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.