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Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity

  • Manmeet Kaur und Saurav Misra EMAIL logo
Veröffentlicht/Copyright: 10. Oktober 2024
Journal of Basic and Clinical Physiology and Pharmacology
Aus der Zeitschrift Journal of Basic and Clinical Physiology and Pharmacology Band 35 Heft 6

Abstract

Bimagrumab is a human monoclonal antibody that prevents activin type II receptors (ActRII) from functioning. This antibody has a higher affinity for muscle activin-2 receptors than natural ligands such as activin and myostatin, which act as negative muscle growth regulators. Blocking the activin receptor with bimagrumab could be a new pharmaceutical approach for managing patients with obesity and type 2 diabetes mellitus (T2DM). Bimagrumab has anabolic effects on skeletal muscle mass by preventing myostatin binding and other negative muscle growth regulators. Preclinical animal models have also shown that ActRII blockade promotes actions beyond skeletal muscle, including effects on brown adipose tissue (BAT) differentiation and activity. In a phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of total body fat mass (FM), lean mass (LM) gain, and metabolic improvements over 48 weeks in overweight or obese patients with type 2 diabetes. The trial involved [number of participants], and the results showed [specific findings]. Currently, Bimagrumab is being evaluated for its potential to treat muscle wasting, functional loss in hip fractures and sarcopenia, as well as obesity. However, it is essential to note that Bimagrumab also blocks the effects of other ActRII ligands, which play a role in the neurohormonal axes, pituitary, gonads, and adrenal glands. These observations suggest that bimagrumab might represent a new approach for treating patients with obesity and related metabolic disturbances.

Keywords: bimagrumab; activin type II receptors (ActRII); myostatin; obesity
Corresponding author: Dr. Saurav Misra, MBBS, MD, Assistant professor, Department of Pharmacology, Kalpana Chawla Government Medical College, Karnal, India, E-mail:

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: MK – Idea, writing of manuscript; SM – Idea, data collection, writing of manuscript, final editing.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interests: None of the authors have conflict of interest.

  6. Research funding: None declared.

  7. Data availability: Not applicable.

References

1. Kaur, M, Misra, S. A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity. Eur J Clin Pharmacol 2024. https://doi.org/10.1007/s00228-024-03646-0.Suche in Google Scholar PubMed

2. World obesity atlas; 2022. Available from: https://s3-eu-west-1.amazonaws.com/wof-files/World_Obesity_Atlas_2022.pdf [Accessed 7 November 2022].Suche in Google Scholar

3. International Diabetes Federation Diabetes Atlas. IDF_Atlas_10th_Edition_2021.pdf; 2021. Available from: https://diabetesatlas.org/ [Accessed 7 November 2022].Suche in Google Scholar

4. Iglay, K, Hannachi, H, Howie, PJ, Xu, J, Li, X, Engelet, SS, et al.. Prevalence and co-prevalence of comorbidities among patients with type 2 diabetes mellitus. Curr Med Res Opin 2016;32:1243–52. https://doi.org/10.1185/03007995.2016.1168291.Suche in Google Scholar PubMed

5. Evert, AB, Franz, MJ. Why weight loss maintenance is difficult. Diabetes Spectr 2017;30:153–6. https://doi.org/10.2337/ds017-0025.Suche in Google Scholar PubMed PubMed Central

6. Müller, TD, Blüher, M, Tschöp, MH, DiMarchi, RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022;21:201–23. https://doi.org/10.1038/s41573-021-00337-8.Suche in Google Scholar PubMed PubMed Central

7. Argiles, JM, Orpi, M, Busquets, S, Lopez-Soriano, FJ. Myostatin: more than just a regulator of muscle mass. Drug Discov Today 2012;17:702–9. https://doi.org/10.1016/j.drudis.2012.02.001.Suche in Google Scholar PubMed

