ライフサイエンスコーパス: ActRIIB

1 ActRIIB binds to the outer edges of the activin finger r

2 ActRIIB pathway blockade abolished the activation of the

3 ActRIIB was targeted using a novel inhibitor comprised o

4 ActRIIB-mFc treatment produces a mild benefit to the dis

5 ActRIIB.Fc effectively blocked and reversed loss of body

6 ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exer

7 ActRIIB:ALK4-Fc induced a systemic increase in muscle ma

8 ActRIIB:ALK4-Fc shows promise as a therapeutic agent, al

9 ramuscular injections of 10 mg kg(-1) wk(-1) ActRIIB.Fc or saline placebo.

10 Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the

11 type II receptor activin A receptor type 2B (ActRIIB).

12 tions in ActRIIB Leu(79) effectively abolish ActRIIB binding to activin A yet not to GDF-11.

13 ) and type II (TGF-betaRII, BMPR-II, ActRII, ActRIIB) receptors.

14 Further analyses revealed that ActRIIA(-/-)ActRIIB(+/-) and about 15% of the ActRIIA(-/-) embryos f

15 e type II TGF-beta family receptors ActRIIA, ActRIIB, and BMPRII have been implicated in ALK1 signali

16 e type II TGF-beta family receptors ActRIIA, ActRIIB, and BMPRII interact with a large group of overl

17 M338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels.

18 th those of activin A, a known high affinity ActRIIB ligand, whereas BMP-2 and BMP-7 affinities for A

19 Type II activin receptors (ActRII and ActRIIB) are single-transmembrane domain serine/threonin

20 LK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by domi

21 , mutations of activin receptors ActRIIA and ActRIIB are shown to disrupt the development of posterio

22 r mutations by interbreeding the ActRIIA and ActRIIB knockout mutants.

23 alysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner a

24 bunits and the activin receptors ActRIIA and ActRIIB was demonstrated by RT-PCR.

25 ae, and that Gdf11 binds to both ActRIIA and ActRIIB, and induces phosphorylation of Smad2.

26 The type II activin receptors, ActRIIA and ActRIIB, have been shown to play critical roles in axial

27 s are capable of binding to both ActRIIA and ActRIIB, with different affinities.

28 9 with the extracellular domains of ALK1 and ActRIIB.

29 ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential eff

30 Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively

31 We further show that RA and ActRIIB mutation have synergistic effects on vertebral p

32 ugh the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blo

33 c muscle and increased life span by blocking ActRIIB with a decoy receptor.

34 etic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertroph

35 oluble activin receptor type IIB-Fc chimera (ActRIIB.Fc).

36 gand, whereas BMP-2 and BMP-7 affinities for ActRIIB are at least 100-fold lower.

37 The structure of GDF11/ActRIIB/Alk5 shows that, across the TGFbeta family, diff

38 istration of a soluble activin receptor IIB (ActRIIB-Fc).

39 CD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I rece

40 /threonine kinase activin receptor type IIB (ActRIIB) has been proposed to bind key regulators of ske

41 tant role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonst

42 The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming gr

43 cts of a modified activin receptor type IIB (ActRIIB) ligand trap (RAP-536) that inhibits Smad2/3 sig

44 r domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding.

45 nase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II re

46 Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormal

47 ways such as, for example, substitutions in ActRIIB Leu(79) effectively abolish ActRIIB binding to a

48 s are more severe in Gdf11-null mice than in ActRIIB-null mice, however, leaving it uncertain whether

49 ropoiesis and reveal potential of a modified ActRIIB ligand trap as a novel therapeutic agent for tha

50 Native ActRIIB has four isoforms that differ in the length of t

51 ype II receptors ActRIIA and BMPRII, but not ActRIIB, and HJV enhances utilization of ActRIIA by BMP-

52 Administration of ActRIIB.Fc was associated with greater gains in body wei

53 Administration of ActRIIB.Fc was associated with higher muscle expression

54 cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting

55 ovide a detailed kinetic characterization of ActRIIB binding to several low and high affinity ligands

56 and GDF-11 bind the extracellular domain of ActRIIB with affinities comparable with those of activin

57 from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-def

58 In addition, we show that glycosylation of ActRIIB is not required for binding to activin A or GDF-

59 We report a study of ActRIIB-mFc treatment in the Acta1 H40Y mouse model of N

60 tor kinases classified as type II (ActRII or ActRIIB) and type I (ALK4).

61 t not activin receptor type IIA (ActRIIA) or ActRIIB, based on changes in BMP signaling by small inte

62 soluble ActRIIb receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-beta/activin family m

63 eterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains o

64 GDF11, in complex with the type II receptor ActRIIB and the type I receptor Alk5.

65 ating cachexia, the activin type-2 receptor (ActRIIB).

66 disruption of the type IIB activin receptor (ActRIIB) by gene targeting results in altered expression

67 i.p. injection of activin type IIB receptor (ActRIIB)-mFc (an inhibitor of myostatin signaling) to pr

68 f ALK2 in complex with the type II receptor, ActRIIB, and the ligand, BMP6, in parallel with the corr

69 actor 11), and the activin type II receptor, ActRIIB, are involved in controlling the spatiotemporal

70 extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction.

71 homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not t

72 We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects o

73 Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling

74 By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile disti

75 These results support ActRIIB-mFC as an effective treatment for the weakness o

76 te-directed mutagenesis, we demonstrate that ActRIIB binds GDF-11 and activin A in different ways suc

77 of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertr

78 m1delta4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to ty

79 e using genetic and biochemical studies that ActRIIB and its subfamily receptor, ActRIIA, cooperative

80 lean mass were significantly greater in the ActRIIB.Fc group than in the placebo group (P < 0.001).

81 We demonstrate that the C terminus of the ActRIIB extracellular domain is crucial for maintaining

82 omprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB)

83 ish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia.

84 specificity and activity determinants of the ActRIIB receptor that combine to effect specificity in t

85 l for maintaining biological activity of the ActRIIB.Fc receptor chimera.

86 These data show that targeting the ActRIIB improves skeletal muscle mass and functional str

87 of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle gro

88 We show here that the ActRIIB-/- mice die after birth with complicated cardiac

89 e findings provide genetic evidence that the ActRIIB-mediated signaling pathway plays a critical role

90 ve been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce m

91 Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense olig

92 Thus ActRIIB antagonism is a promising new approach for treat

93 ate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and

94 l hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle gro

95 BMP-3 acts by binding to ActRIIB, the common type II receptor for these proteins.

96 Once BMP-3 binds to ActRIIB, it cannot be competed off by excess ligand maki

97 fferent from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibi

98 aving it uncertain whether Gdf11 signals via ActRIIB.

99 ior murine work; we therefore tested whether ActRIIB-mFc could improve weakness in NM mice through my

100 Treatment of Mtm1delta4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with t

101 rs, SNX6 was found to interact strongly with ActRIIB and more moderately with wild type and kinase-de

102 purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-beta/activin family m

103 SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function,

104 n Acta1 H40Y mice that had been treated with ActRIIB-mFc.