Development of novel activin-targeted therapeutics

Mol Ther. 2015 Mar;23(3):434-44. doi: 10.1038/mt.2014.221. Epub 2014 Nov 17.


Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-β proteins, can increase muscle and bone mass, correct anemia or protect against diet-induced obesity. While exciting, these multiple actions of soluble ActRIIA/IIB limit their therapeutic potential and highlight the need for new reagents that target specific ActRIIA/IIB ligands. Here, we modified the activin A and activin B prodomains, regions required for mature growth factor synthesis, to generate specific activin antagonists. Initially, the prodomains were fused to the Fc region of mouse IgG2A antibody and, subsequently, "fastener" residues (Lys(45), Tyr(96), His(97), and Ala(98); activin A numbering) that confer latency to other TGF-β proteins were incorporated. For the activin A prodomain, these modifications generated a reagent that potently (IC(50) 5 nmol/l) and specifically inhibited activin A signaling in vitro, and activin A-induced muscle wasting in vivo. Interestingly, the modified activin B prodomain inhibited both activin A and B signaling in vitro (IC(50) ~2 nmol/l) and in vivo, suggesting it could serve as a general activin antagonist. Importantly, unlike soluble ActRIIA/IIB, the modified prodomains did not inhibit myostatin or GDF-11 activity. To underscore the therapeutic utility of specifically antagonising activin signaling, we demonstrate that the modified activin prodomains promote significant increases in muscle mass.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / antagonists & inhibitors
  • Activins / genetics
  • Activins / metabolism*
  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Dependovirus / genetics
  • Gene Expression Regulation
  • Genetic Engineering / methods*
  • Genetic Vectors / genetics
  • Growth Differentiation Factors / genetics
  • Growth Differentiation Factors / metabolism
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / metabolism
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Myostatin / genetics
  • Myostatin / metabolism
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Signal Transduction*
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Bone Morphogenetic Proteins
  • GDF11 protein, human
  • Growth Differentiation Factors
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • MSTN protein, human
  • Myostatin
  • Recombinant Fusion Proteins
  • Transforming Growth Factor beta
  • activin A
  • activin B
  • Activins