luspatercept

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Ligands
luspatercept

GtoPdb Ligand ID: 10538

Synonyms: ACE-536 | ACE536 | luspatercept-aamt | Reblozyl®

luspatercept is an approved drug (FDA (2019), EMA (2020))

Comment: Luspatercept (ACE-536) is a fusion protein comprising human ACVR2B (activin receptor type 2B) extracellular domain (which is mutated to reduce activin binding), fused with human immunoglobulin G1 Fc fragment [2]. Luspatercept was initially proposed as a ligand trap for growth/differentiation factor-11 (GDF11; and other TGFβ family ligands). Mechanistically, it reduces Smad2/3 activation, and promotes maturation of late-stage erythroid precursors, independently of the erythropoietin (EPO) pathway. In contrast, erythropoietin stimulates proliferation of early-stage erythrocyte precursors.
Using Gdf11 knockout, Guerra et al. (2019) disputed GDF11 as an important molecular target of luspatercept and its proposed inhibitory effect on late erythropoiesis [1].

References
1. Guerra A, Oikonomidou PR, Sinha S, Zhang J, Lo Presti V, Hamilton CR, Breda L, Casu C, La P, Martins AC et al.. (2019) Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia. Blood, 134 (6): 568-572. DOI: 10.1182/blood.2019001057 [PMID:31151988]
2. Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, Davies MV, Alexander MJ, Devine M, Loveday KS et al.. (2014) Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med, 20 (4): 408-14. [PMID:24658078]

References

1. Guerra A, Oikonomidou PR, Sinha S, Zhang J, Lo Presti V, Hamilton CR, Breda L, Casu C, La P, Martins AC et al.. (2019)
Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia.
Blood, 134 (6): 568-572. DOI: 10.1182/blood.2019001057 [PMID:31151988]

2. Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, Davies MV, Alexander MJ, Devine M, Loveday KS et al.. (2014)
Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis.
Nat Med, 20 (4): 408-14. [PMID:24658078]