Description
Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor. Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. Type II receptors are considered to be constitutively active kinases. This gene encodes activin A type IIB receptor, which displays a 3- to 4-fold higher affinity for the ligand than activin A type II receptor. ACE-031 (Neuromuscular Disease) ACE-031 is a novel, muscle-building agent that is being developed for the treatment of patients with Duchenne Muscular Dystrophy with the goal of improving strength and preserving physical function. What is ACE-031? ACE-031 is an investigational protein therapeutic that builds muscle and increases strength by inhibiting molecules that bind to and signal through a cell surface receptor called Activin Receptor Type IIB (ActRIIB). ACE-031 is a recombinant fusion protein that is produced by joining a portion of the human ActRIIB receptor to a portion of a human antibody. This creates a freely circulating, decoy version of ActRIIB which removes proteins, such as GDF-8 (myostatin) and other related molecules that limit the growth and strength of muscle. Muscle growth is regulated by proteins in the TGF-ß protein superfamily that serve as “on” or “off” switches for muscle production. Several molecules including GDF-8 interact with the ActRIIB receptor and send an “off” signal to stop muscle production. In the absence of these “off” switch molecules that signal through the ActRIIB receptor, muscle mass increases dramatically. n nature, this effect has been observed in numerous species, particularly in animals that have been bred for increased musculature and strength. For example, Belgian Blue cattle lack the gene for GDF-8, which is one of several molecules that activate the ActRIIB receptor. A deficiency of this protein results in cattle with tremendously developed musculature and strength. Similar effects have been observed in other species, including rodents, dogs and even humans. ACE-031 Builds Skeletal Muscle Treatment with ACE-031 promotes muscle growth by inhibiting ActRIIB signaling. ACE-031 binds to proteins that signal through the ActRIIB receptor to limit muscle growth. When ACE-031 binds to these proteins, it prevents them from interacting with the ActRIIB receptor, thus allowing muscle to grow. Moreover, because ACE-031 prevents GDF-8 and other proteins that regulate muscle mass from signaling through the ActRIIB receptor, its effects on lean muscle exceed those of inhibitors of GDF-8 (myostatin) alone. When animals are treated with ACE-031, they experience growth in lean muscle and are considerably stronger than their untreated counterparts. This has been shown in several species, and in both healthy animals and in animals with diseases associated with muscle weakness and wasting. Clinical Development Status Acceleron has completed a single dose study (A031-01) of ACE-031 in healthy volunteers.
