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Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy.
Proc Natl Acad Sci U S A. 2017 11 21; 114(47):12448-12453.PN

Abstract

The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.

Authors+Show Affiliations

MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Chemical Biology and Therapeutics, Structural Biophysics Group, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Chemical Biology and Therapeutics, Structural Biophysics Group, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Chemical Biology and Therapeutics, Structural Biophysics Group, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Novartis Biologics Center, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Novartis Biologics Center, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.MorphoSys AG, 82152 Martinsried/Planegg, Germany.Chemical Biology and Therapeutics, Structural Biophysics Group, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Chemical Biology and Therapeutics, Structural Biophysics Group, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Novartis Biologics Center, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA 02139.MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland; estelle.trifilieff@novartis.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29109273

Citation

Morvan, Frederic, et al. "Blockade of Activin Type II Receptors With a Dual anti-ActRIIA/IIB Antibody Is Critical to Promote Maximal Skeletal Muscle Hypertrophy." Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 47, 2017, pp. 12448-12453.
Morvan F, Rondeau JM, Zou C, et al. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc Natl Acad Sci USA. 2017;114(47):12448-12453.
Morvan, F., Rondeau, J. M., Zou, C., Minetti, G., Scheufler, C., Scharenberg, M., Jacobi, C., Brebbia, P., Ritter, V., Toussaint, G., Koelbing, C., Leber, X., Schilb, A., Witte, F., Lehmann, S., Koch, E., Geisse, S., Glass, D. J., & Lach-Trifilieff, E. (2017). Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 114(47), 12448-12453. https://doi.org/10.1073/pnas.1707925114
Morvan F, et al. Blockade of Activin Type II Receptors With a Dual anti-ActRIIA/IIB Antibody Is Critical to Promote Maximal Skeletal Muscle Hypertrophy. Proc Natl Acad Sci USA. 2017 11 21;114(47):12448-12453. PubMed PMID: 29109273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. AU - Morvan,Frederic, AU - Rondeau,Jean-Michel, AU - Zou,Chao, AU - Minetti,Giulia, AU - Scheufler,Clemens, AU - Scharenberg,Meike, AU - Jacobi,Carsten, AU - Brebbia,Pascale, AU - Ritter,Veronique, AU - Toussaint,Gauthier, AU - Koelbing,Claudia, AU - Leber,Xavier, AU - Schilb,Alain, AU - Witte,Florian, AU - Lehmann,Sylvie, AU - Koch,Elke, AU - Geisse,Sabine, AU - Glass,David J, AU - Lach-Trifilieff,Estelle, Y1 - 2017/11/06/ PY - 2017/11/8/pubmed PY - 2018/6/22/medline PY - 2017/11/8/entrez KW - ActRII KW - activin KW - dual antibody KW - hypertrophy KW - myostatin SP - 12448 EP - 12453 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 114 IS - 47 N2 - The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/29109273/Blockade_of_activin_type_II_receptors_with_a_dual_anti_ActRIIA/IIB_antibody_is_critical_to_promote_maximal_skeletal_muscle_hypertrophy_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=29109273 DB - PRIME DP - Unbound Medicine ER -