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

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 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.

TGF-β signaling in the control of hematopoietic stem cells

“…72 Similarly, a number of recent studies highlight the feasibility of manipulating the TGF-b pathway in hematopoietic disorders like MDS and anemia. 115,118,119 In addition, the complexity of the SMAD pathway continues to be exposed as new layers of regulatory mechanisms are found. For example, the linker region of SMADs is subject to negative regulation by glycogen synthase kinase 3, FGF, and epidermal growth factor.…”

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

“…We tested this idea by treating Bmpr2-floxed and Bmpr2-cKO mice with ACVR2B receptor decoy (ACVR2B-Fc), which sequesters activins with high affinity (Koncarevic et al, 2012;Sako et al, 2010), selectively reduces SMAD2/3 activation (supplementary material Fig. S4A,B; Ohsawa et al, 2006;Suragani et al, 2014;Zhou et al, 2010) and increases bone mass (Attie et al, 2013;Koncarevic et al, 2010). We reasoned that, if the reduced activin signaling underlies high bone mass in Bmpr2-cKO mice, then sequestration of activins with receptor decoy would have little or no additional effect on bone mass.…”

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…141 The observation triggered further investigation into this, and another trap ligand targeting ActRIIB (ACE-536), in mouse models of myelodysplastic syndromes (MDS) as well as b-thalassemia, showed a significant improvement of the anemia. [142][143][144] In both these disorders it has been suggested that the mechanism of action of these drugs is mediated by targeting Gdf11, which in turn decreases Smad2/3 activation in erythroid progenitors, and ultimately improves erythroid maturation and RBC production. [142][143][144] In addition, in Hbb th1/th1 mice, it has been shown that oxidative stress, through the Gdf11 ligand (Figure 3), also decreases apoptosis through overactivation of the Fas-Fas ligand pathway.…”

“…[142][143][144] In both these disorders it has been suggested that the mechanism of action of these drugs is mediated by targeting Gdf11, which in turn decreases Smad2/3 activation in erythroid progenitors, and ultimately improves erythroid maturation and RBC production. [142][143][144] In addition, in Hbb th1/th1 mice, it has been shown that oxidative stress, through the Gdf11 ligand (Figure 3), also decreases apoptosis through overactivation of the Fas-Fas ligand pathway. 126,127 As mentioned previously, both decreased apoptotic rate and maturation of early erythroid precursors leads to exacerbation of IE, splenomegaly, and increased iron absorption.…”