title: 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.
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Estelle
authors.initials: E
authors.lastname: Lach-Trifilieff
authors.forename: Giulia C
authors.initials: GC
authors.lastname: Minetti
authors.forename: KellyAnn
authors.initials: K
authors.lastname: Sheppard
authors.forename: Chikwendu
authors.initials: C
authors.lastname: Ibebunjo
authors.forename: Jerome N
authors.initials: JN
authors.lastname: Feige
authors.forename: Steffen
authors.initials: S
authors.lastname: Hartmann
authors.forename: Sophie
authors.initials: S
authors.lastname: Brachat
authors.forename: Helene
authors.initials: H
authors.lastname: Rivet
authors.forename: Claudia
authors.initials: C
authors.lastname: Koelbing
authors.forename: Frederic
authors.initials: F
authors.lastname: Morvan
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
mesh_terms: D030301:Activin Receptors, Type II / Q000276:immunology* / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001284:Atrophy / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D051899:Smad2 Protein; D051900:Smad3 Protein; C422405:activin A; D028341:Activins; D030301:Activin Receptors, Type II; C000596367:bimagrumab