Research Project
9460755
DESCRIPTION (provided by applicant): Junin virus, the causative agent of Argentine hemorrhagic fever, is an arenavirus identified by the Centers for Disease Control and Prevention (CDC) as a Category A agent, or high-priority agent ... that pose(s) a risk to national security. There are currently no FDA approved drugs available for preventing or treating infections with Junin. There is a clear unmet need for a Junin immunoprotectant to address the threat of biowarfare as well as for public health protection during regular naturally occurring outbreaks. We have identified highly potent neutralizing monoclonal antibody (mAbs) that bind the Junin glycoprotein (GP). Clinical studies using polyclonal sera have demonstrated a clear relationship between neutralization and therapeutic efficacy, providing excellent proof-of-concept support for this effort. The goal of this proposed effort is the development of an immunoprotectant for Junin virus, manufactured in a rapid and cost-effective plant system (RAMP: Rapid Antibody Manufacturing Platform), for prevention and post-exposure treatment of infection. The Specific Aims of this proposed effort are: Specific Aim 1. Determine therapeutic window of lead product candidate. The guinea pig model will be used to identify the therapeutic window of the product candidate. Specific Aim 2. Elucidate structural and functional activities of the mAb and Junin virus. The epitope of MJ-01 will be mapped by X-ray crystallography and its potency quantified by neutralization assays (with and without complement), and antibody dependent cellular cytotoxicity (ADCC). An understanding of the mechanism of action is required for the future Investigational New Drug submission (Aim 4). Specific Aim 3. Humanize the Junin immunoprotectant and manufacture drug product using a versatile and inexpensive GMP platform. The lead product candidate will be humanized and then produced using the RAMP system. A stable formulation will be identified, and Good Manufacturing Practices (GMP) performed to supply the drug product for IND-enabling studies. Specific Aim 4. Complete Investigational New Drug (IND) enabling studies All IND-enabling pharmacology, toxicology, and Chemistry, Manufacturing and Controls (CMC) studies will be performed, with a final goal of filing an IND application to support a Phase 1 human safety trial.
