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

Yoon, Byung-Hak; Esquivies, Luis; Ahn, Chihoon; Gray, Peter C; Ye, Sang-kyu; Kwiatkowski, Witek; Choe, Senyon

doi:10.1002/jbmr.2238

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

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, v.29 no.9, 2014년, pp.1950 - 1959

Yoon, Byung-Hak (Department of PharmacologySeoul National University College of MedicineSeoulRepublic of Korea) , Esquivies, Luis (Structural Biology LaboratoryThe Salk Institute for Biological StudiesLa JollaCAUSA) , Ahn, Chihoon (Protein Engineering LaboratoryJoint Center for Biosciences at Songdo Global University CampusIncheonRepublic of Korea) , Gray, Peter C (Clayton Foundation Laboratories for Peptide BiologySalk Institute for Biological StudiesLa JollaCAUSA) , Ye, Sang-kyu (Department of PharmacologySeoul National University College of MedicineSeoulRepublic of Korea) , Kwiatkowski, Witek (Structural Biology LaboratoryThe Salk Institute for Biological StudiesLa JollaCAUSA) , Choe, Senyon (Structural Biology LaboratoryThe Salk Institute for Biological StudiesLa JollaCAUSA)

Abstract ▼ AI-Helper

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

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

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