8. Elkina, Y, von, HS, Anker, SD, Springer, J. The role of myostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle 2011;2:143–51. https://doi.org/10.1007/s13539-011-0035-5.Suche in Google Scholar PubMed PubMed Central

9. Lach‐Trifilieff, E, Minetti, GC, Sheppard, K, Ibebunjo, C, Feige, JN, Hartmann, S, et al.. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol 2014;34:606–18. https://doi.org/10.1128/mcb.01307-13.Suche in Google Scholar PubMed PubMed Central

10. Lee, SJ. Regulation of muscle mass by myostatin. Ann Rev Cell Dev Biol 2004;20:61–86. https://doi.org/10.1146/annurev.cellbio.20.012103.135836.Suche in Google Scholar PubMed

11. Trendelenburg, AU, Meyer, A, Rohner, D, Boyle, J, Hatakeyama, S, Glass, DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol 2009;296:C1258–70. https://doi.org/10.1152/ajpcell.00105.2009.Suche in Google Scholar PubMed

12. Lee, SJ, McPherron, AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001;98:9306–11. https://doi.org/10.1073/pnas.151270098.Suche in Google Scholar PubMed PubMed Central

13. Lee, SJ, Reed, LA, Davies, MV, Girgenrath, S, Goad, ME, Tomkinson, KN, et al.. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA 2005;102:18117–22. https://doi.org/10.1073/pnas.0505996102.Suche in Google Scholar PubMed PubMed Central

14. Tan, CK, Leuenberger, N, Tan, MJ, Yan, YW, Chen, Y, Kambadur, R, et al.. Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet. Diabetes 2011;60:464–76. https://doi.org/10.2337/db10-0801.Suche in Google Scholar PubMed PubMed Central

15. Goncalves, MD, Pistilli, EE, Balduzzi, A, Birnbaum, MJ, Lachey, J, Khurana, TS, et al.. Akt deficiency attenuates muscle size and function but not the response to ActRIIB inhibition. PLoS One 2010;5:e12707. https://doi.org/10.1371/journal.pone.0012707.Suche in Google Scholar PubMed PubMed Central

16. LeBrasseur, NK, Schelhorn, TM, Bernardo, BL, Cosgrove, PG, Loria, PM, Brown, TA. Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J Gerontol A Biol Sci Med Sci 2009;64:940–8. https://doi.org/10.1093/gerona/glp068.Suche in Google Scholar PubMed

17. Rebbapragada, A, Benchabane, H, Wrana, JL, Celeste, AJ, Attisano, L. Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol Cell Biol 2003;23:7230–42. https://doi.org/10.1128/mcb.23.20.7230-7242.2003.Suche in Google Scholar

18. McPherron, AC, Lee, SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A 1997;94:12457–61. https://doi.org/10.1073/pnas.94.23.12457.Suche in Google Scholar PubMed PubMed Central

19. McPherron, AC, Lawler, AM, Lee, SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83–90. https://doi.org/10.1038/387083a0.Suche in Google Scholar PubMed

20. Mosher, DS, Quignon, P, Bustamante, CD, Sutter, NB, Mellersh, CS, Parker, HG, et al.. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet 2007;3:e79. https://doi.org/10.1371/journal.pgen.0030079.eor.Suche in Google Scholar

21. Schuelke, M, Wagner, KR, Stolz, LE, Hubner, C, Riebel, T, Komen, W, et al.. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004;350:2682–8. https://doi.org/10.1056/nejmoa040933.Suche in Google Scholar PubMed

22. Allen, DL, Cleary, AS, Speaker, KJ, Lindsay, SF, Uyenishi, J, Reed, JM, et al.. Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Endocrinol Metab 2008;294:E918–927. https://doi.org/10.1152/ajpendo.00798.2007.Suche in Google Scholar PubMed

23. Hittel, DS, Berggren, JR, Shearer, J, Boyle, K, Houmard, JA. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 2009;58:30–8. https://doi.org/10.2337/db08-0943.Suche in Google Scholar PubMed PubMed Central

