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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)

  1. Fig. 2.

    ActRIIA (Upper) and ActRIIB (Lower) epitope recognized by bimagrumab. The Upper part of each panel shows the number of direct intermolecular contacts between nonhydrogen atoms within a 4.0-? distance; Lower part shows the reduction in solvent-accessible surface upon complex formation. The amino acid sequence of the respective ActRII LBD is displayed on the horizontal axis, together with a schematic representation of the secondary structure elements (arrows, β-strands; thick lines, connecting loops).

  2. Fig. 3.

    Cellular responses to ActRIIA and ActRIIB neutralization. (A) Binding of anti-ActRIIA (CSJ089, blue), anti-ActRIIB (CQI876, orange), anti-ActRIIA and ActRIIB Abs combination (black), bimagrumab (green), or isotype control Ab (gray) to HEK293T/17 cells. (B) Efficacy/potency of antibodies or combination thereof at blocking myostatin or activin A-induced Smad2/3 response. Single-specificity Abs (CSJ089, blue), (CQI876, orange), or combination thereof (CSJ089 and CQI876, black), or bimagrumab (green, triangle) or CDD861 (green, circle) were tested for their ability to inhibit myostatin (10 ng/mL) or activin A (10 ng/mL)-induced Smad2/3 response in a CAGA-luciferase reporter gene assay in HEK293T/17 cells.

  3. Fig. 4.

    Hypertrophy response as measured via (A) body weight, (B) muscle weight change from sham group, after 4-wk treatment with ActRIIA-specific Ab, ActRIIB-specific Ab, combination thereof, and bimagrumab in SCID mice (n = 12 per group). Mice were untreated, sham group (white), or treated with weekly s.c. injection of isotype control antibody (20 mg/kg/wk) or of anti-ActRIIA Ab (CSJ089, blue, 6 or 20 mg/kg), an anti-ActRIIB Ab (CQI876, orange, 6 or 20 mg/kg), a combination of CSJ089 and CQI876 (black, 6 or 20 mg/kg of each Ab), or bimagrumab (green, 6 or 20 mg/kg). (C) Invasive muscle contractile function determination in gastrocnemius muscle of sham (white) and bimagrumab (green, 6 and 20 mg/kg)-treated groups, average of three stimulations. Hypertrophy response was measured through gastrocnemius and quadriceps muscle weight changes in SCID mice, (D) after 2-wk treatment with the same antibodies as in A, all dosed at 20 mg/kg, with CQI876 being also dosed at 100 mg/kg (orange crosses), (E) after 4-wk treatment with weekly s.c. injection of isotype control antibody (stripes), dual anti-ActRIIA/ActRIIB Ab (CDD861, green pattern, 20 mg/kg), and bimagrumab (green, 20 mg/kg). (F) Activin A (inhba gene) expression changes in gastrocnemius muscle of SCID mice, after 2-wk treatment with isotype control, combination of anti-ActRIIA and anti-ActRIIB Abs (black), or bimagrumab (green) as in D. (G) ELISA data for activin A level in serum from mice of D/F. Data are presented as mean ± SEM analyzed using one-way ANOVA; differences vs. control were considered statistically significant, *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Unpaired t test 20 vs. 6 mg/kg, #P < 0.05.

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