Anemia is a common debilitating complication arising from diverse causes, including myelodysplastic syndromes (MDS), thalassemia, cancer chemotherapy, chronic kidney disease and hemorrhage. Although endogenous erythropoietin (EPO) and its cognate receptor are critical for the survival, proliferation and differen-tiation of erythroid progenitors during early-stage erythropoiesis. However, erythroblast differentiation and maturation during late-stage erythropoiesis is independent of EPO. Moreover, study shows that TGF-β superfamily signaling pathways may represent new EPO-independent therapeutic targets that are particularly relevant to the treatment of anemia in patients with diseases characterized by ineffective erythropoiesis. Hence, we will introduce an ActRIIB Fusion Protein, Luspatercept (ACE-536), which can efficiently increases the erythrocyte numbers and promotes maturation of erythroid precursors.

Luspatercept (ACE-536)is a recombinant modified ActRIIB fusion protein.

Luspatercept (ACE-536) consists of a modified human ActRIIB extracellular domain linked to the human IgG1 Fc domain, or RAP-536, a mouse version of Luspatercept with an identical ligand-binding domain. Moreover, Luspatercept binds with transforming growth factor β superfamily ligands. Importantly, Luspatercept corrects anemia by promoting late-stage. Unlike EPO, RAP-536 promoted maturation of latestage erythroid precursors in vivo.

In vitro, Luspatercept (0.1-1000 ng/mL) inhibits Smad2 and Smad 3 signaling induced by GDF11 and GDF8 in A204 cells.

In vivo, Luspatercept (0.1-60 mg/kg, s.c.; 10 mg/kg, i.v.; twice weekly for 8 weeks) increases red blood cell (RBC) count, hemoglobin levels and hematocrit in mice, rats and monkeys. In addition, Luspatercept (10 mg/kg; s.c., single) reduces erythroid burst forming units (BFU-Es) and erythroid colony-forming units (CFU-Es) from bone marrow and spleen of C57BL/6 mice. Moreover, Luspatercept (10 mg/kg; i.p., single) inhibits Smad2/3 phosphorylation in mouse spleen.

Unlike EPO, RAP-536 (a mouse version of Luspatercept) promotes maturation of latestage erythroid precursors in vivo. Cotreatment with Luspatercept and EPO produces a synergistic erythropoietic response.

In summary, Luspatercept provides an opportunity to fight anemia associated with disorders.


  1. Suragani RN, et al. Nat Med. 2014 Apr;20(4):408-14.