An Activin A/BMP2 Chimera, AB204, Displays Bone‐Healing Properties Superior to Those of BMP2. (September 2014)

• Record Type: Journal Article
• Authors: Yoon, Byung‐Hak; Esquivies, Luis; Ahn, Chihoon; Gray, Peter C; Ye, Sang‐kyu; Kwiatkowski, Witek; Choe, Senyon
• Is Part Of: Journal of bone and mineral research. Volume 29:Number 9(2014:Sep.)
• Page Start: 1950
• Page End: 1959
• Publication Date: 2014-09
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2238
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2238-sec-0001" sec-type="section"> <p>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.</p> </sec> </abstract>