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Synonyms: ACE-536 | ACE536 | luspatercept-aamt | Reblozyl®
luspatercept is an approved drug (FDA (2019), EMA (2020))
Compound class:
Peptide or derivative
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]. Mechanistically luspatercept acts as a ligand trap for growth/differentiation factor-11 (GDF11; and other Smad2/3-activating ligands), which reduces GDF11-induced Smad2/3 activation, and blocks the inhibitory effect of GDF11 on erythroid precursor maturation. Functionally, it promotes maturation of late-stage erythroid precursors, which is in contrast to erythropoietin, which stimulates proliferation of early-stage erythrocyte precursors. Using Gdf11 knockout, Guerra et al. (2019) dispute GDF11 as the molecular target of luspatercept and its proposed inhibitory effect on late erythropoiesis [1]. They do not propose an alternative mechanism of action.
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| References |
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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] |
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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] |
