Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof‐of‐Concept Study

Rooks, Daniel; Præstgaard, Jens; Hariry, Sam; Laurent, Didier; Pétricoul, Olivier; Perry, Robert G.; Lach-Trifilieff, Estelle; Roubenoff, Ronenn

doi:10.1111/jgs.14927

Cited by 178 publications

(138 citation statements)

References 20 publications

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“…Clinical trials involving ACVR2B decoy receptors, however, were terminated due to severe adverse effects, including bleeding . More specific antibodies directed towards the ACVR2B are being tested in clinical trials; however, because ACVR2 are central receptors for multiple TGFβ family members, and our study points to the central role of activin A, specific inhibition of activin A itself may prove less invasive and equally efficient.…”

Section: Discussionmentioning

confidence: 93%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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Background The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development. Methods We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice. Results We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). Conclusions Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

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Section: Discussionmentioning

confidence: 93%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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“…Myostatin and activins negatively regulate muscle mass through binding to their receptors activin receptor type 2 (ACVR2) A and B . Blocking these ligands or their receptors can increase muscle mass and prevent muscle wasting in various animal models, but also in humans …”

Section: Introductionmentioning

confidence: 99%

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Nissinen

Hentilä

Penna

et al. 2018

J cachexia sarcopenia muscle

162

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BackgroundCancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered.MethodsThe effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking.ResultsBlocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis.ConclusionsThe prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.

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“…Bimagrumab is a human monoclonal antibody that blocks ActRIIs from binding endogenous ligands: activins A and B, myostatin (growth and differentiation factor‐8, GDF‐8) and GDF‐11 . The blockade of myostatin binding to ActRII in the skeletal muscle is the target that bimagrumab tackles for further development for conditions of muscle atrophy/weakness and for obesity in type II diabetes . Indeed, the use of a soluble ActRIIB/Fc fusion protein in mice resulted in skeletal muscle growth, prevention of obesity and increased insulin sensitivity; but ActRIIs are also widely expressed in humans pituitary, gonadal and adrenal glands.…”

Section: Introductionmentioning

confidence: 99%

Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes

Garito

Zakaria

Papanicolaou

et al. 2018

Clinical Endocrinology

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Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof‐of‐Concept Study

Abstract: Treatment with bimagrumab over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed.

Cited by 178 publications

References 20 publications

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes

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