An Antibody Blocking Activin Receptors type II Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

The myostatin / Activin type II receptors (ActRII) pathway has been identified as critical in regulating skeletal muscle size. Blockade of the ligands (myostatin, GDF11, and activin) that activate these receptors, has resulted in preservation of muscle in multiple pre-clinical settings of skeletal muscle wasting. We have developed a novel, human anti-ActRII antibody (“Bimagrumab”, aka BYM338) to prevent binding of ligandsand thus inhibiting ActRII signaling. At the cellular level, BYM338 enhances differentiation of primary human skeletal myoblasts, and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 promotes skeletal muscle hypertrophy and prevents myostatin or activin A induced atrophy through inhibition of Smad2/3 phosphorylation and preservation of myosin (MyHC). BYM338 dramatically increases skeletal muscle mass in healthy naive mice, beyond sole inhibition of myostatin as detected upon administration of myostatin propeptide. A mouse chimeric antibody induces further muscle hypertrophy in myostatin-deficient mice, confirming a beneficial effect on muscle growth through blockade of ActRII ligands beyond myostatin. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness, via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of multiple settings of skeletal muscle atrophy and weakness.