Anti-hepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia
Sasu BJ, Cooke KS, Arvedson TL, Plewa C, Ellison AR, Sheng J, Winters A, Juan T, Li H, Begley CG, Molineux G.
Iron maldistribution has been implicated in multiple diseases including the anemia of inflammation (AI), atherosclerosis, diabetes and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25 amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered and thus potentially contributes to AI. Human hepcidin (hHepc) over-expression in mice caused an iron deficient phenotype including runted growth, hair loss and iron-deficient erythropoiesis. It also caused resistance to supraphysiological levels of erythropoiesis stimulating agent (ESA), supporting the hypothesis that hepcidin may influence response to treatment in AI. To explore the role of hepcidin in inflammatory anemia, a mouse AI model was developed using heat-killed Brucella abortus treatment. Suppression of hepcidin mRNA was a successful anemia treatment in this model. High affinity antibodies specific for hHepc were generated and hHepc knock-in mice were produced to enable antibody testing. Antibody treatment neutralized hHepc in vitro and in vivo and facilitated anemia treatment in hHepc knock-in mice with AI. These data indicate that anti-hepcidin antibodies may be an effective treatment for patients with inflammatory anemia. The ability to manipulate iron metabolism in vivo may also allow investigation of the role of iron in a number of other pathological conditions.