24. Lee, SJ, Reed, LA, Davies, MV, Girgenrath, S, Goad, ME, Tomkinson, KN, et al.. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA 2005;102:18117–22. https://doi.org/10.1073/pnas.0505996102.Suche in Google Scholar PubMed PubMed Central

25. Wilkes, JJ, Lloyd, DJ, Gekakis, N. A loss-of-function mutation in myostatin reduces TNF{alpha} production and protects liver against obesity-induced insulin resistance. Diabetes 2009;58:1133–43. https://doi.org/10.2337/db08-0245.Suche in Google Scholar PubMed PubMed Central

26. McPherron, AC, Lee, SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002;109:595–601. https://doi.org/10.1172/jci200213562.Suche in Google Scholar

27. Zhao, B, Wall, RJ, Yang, J. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem Biophys Res Commun 2005;337:248–55. https://doi.org/10.1016/j.bbrc.2005.09.044.Suche in Google Scholar PubMed

28. Akpan, I, Goncalves, MD, Dhir, R, Yin, X, Pistilli, EE, Bogdanovich, S, et al.. The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int J Obes 2009;33:1265–73. https://doi.org/10.1038/ijo.2009.162.Suche in Google Scholar PubMed PubMed Central

29. McPherron, AC. Metabolic functions of myostatin and GDF11. Immunol Endocr Metab Agents Med Chem. 2010;10:217–31. https://doi.org/10.2174/187152210793663810.Suche in Google Scholar PubMed PubMed Central

30. Lee, SJ, McPherron, AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001;98:9306–11. https://doi.org/10.1073/pnas.151270098.Suche in Google Scholar PubMed PubMed Central

31. Lee, SJ, Reed, LA, Davies, MV, Girgenrath, S, Goad, ME, Tomkinson, KN, et al.. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA 2005;102:18117–22. https://doi.org/10.1073/pnas.0505996102.Suche in Google Scholar

32. Fournier, B, Murray, B, Gutzwiller, S, Marcaletti, S, Marcellin, D, Bergling, S, et al.. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol Cell Biol 2012;32:2871–9. https://doi.org/10.1128/mcb.06575-11.Suche in Google Scholar

33. McPherron, AC. Metabolic functions of myostatin and GDF11. Immunol Endocr Metab Agents Med Chem 2010;10:217–31. https://doi.org/10.2174/187152210793663810.Suche in Google Scholar PubMed PubMed Central

34. Whittemore, LA, Song, K, Li, X, Aghajanian, J, Davies, M, Girgenrath, S, et al.. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun 2003;300:965–71. https://doi.org/10.1016/s0006-291x(02)02953-4.Suche in Google Scholar PubMed

35. Lee, SJ, McPherron, AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001;98:9306–11. https://doi.org/10.1073/pnas.151270098.Suche in Google Scholar PubMed PubMed Central

36. Lee, SJ, Reed, LA, Davies, MV, Girgenrath, S, Goad, ME, Tomkinson, KN, et al.. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA 2005;102:18117–22. https://doi.org/10.1073/pnas.0505996102.Suche in Google Scholar PubMed PubMed Central

37. Nunn, E, Jaiswal, N, Gavin, M, Uehara, K, Stefkovich, M, Drareni, K, et al.. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metabol 2024;80:101880. https://doi.org/10.1016/j.molmet.2024.101880.Suche in Google Scholar PubMed PubMed Central

38. Petricoul, O, Nazarian, A, Schuehly, U, Schramm, U, David, OJ, Laurent, D, et al.. Pharmacokinetics and pharmacodynamics of bimagrumab (BYM338). Clin Pharmacokinet 2023;62:141–55. https://doi.org/10.1007/s40262-022-01189-0.Suche in Google Scholar PubMed

