Modified MIS Production & Process Development for Preclinical & Clinical Studies

描述（由申请人提供）：卵巢癌是一种高致死性妇科癌症，在美国每年估计有21，860例新发病例和约13，850例死亡。在绝大多数患者中，癌症在初始治疗后复发，并表现出对常规和新型化疗剂的耐药性，从而代表了一个巨大的临床挑战，可以通过生产新型靶向治疗来缓解。最近，马萨诸塞州总医院（MGH）的Donahoe实验室显示，重组人苗勒管抑制物质（rhMIS）特异性靶向对目前使用的化疗药物反应较差的卵巢癌细胞群，表明MIS可用作一种创新的靶向药物，以解决复发性多药耐药卵巢癌。在体内，当MIS作为单一药剂在小鼠中测试时，发现在持续80至100天的实验中抑制肿瘤生长。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治疗进展的一个显著未满足的需求是以合理的经济性开发蛋白质的规模化生产。该R43提案描述了平行分子生物学处理方法，以规模化生产新构建体，该构建体提供增强的切割、纯度和效力，用作标准制剂以在临床前试验中进行研究，并随后用于针对人卵巢癌的I期临床试验，后者将是另一项赠款的主题，为此，根据本建议编制的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的团队提议将开发和表征在一次性生物制造设备中生产rhMIS所需的方法和工艺作为本R43申请的主题。NMI正在建立一个符合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。

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.