Hepcidin Antagonist Therapy for Anemia of Chronic Disease

DESCRIPTION provided by applicant The anemia of chronic disease ACD anemia of inflammation is commonly observed in chronic inflammatory states and may hinder patient recovery and survival Induction of hepcidin mediated by IL leads to iron limited erythropoiesis and anemia Gardenghi Iron homeostasis reviewed by Ganz depends on regulated absorption and transport of dietary iron by means of the iron transport protein ferroportin and its regulatory peptide hepcidin All iron releasing cells including enterocytes macrophages and hepatocytes contain ferroportin Ferroportin activity is controlled by hepcidin Upon binding hepcidin ferroportin is internalized and degraded Fig When hepcidin concentrations are high ferroportin degradation exceeds its rate of synthesis and ferroportin is lost from cell membranes Without ferroportin macrophages fail to release iron recycled from senescent erythrocytes and hepatocytes retain stored iron Ongoing erythropoiesis depletes extracellular iron within hours Conversely when hepcidin concentrations are low ferroportin synthesis exceeds its degradation ferroportin re accumulates in cell membranes and increased amounts of iron flow from iron exporting cells into the extracellular fluid In ACD excessive hepcidin prevents iron mobilization for erythropoiesis Recently an erythroid factor erythroferrone ERFE was discovered to down regulate hepcidin in response to erythropoietic stimuli The size and composition of ERFE will lead to a short plasma half life and will limit its chronic use Therefore in this Phase I project we will construct a fusion protein containing ERFE fused to the human IgG Fc domain Fc fusion proteins have extended plasma half lives due to recycling by the FcRN receptor We will verify that the Fc fusions are active by measuring hepcidin down regulation in vitro evaluate the ability of ERFE Fc to increase serum iron levels in mice In addition we will carry out preliminary pharmacokinetic experiments to determine plasma half life Phase will focus on obtaining the preclinical data necessary for submission of an IND We expect ERFE Fc to address the unmet need of a rational therapy for the anemia of chronic disease PUBLIC HEALTH RELEVANCE The anemia of chronic disease ACD anemia of inflammation is associated with infectious inflammatory or neoplastic disease While often mild ACD complicates recovery of the patient We have identified an approach to treat ACD by targeting an iron metabolism pathway This therapeutic will allow rapid recovery from anemia with a convenient treatment regimen