title: RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice.
abstract: 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.
authors.affiliation: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Langdon
authors.forename: Sangjucta
authors.initials: S
authors.lastname: Barkataki
authors.forename: Alan E
authors.initials: AE
authors.lastname: Berger
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Qian-Li
authors.initials: QL
authors.lastname: Xue
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
authors.forename: Cindy N
authors.initials: CN
authors.lastname: Roy
mesh_terms: D030301:Activin Receptors, Type II / Q000737:chemistry; D000818:Animals; D001692:Biological Transport; D001772:Blood Cell Count; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D006454:Hemoglobins / Q000032:analysis*; D064451:Hepcidins / Q000235:genetics*; D007074:Immunoglobulin G / Q000737:chemistry; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008024:Ligands; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013154:Spleen / Q000378:metabolism
chemical_list: D030301:Activin Receptors, Type II; D004921:Erythropoietin; D006454:Hemoglobins; D064451:Hepcidins; D007074:Immunoglobulin G; D007501:Iron; D008024:Ligands; D011993:Recombinant Fusion Proteins; C542017:sotatercept; C000595663:ActRIIA-mIgG2aFc fusion protein; C579599:Hamp protein, mouse; C425585:activin receptor type II-A