Modified MIS Production & Process Development for Preclinical & Clinical Studies

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21860例新病例和大约13850例死亡。在绝大多数患者中，癌症在初始治疗后复发，并对传统和新型化疗药物表现出耐药性，因此代表了一个巨大的临床挑战，可以通过生产新的靶向治疗来缓解。最近，麻省总医院（MGH）的Donahoe实验室发现，重组人<s:1>勒氏杆菌抑制物质（rhMIS）特异性靶向对目前使用的化疗药物反应不佳的卵巢癌细胞群，这表明MIS可以作为一种创新的靶向药物来治疗复发性多药耐药卵巢癌。在体内，当MIS作为单一药物在小鼠身上进行测试时，在持续80至100天的实验中发现它可以抑制肿瘤的生长。此外，由于MIS受体在内源性组织中的表达有限；预计rhMIS的全身毒性较低。阻碍卵巢癌rhMIS治疗进展的一个重要未满足的需求是合理经济地大规模生产蛋白质的发展。该R43提案描述了平行的分子生物学处理方法，以大规模生产一种新结构，该结构提供了增强的裂解，纯度和效力，可作为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，由本提案产生的MIS将为最终使用的材料奠定基础。Nemucore Medical Innovations （NMI）、蓝天生物服务公司（Blue Sky BioServices）和MGH的团队提议，作为R43申请的主题，开发和表征在一次性生物制造设备中生产rhMIS所需的方法和工艺。NMI正在建立一个符合FDA药品质量体系指南的模块化生物生产设施，以使诸如rhMIS之类的新型生物治疗药物能够用于临床研究。

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.