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Abstract

The myostatin/Activin type II receptor (ActRII) pathway has been identified as critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the Activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody ("Bimagrumab", aka BYM338) to prevent binding of ligands to the receptors, and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts, and counteracts the inhibition of differentiation induced by myostatin or Activin A. BYM338 prevents myostatin or Activin A induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin as detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin-mutant mice, further confirming a beneficial effect on muscle growth through blockade of ActRII ligands beyond myostatin inhibition alone. 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.