Development of novel activin-targeted therapeutics

Justin Chen, Kelly Walton, Sara Al-Musawi, Emily Mae Kelly, Hongwei Qian, Mylinh La, Louis Lu, George O Lovrecz, Mark Ziemann, Ross Lazarus, Assam El-Osta, Paul Gregorevic, Craig Anthony Harrison

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-beta 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 (Lys45, Tyr96, His97, and Ala98; activin A numbering) that confer latency to other TGF-beta proteins were incorporated. For the activin A prodomain, these modifications generated a reagent that potently (IC50 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 (IC50 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.
Original languageEnglish
Pages (from-to)434-444
Number of pages11
JournalMolecular Therapy
Volume23
Issue number3
DOIs
Publication statusPublished - 2015

Cite this

Chen, Justin ; Walton, Kelly ; Al-Musawi, Sara ; Kelly, Emily Mae ; Qian, Hongwei ; La, Mylinh ; Lu, Louis ; Lovrecz, George O ; Ziemann, Mark ; Lazarus, Ross ; El-Osta, Assam ; Gregorevic, Paul ; Harrison, Craig Anthony. / Development of novel activin-targeted therapeutics. In: Molecular Therapy. 2015 ; Vol. 23, No. 3. pp. 434-444.
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abstract = "Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-beta 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 (Lys45, Tyr96, His97, and Ala98; activin A numbering) that confer latency to other TGF-beta proteins were incorporated. For the activin A prodomain, these modifications generated a reagent that potently (IC50 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 (IC50 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.",
author = "Justin Chen and Kelly Walton and Sara Al-Musawi and Kelly, {Emily Mae} and Hongwei Qian and Mylinh La and Louis Lu and Lovrecz, {George O} and Mark Ziemann and Ross Lazarus and Assam El-Osta and Paul Gregorevic and Harrison, {Craig Anthony}",
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Chen, J, Walton, K, Al-Musawi, S, Kelly, EM, Qian, H, La, M, Lu, L, Lovrecz, GO, Ziemann, M, Lazarus, R, El-Osta, A, Gregorevic, P & Harrison, CA 2015, 'Development of novel activin-targeted therapeutics' Molecular Therapy, vol. 23, no. 3, pp. 434-444. https://doi.org/10.1038/mt.2014.221

Development of novel activin-targeted therapeutics. / Chen, Justin; Walton, Kelly; Al-Musawi, Sara; Kelly, Emily Mae; Qian, Hongwei; La, Mylinh; Lu, Louis; Lovrecz, George O; Ziemann, Mark; Lazarus, Ross; El-Osta, Assam; Gregorevic, Paul; Harrison, Craig Anthony.

In: Molecular Therapy, Vol. 23, No. 3, 2015, p. 434-444.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Chen, Justin

AU - Walton, Kelly

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AU - Kelly, Emily Mae

AU - Qian, Hongwei

AU - La, Mylinh

AU - Lu, Louis

AU - Lovrecz, George O

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UR - http://www.nature.com/mt/journal/vaop/ncurrent/pdf/mt2014221a.pdf

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DO - 10.1038/mt.2014.221

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Chen J, Walton K, Al-Musawi S, Kelly EM, Qian H, La M et al. Development of novel activin-targeted therapeutics. Molecular Therapy. 2015;23(3):434-444. https://doi.org/10.1038/mt.2014.221