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Development of novel activin-targeted therapeutics.

ABSTRACT: Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-? 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-? 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.

SUBMITTER: Chen JL

PROVIDER: S-EPMC4351455 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Development of novel activin-targeted therapeutics.

Chen Justin L JL Walton Kelly L KL Al-Musawi Sara L SL Kelly Emily K EK Qian Hongwei H La Mylinh M Lu Louis L Lovrecz George G Ziemann Mark M Lazarus Ross R El-Osta Assam A El-Osta Assam A Gregorevic Paul P Harrison Craig A CA

Molecular therapy : the journal of the American Society of Gene Therapy 20141117 3

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 ...[more]

PMID: 25399825

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Development of novel activin-targeted therapeutics.

Publications

Development of novel activin-targeted therapeutics.

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