Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis

Nat Med. 2014 Apr;20(4):408-14. doi: 10.1038/nm.3512. Epub 2014 Mar 23.


Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a new potential treatment for anemia, including that caused by ineffective erythropoiesis.

MeSH terms

  • Activin Receptors, Type II*
  • Anemia / blood*
  • Animals
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Morphogenetic Proteins / drug effects*
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Erythrocyte Count
  • Erythroid Precursor Cells / drug effects*
  • Erythropoiesis / drug effects*
  • Erythropoietin / pharmacology
  • Growth Differentiation Factors / antagonists & inhibitors
  • Growth Differentiation Factors / drug effects*
  • Haplorhini
  • Hematinics / pharmacology*
  • Humans
  • Ligands
  • Mice
  • Myelodysplastic Syndromes / blood*
  • Rats
  • Recombinant Fusion Proteins / pharmacology*
  • Reticulocyte Count
  • Signal Transduction / drug effects
  • Smad2 Protein / drug effects
  • Smad3 Protein / drug effects


  • Bone Morphogenetic Proteins
  • GDF11 protein, human
  • Growth Differentiation Factors
  • Hematinics
  • Ligands
  • RAP-536
  • Recombinant Fusion Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Erythropoietin
  • Activin Receptors, Type II
  • activin receptor type II-B