39. Rooks, D, Petricoul, O, Praestgaard, J, Bartlett, M, Laurent, D, Roubenoff, R. Safety and pharmacokinetics of bimagrumab in healthy older and obese adults with body composition changes in the older cohort. J Cachexia Sarcopenia Muscle 2020;11:1525–34. https://doi.org/10.1002/jcsm.12639.Suche in Google Scholar PubMed PubMed Central

40. Rooks, DS, Laurent, D, Praestgaard, J, Rasmussen, S, Bartlett, M, Tankó, LB. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J Cachexia Sarcopenia Muscle 2017;8:727–34. https://doi.org/10.1002/jcsm.12205.Suche in Google Scholar PubMed PubMed Central

41. Garito, T, Zakaria, M, Papanicolaou, DA, Li, Y, Pinot, P, Petricoul, O, et al.. Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes. Clin Endocrinol 2018;88:908–19. https://doi.org/10.1111/cen.13601.Suche in Google Scholar PubMed

42. Garito, T, Roubenoff, R, Hompesch, M, Morrow, L, Gomez, K, Rooks, D, et al.. Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals. Diabetes Obes Metabol 2018;20:94–102. https://doi.org/10.1111/dom.13042.Suche in Google Scholar PubMed

43. Heymsfield, SB, Coleman, LA, Miller, R, Rooks, DS, Laurent, D, Petricoul, O, et al.. Effect of bimagrumab vs placebo on body fat mass among adults with type 2 diabetes and obesity: a phase 2 randomized clinical trial. JAMA Netw Open 2021;4:e2033457. https://doi.org/10.1001/jamanetworkopen.2020.33457.Suche in Google Scholar PubMed PubMed Central

44. Wilding, JPH, Batterham, RL, Calanna, S, Davies, M, Van Gaal, LF, Lingvay, I, et al.. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989e1002. https://doi.org/10.1056/nejmoa2032183.Suche in Google Scholar

45. Jastreboff, AM, Aronne, LJ, Ahmad, NN, Wharton, S, Connery, L, Alves, B, et al.. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205e16. https://doi.org/10.1056/nejmoa2206038.Suche in Google Scholar

46. Jastreboff, AM, Kaplan, LM, Frías, JP, Wu, Q, Du, Y, Gurbuz, S, et al.. Triplehormone-receptor agonist retatrutide for obesity - a phase 2 trial. N Engl J Med 2023;389:514e26. https://doi.org/10.1056/nejmoa2301972.Suche in Google Scholar PubMed

47. Wilding, JPH, Batterham, RL, Davies, M, Van Gaal, LF, Kandler, K, Konakli, K, et al.. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metabol 2022;24:1553e64. https://doi.org/10.1111/dom.14725.Suche in Google Scholar PubMed PubMed Central

48. Christoffersen, BØ, Sanchez-Delgado, G, John, LM, Ryan, DH, Raun, K, Ravussin, E. Beyond appetite regulation: targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss. Obesity (Silver Spring) 2022;30(4):841e57.10.1002/oby.23374Suche in Google Scholar PubMed PubMed Central

49. Sartori, R, Romanello, V, Sandri, M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun 2021;12:330. https://doi.org/10.1038/s41467-020-20123-1.Suche in Google Scholar PubMed PubMed Central

50. Safety and efficacy of bimagrumab and semaglutide in adults who are overweight or obese. NCT05616013. U.S. National Library of Medicine; 2024. Available from: https://Clinicaltrials.Gov/Study/NCT05616013 Suche in Google Scholar

51. Safety, pharmacokinetics and efficacy of bimagrumab in overweight and obese patients with type 2 diabetes. NCT03005288. U.S. National Library of Medicine; 2024. Available from: https://clinicaltrials.gov/study/NCT03005288?intr=Bimagrumab&page=1&rank=6 Suche in Google Scholar

