ACE-031

ACE-031, also written ActRIIB-Fc or ramatercept, is not a peptide but a recombinant fusion protein: the extracellular ligand-binding region of the activin receptor type IIB, a single-transmembrane serine/threonine kinase receptor, joined to the Fc portion of immunoglobulin G1. Because the extracellular domain retains its ligand-binding surface but has no signalling kinase, the construct acts as a soluble decoy, or ligand trap, that sequesters transforming growth factor-beta superfamily ligands before they can engage receptors at the cell surface.

ACE-031 in the research literature

Kinetic characterisation of the soluble chimera showed that GDF-8 (myostatin) and GDF-11 bind the ActRIIB extracellular domain with affinities comparable to activin A, a known high-affinity ligand, while BMP-2 and BMP-7 bind at least 100-fold more weakly. Site-directed mutagenesis distinguished the binding modes: substitutions at ActRIIB Leu79 abolished binding to activin A but not to GDF-11. The C-terminal portion of the extracellular domain proved necessary for activity of the chimera, whereas glycosylation was not required for binding activin A or GDF-11.

Structural work on an ActRIIB-activin A complex showed the receptor binding at the outer edges of the ligand finger regions in a mode differing from TGF-beta3. In wild-type mice, a soluble form of the type IIB receptor produced effects that were attenuated but not abolished in myostatin-null animals, which was read as evidence that ligands besides myostatin signal through activin type II receptors.