An Activin A/BMP2 Chimera, AB204, Displays Bone-Healing Properties Superior to Those of BMP2

Authors

  • Byung-Hak Yoon,

    1. Protein Engineering Laboratory, Joint Center for Biosciences at Songdo Global University Campus, Incheon, Republic of Korea
    2. Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
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  • Luis Esquivies,

    1. Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
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  • Chihoon Ahn,

    1. Protein Engineering Laboratory, Joint Center for Biosciences at Songdo Global University Campus, Incheon, Republic of Korea
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  • Peter C Gray,

    1. Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA, USA
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  • Sang-kyu Ye,

    1. Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
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  • Witek Kwiatkowski,

    1. Protein Engineering Laboratory, Joint Center for Biosciences at Songdo Global University Campus, Incheon, Republic of Korea
    2. Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
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  • Senyon Choe

    Corresponding author
    1. Protein Engineering Laboratory, Joint Center for Biosciences at Songdo Global University Campus, Incheon, Republic of Korea
    2. Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
    • Address correspondence to: Senyon Choe, PhD, Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA, E-mail: choe@sbl.salk.edu

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ABSTRACT

Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10-fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2-like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100-fold greater than that of BMP2. The structure also led to our identification of a single Activin A-derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non-union bone fractures. © 2014 American Society for Bone and Mineral Research.

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