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RAP‐011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice

Over expression of hepcidin antimicrobial peptide is a common feature of iron‐restricted anemia in humans. We investigated the erythroid response to either erythropoietin or RAP‐011, a “murinized” ortholog of sotatercept, in C57BL/6 mice and in hepcidin antimicrobial peptide 1 over expressing mice. Sotatercept, a soluble, activin receptor type IIA ligand trap, is currently being evaluated for the treatment of anemias associated with chronic renal disease, myelodysplastic syndrome, β‐thalassemia, and Diamond Blackfan anemia and acts by inhibiting signaling downstream of activin and other Transforming Growth Factor‐β superfamily members. We found that erythropoietin and RAP‐011 increased hemoglobin concentration in C57BL/6 mice and in hepcidin antimicrobial peptide 1 over expressing mice. While erythropoietin treatment depleted splenic iron stores in C57BL/6 mice, RAP‐011 treatment did not deplete splenic iron stores in mice of either genotype. Bone marrow erythroid progenitors from erythropoietin‐treated mice exhibited iron‐restricted erythropoiesis, as indicated by increased median fluorescence intensity of transferrin receptor immunostaining by flow cytometry. In contrast, RAP‐011‐treated mice did not exhibit the same degree of iron‐restricted erythropoiesis. In conclusion, we have demonstrated that RAP‐011 can improve hemoglobin concentration in hepcidin antimicrobial peptide 1 transgenic mice. Our data support the hypothesis that RAP‐011 has unique biologic effects which prevent or circumvent depletion of mouse splenic iron stores. RAP‐011 may, therefore, be an appropriate therapeutic for trials in human anemias characterized by increased expression of hepcidin antimicrobial peptide and iron‐restricted erythropoiesis. Am. J. Hematol. 90:8–14, 2015. © 2014 Wiley Periodicals, Inc.