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luspatercept   Click here for help

GtoPdb Ligand ID: 10538

Synonyms: ACE-536 | ACE536 | luspatercept-aamt | Reblozyl®
Approved drug
luspatercept is an approved drug (FDA (2019), EMA (2020))
Compound class: Peptide
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 [4]. 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].
Bioactivity Comments
In contrast to the broad binding profile detected in cell free SPR analysis, in cell-based reporter gene assays ACE-536 only inhibited GDF11- and GDF8-induced Smad2/3 signalling. It did not inhibit signalling induced by other ligands including activins and TGF-β1 [4].
Selectivity at ligand targets
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
growth/differentiation factor-11 Hs Fusion protein Binding 10.1 pKd - 4
⤷ pKd 10.1 (Kd 7.4x10-11 M) [4]
Description: Binding to GDF11 determined by surface plasmon resonance (SPR).
BMP-10 Hs Fusion protein Binding 10.1 pKd - 4
⤷ pKd 10.1 (Kd 8.7x10-11 M) [4]
Description: Binding to BMP10 determined by surface plasmon resonance (SPR).
BMP-6 Hs Fusion protein Binding 10.1 pKd - 4
⤷ pKd 10.1 (Kd 9x10-11 M) [4]
Description: Binding to BMP6 determined by surface plasmon resonance (SPR).
myostatin Hs Fusion protein Binding 9.7 pKd - 4
⤷ pKd 9.7 (Kd 2x10-10 M) [4]
Description: Binding to GDF8 determined by surface plasmon resonance (SPR).
activin B Hs Fusion protein Binding 9.2 pKd - 4
⤷ pKd 9.2 (Kd 6.2x10-10 M) [4]
Description: Binding to activin B determined by surface plasmon resonance (SPR).
BMP-9 Hs Fusion protein Binding 8.6 pKd - 4
⤷ pKd 8.6 (Kd 2.7x10-9 M) [4]
Description: Binding to BMP9 determined by surface plasmon resonance (SPR).
activin A Hs Fusion protein Binding 7.6 pKd - 4
⤷ pKd 7.6 (Kd 2.3x10-8 M) [4]
Description: Binding to activin B determined by surface plasmon resonance (SPR).
Targets where the ligand is described in the comment field
Target Comment
activin A receptor type 2B Ligand traps (decoys) based on the ectodomain structure of activin A receptor type 2B (ActRIIB) are proposed for therapeutic benefit in diseases/conditions that are associated with pathway activation by TGFβ superfamily ligands such as the TGFβs, bone morphogenic proteins (BMPs), activins, and Nodal.

Two approved drugs, sotatercept and luspatercept, are ActRIIA/IIB and ActRIIB traps that are used to treat pulmonary arterial hypertension (PAH) and anemias, respectively. Since these original approvals, GSK/35Pharma have developed ActRIIB-based ligand trap HS235, which is proposed to selectively bind pathological activins and GDFs whilst sparing BMP-9 and BMP-10 which are essential for maintaining blood vessel and lymphatic system integrity. HS235 is intended to treat PAH, heart failure and obesity [3]. Keros Therapeutics have developed RKER-012 which also intended for PAH, via neutralisation of ligands including activins A and B, GDFs 8 (myostatin) and 11 [2].