52. Effect of bimagrumab on body composition, insulin sensitivity, and bone in adults with obesity. NCT05933499. U.S. National Library of Medicine; 2024. Available from: https://clinicaltrials.gov/study/NCT05933499?intr=Bimagrumab&page=2&rank=14 Suche in Google Scholar

53. An extension study of the efficacy, safety and tolerability of BYM338 (Bimagrumab) in patients with sporadic inclusion body myositis who previously participated in the core study CBYM338B2203. NCT02573467. U.S. National Library of Medicine; 2024. Available from: https://clinicaltrials.gov/study/NCT02573467?intr=Bimagrumab&page=1&rank=2 Suche in Google Scholar

54. Study of efficacy and safety of bimagrumab in patients after hip fracture surgery. NCT02152761. U.S. National Library of Medicine; 2024. Available from: https://clinicaltrials.gov/study/NCT02152761?intr=Bimagrumab&page=1&rank=3 Suche in Google Scholar

55. Effect of bimagrumab on body composition, insulin sensitivity, and bone in adults with obesity. NCT05933499. U.S. National Library of Medicine; 2024 Available from: https://clinicaltrials.gov/study/NCT05933499?intr=Bimagrumab&page=2&rank=14 Suche in Google Scholar

56. Clinical study of BYM338 for the treatment of unintentional weight loss in patients with cancer of the lung or the pancreas NCT01433263. U.S. National Library of Medicine; 2024. Available from: https://clinicaltrials.gov/study/NCT01433263?intr=Bimagrumab&page=2&rank=13 Suche in Google Scholar

57. BYM338 in chronic obstructive pulmonary disease (COPD) patients with cachexia NCT01669174. U.S. National Library of Medicine; 2024. Available from: https://clinicaltrials.gov/study/NCT01669174?intr=Bimagrumab&page=2&rank=11 Suche in Google Scholar
Received: 2024-04-27
Accepted: 2024-09-19
Published Online: 2024-10-10

© 2024 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. IcoSema’s leap forward: new data from COMBINE 3 paves the way
  4. Reviews
  5. Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity
  6. The challenge of thigh tendon reinjuries: an expert opinion
  7. Original Articles
  8. Effect of omega-3 fatty acids supplementation on muscle mass, fat mass, and visceral fat of hemodialysis patients; A randomized clinical trial
  9. Identification of ocular artifact in EEG signals using VMD and Hurst exponent
  10. Choroidal and retinal alteration after long-term use of tadalafil: a prospective non-randomized clinical trial
  11. Short Communication
  12. Immediate effect of sunlight exposure through blue glass on blood pressure in hypertensive patients: a randomized controlled trial
  13. Letter to the Editor
  14. The alarming link between the COVID-19 pandemic and stroke: why ignoring this association after relapse of the disease has dangerous consequences
  15. Corrigendum
  16. Corrigendum to: 6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels
https://doi.org/10.1515/jbcpp-2024-0065
Schlagwörter für diesen Artikel
bimagrumab; activin type II receptors (ActRII); myostatin; obesity

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. IcoSema’s leap forward: new data from COMBINE 3 paves the way
  4. Reviews
  5. Bimagrumab: an investigational human monoclonal antibody against activin type II receptors for treating obesity
  6. The challenge of thigh tendon reinjuries: an expert opinion
  7. Original Articles
  8. Effect of omega-3 fatty acids supplementation on muscle mass, fat mass, and visceral fat of hemodialysis patients; A randomized clinical trial
  9. Identification of ocular artifact in EEG signals using VMD and Hurst exponent
  10. Choroidal and retinal alteration after long-term use of tadalafil: a prospective non-randomized clinical trial
  11. Short Communication
  12. Immediate effect of sunlight exposure through blue glass on blood pressure in hypertensive patients: a randomized controlled trial
  13. Letter to the Editor
  14. The alarming link between the COVID-19 pandemic and stroke: why ignoring this association after relapse of the disease has dangerous consequences
  15. Corrigendum
  16. Corrigendum to: 6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels
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