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

Nature Medicine volume 20, pages 408–414 (2014)Cite this article

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Abstract

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 erythropoiesis1,2, which is EPO independent2,3. 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.

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Figure 1: ACE-536, a modified ActRIIB fusion protein, increases RBC numbers, hemoglobin concentrations and hematocrit values by promoting maturation of late-stage erythroblasts.
Figure 2: ACE-536 promotes maturation of erythroblasts independently of EPO and acts synergistically with EPO to increase RBC production.
Figure 3: GDF11-ActRIIB-Smad2/3 signaling in late-stage erythroid differentiation.
Figure 4: ACE-536 inhibits Smad2/3 activation, mitigates ineffective erythropoiesis and ameliorates anemia in a NUP98-HOXD13 mouse model of MDS at multiple stages of disease severity.

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Acknowledgements

We thank J. Knopf for critical review and T. Ahern for editorial contributions. We acknowledge the Cell Biology, Protein Purification and Preclinical Pharmacology groups at Acceleron Pharma for their contributions in support of this work. We also thank G. Paradis and A. Parmelee for their assistance with flow cytometry. NUP98-HOXD13 MDS mice and age-matched FVB wild-type mice were obtained from P. Aplan's laboratory at the US National Institutes of Health. Inhbctm1Zuk and Inhbctm2Zuk mice were obtained from M. Matzuk, Baylor College of Medicine.

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  1. Samuel M Cadena and Sharon M Cawley: These authors contributed equally to this work.

Authors and Affiliations

  1. Acceleron Pharma, Cambridge, Massachusetts, USA

    Rajasekhar N V S Suragani, Samuel M Cadena, Sharon M Cawley, Dianne Sako, Dianne Mitchell, Robert Li, Monique V Davies, Mark J Alexander, Matthew Devine, Kenneth S Loveday, Kathryn W Underwood, Asya V Grinberg, John D Quisel, R Scott Pearsall, Jasbir Seehra & Ravindra Kumar

  2. Translational Development Department, Celgene, San Francisco, California, USA

    Rajesh Chopra

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Contributions

R.N.V.S.S., S.M. Cadena, S.M. Cawley, J.D.Q., R.C., R.S.P., J.S. and R.K. planned and designed the experiments. R.N.V.S.S., S.M. Cadena, S.M. Cawley, D.S. and R.L. conducted the experiments. R.N.V.S.S., S.M. Cadena, S.M. Cawley, D.S., D.M., R.L., M.V.D., M.D., K.S.L., K.W.U. and A.V.G. collected and interpreted data. R.N.V.S.S. and M.J.A. drafted and revised the manuscript.

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Correspondence to Ravindra Kumar.

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Competing interests

R.N.V.S.S., S.M. Cadena, S.M. Cawley, D.S., D.M., R.L., M.V.D., M.J.A., K.S.L., K.W.U., A.V.G., J.D.Q., R.S.P., J.S. and R.K. are current or former employees of Acceleron Pharma with ownership interest in the company. R.C. is an employee of Celgene with ownership interest in the company.

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Suragani, R., Cadena, S., Cawley, S. et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med 20, 408–414 (2014). https://doi.org/10.1038/nm.3512

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