ACE-031

ACE-031 is a recombinant fusion protein in which the extracellular ligand-binding domain of the human activin receptor type IIB (ActRIIB / ACVR2B) is joined to the Fc region of human immunoglobulin G1, forming a disulfide-linked homodimer. It is not a synthetic peptide: it is a glycosylated biologic produced by recombinant expression, assigned the international nonproprietary name ramatercept. Molecules of this class act as soluble decoy receptors, or “ligand traps,” that bind ActRIIB ligands in the extracellular space instead of at the cell surface. In published preclinical work, soluble ActRIIB-Fc proteins have been used as laboratory tools for studying myostatin (GDF-8) and activin signaling, skeletal muscle mass regulation, and bone formation in rodent models. This material is supplied for research use only and is not for human consumption.

In published preclinical models, soluble ActRIIB-Fc proteins act by sequestering ligands of the activin type II receptors before those ligands can engage membrane-bound receptor, thereby limiting downstream SMAD2/3 signaling that normally restrains muscle growth. Lee and colleagues reported that a soluble form of ACVR2B produced large increases in muscle mass in wild-type mice, and that the response was attenuated but not abolished in myostatin-null (Mstn-/-) animals, indicating that at least one ligand other than myostatin also limits muscle growth through these receptors. Consistent with that breadth, work in bone described ActRIIB-Fc as a myostatin and activin decoy receptor whose skeletal effects were not reproduced by a myostatin-neutralizing antibody. ACE-031 is therefore studied as a broad activin type II receptor ligand trap rather than a myostatin-selective inhibitor.

Soluble ActRIIB and Multiple Muscle-Regulating Ligands

Lee et al. (2005) described a soluble form of the activin type IIB receptor (ACVR2B) as a potent myostatin inhibitor that caused increases in muscle mass of up to 60% within two weeks when injected into wild-type mice. The effect was attenuated but not eliminated in myostatin-deficient mice, and genetic evidence indicated that the relevant ligands signal through both ACVR2 and ACVR2B [1].

Muscle Growth Independent of Fiber Type

Cadena et al. (2010) treated 8-week-old C57BL/6 mice with ACE-031 or vehicle for 28 days and reported increased wet weights of the soleus, plantaris, gastrocnemius and extensor digitorum longus muscles, with increased mean fiber cross-sectional area in both type I and type II soleus fibers and no change in soleus fiber-type distribution. The authors reported this as the first evidence that soluble ActRIIB increases muscle mass independent of fiber-type expression, distinguishing it from selective myostatin inhibition [2].

Ligand Trapping and Bone Mass in Mice

Bialek et al. (2014) compared a myostatin-neutralizing antibody with a soluble ActRIIB-Fc decoy receptor in young adult mice. Both increased muscle mass, but only ActRIIB-Fc increased bone volume fraction by microCT in the distal femur and lumbar vertebrae, an effect also seen in myostatin-deficient mice. The authors concluded that a ligand other than myostatin contributes to the skeletal response, and showed it was not explained by BMP3 neutralization [3].