Modified MIS Production & Process Development for Preclinical & Clinical Studies

DESCRIPTION provided by applicant Ovarian cancer is a highly lethal gynecologic cancer with an estimated new cases and approximately 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 M llerian 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 to 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 R 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 R 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 FDAandapos s pharmaceutical quality system guidance to enable such novel biotherapeutics as rhMIS for clinical investigation PUBLIC HEALTH RELEVANCE Ovarian cancer is a highly lethal gynecologic cancer After initial diagnosis and treatment most patientsandapos tumors disappear but a large majority of these cancers reemerge and manifest resistance to most therapeutic agents Clearly treatment of ovarian cancer represents a formidable clinical challenge and could benefit from the development of new therapies The objective of this proposal is to define a new way to scale production of recombinant human M llerian Inhibiting Substance rhMIS since our recent work has demonstrated that rhMIS specifically targets ovarian cancer cell populations that respond poorly to the currently used chemotherapeutic agents