title: An activin A/BMP2 chimera, AB204, displays bone-healing properties superior to those of BMP2.
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.
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences at Songdo Global University Campus, Incheon, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Yoon
authors.forename: Luis
authors.initials: L
authors.lastname: Esquivies
authors.forename: Chihoon
authors.initials: C
authors.lastname: Ahn
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gray
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Witek
authors.initials: W
authors.lastname: Kwiatkowski
authors.forename: Senyon
authors.initials: S
authors.lastname: Choe
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D028341:Activins / Q000737:chemistry / Q000494:pharmacology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000494:pharmacology*; D002113:