?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-6, leads to iron-limited erythropoiesis and anemia (Gardenghi, 2014). Iron homeostasis (reviewed by Ganz, 2012) 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. 1). 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 IgG4 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 2 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 Statement: 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.
Project Terms: absorption; Address; Anemia; Anemia due to Chronic Disorder; Animal Model; Animals; Binding; Carrier Proteins; Cell membrane; Cells; Chimeric Proteins; Chronic; Data; Dietary Iron; Disease; Down-Regulation; Drug Kinetics; Enterocytes; Epithelial Cells; Erythrocytes; Erythroid; Erythropoiesis; extracellular; Extracellular Fluid; Fc domain; Half-Life; Hemochromatosis; Hepatocyte; hepcidin; Homeostasis; Hour; Human; IgG4; In Vitro; in vivo; Inflammatory; Interleukin-6; Intestines; Iron; iron deficiency; iron metabolism; Iron Overload; Lead; macrophage; Measures; Mediating; metal transporting protein 1; Mus; neoplastic; Pathway interactions; Patients; peptide hormone; Peptides; Phase; Plasma; pre-clinical; prevent; public health relevance; receptor; Recombinants; Recovery; Recycling; research study; response; senescence; Serum iron level result; Stimulus; Thalassemia; Therapeutic; Time; Toxic effect; Treatment Protocols; Work
