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.
