clinical Studies

改进的MIS生产

• 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
• 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

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（由申请人提供）：卵巢癌是一种高度致命的妇科癌症，在美国每年估计有 21,860 例新发病例和约 13,850 例死亡。在大多数患者中，癌症在初次治疗后复发，并对传统和新型化疗药物表现出耐药性，从而构成了巨大的临床挑战，而这一挑战可以通过新型靶向疗法的产生来缓解。最近，马萨诸塞州总医院 (MGH) 的多纳霍实验室表明，重组人苗勒氏管抑制物质 (rhMIS) 专门针对对目前使用的化疗药物反应不佳的卵巢癌细胞群，表明 MIS 可作为一种创新的靶向药物来治疗复发性多重耐药性卵巢癌。当 MIS 作为单一药物在小鼠体内进行测试时，发现它可以在持续 80 至 100 天的实验中抑制肿瘤生长。此外，由于 MIS 受体的表达仅限于内源性组织； rhMIS 的全身毒性预计较低。阻碍 rhMIS 治疗卵巢癌进展的一个重要的未满足需求是以合理的经济规模开发蛋白质的规模生产。该 R43 提案描述了并行分子生物学加工方法，以扩大新构建体的生产规模，该构建体提供增强的裂解、纯度和效力，可用作临床前试验研究的标准制剂，并随后用于针对人类卵巢癌的 I 期临床试验，后者将是另一项拨款的主题，本提案产生的 MIS 将为最终使用的材料奠定基础。来自 Nemucore Medical Innovations (NMI)、Blue Sky BioServices 和 MGH 的团队提出，作为 R43 应用的主题，开发和表征在一次性生物制造设备中生产 rhMIS 所需的方法和流程。 NMI 正在建立符合 FDA 药品质量体系指南的模块化生物制造设施，以使 rhMIS 等新型生物治疗药物能够用于临床研究。