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

Abstract

The myostatin/activin type II receptor (ActRII) pathway has been identified to be 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, or 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 the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, 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 beyond myostatin inhibition alone through blockade of ActRII ligands. 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 skeletal muscle atrophy and weakness in multiple settings.

Effect of bimagrumab on thigh muscle volume and composition in men with casting‐induced atrophy

“…Recently published results in rodents and humans have highlighted the potential competitive advantages of ActRII involvement in the treatment of muscle wasting conditions 23, 24. The present observations add further support for a receptor antagonist by demonstrating the ability of bimagrumab to induce a rapid and marked increase in TMV in an established human experimental model of disuse atrophy.…”

“…Bimagrumab, a human monoclonal anti‐ActRII antibody, prevents the binding of these ligands to their receptor, which promotes muscle hypertrophy, and accelerates recovery from muscle wasting conditions (e.g. glucocorticoid‐induced atrophy) in animals 24. Translation of this effect of bimagrumab to increase muscle size and function in patients could hold considerable clinical potential.…”

Lack of evidence for GDF 11 as a rejuvenator of aged skeletal muscle satellite cells

“…1C). These data are consistent with the fact that GDF11 shares a high degree of sequence identity with GDF8, activates similar signaling pathways (Lach‐Trifilieff et al ., 2014), does not promote SC outgrowth, and reduces lean mass in mice. Thus in these findings, GDF11 exhibits activity similar to that of GDF8.…”

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective

“…Because MSTN expression is increased in COPD, pharmacological inhibition of MSTN might be beneficial to prevent COPD‐induced muscle wasting. This idea is supported by the finding that in mice with chronic kidney failure, pharmacological inhibition of MSTN blocks muscle atrophy,109 and that pharmacological inhibition of the ActII‐receptor, which mediates MSTN signalling, prevents glucocorticoid‐induced muscle atrophy 110111.…”