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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

  1. Estelle Lach-Trifilieffa,1
  1. aMusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland;
  2. bChemical Biology and Therapeutics, Structural Biophysics Group, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland;
  3. cNovartis Biologics Center, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland;
  4. dMorphoSys AG, 82152 Martinsried/Planegg, Germany;
  5. eChemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA 02139
  1. Edited by Se-Jin Lee, Johns Hopkins University, Baltimore, MD, and approved October 11, 2017 (received for review May 15, 2017)

Significance

We recently reported that activin type II receptors (ActRIIs) blockade using bimagrumab could positively impact muscle wasting in mice and humans. However, the specific role of each individual ActRII at regulating adult muscle mass had not been clarified. Here, we highlight the importance of concomitant neutralization of both ActRIIs in controlling muscle mass. Through comparison with single specificity antibodies, we uncover unique features related to bimagrumab and its neutralizing interactions with both ActRIIA and ActRIIB at the structural and cellular levels and in vivo in adult mice. The need for simultaneous engagement and neutralization of both ActRIIs to generate a strong skeletal muscle response confers unique therapeutic potential to bimagrumab, in the context of muscle wasting conditions.

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.

Footnotes

  • ?1To whom correspondence should be addressed. Email: estelle.trifilieff{at}novartis.com.
  • Author contributions: F.M., J.-M.R., C.Z., G.M., M.S., C.J., S.G., D.J.G., and E.L.-T. designed research; J.-M.R., C.Z., C.S., P.B., V.R., G.T., C.K., X.L., A.S., F.W., S.L., E.K., and S.G. performed research; C.S., S.L., E.K., and S.G. contributed new reagents/analytic tools; F.M., J.-M.R., C.Z., G.M., M.S., C.J., S.G., D.J.G., and E.L.-T. analyzed data; and F.M., J.-M.R., G.M., D.J.G., and E.L.-T. wrote the paper.

  • Conflict of interest statement: All authors but F.W. are employees of Novartis Pharma AG (F.M., C.Z., C.S., J.-M.R., C.J., A.S., P.B., V.R., G.T., M.K., X.L., S.L., E.K., G.M., C.K., S.G., D.J.G., E.L.-T.), and some are also shareholders of Novartis. F.W. was an employee of MorphoSys AG at the time of contribution.

  • This article is a PNAS Direct Submission.

  • Data deposition: Coordinates and structure factors for the bimagrumab Fab, the bimagrumab Fv complex with the ActRIIA-LBD, and with ActRIIB-LBD (cubic and orthorhombic crystal forms) are available from the Protein Data Bank under accession codes 5NHW, 5NH3, 5NHR, and 5NGV, respectively.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1707925114/-/DCSupplemental.

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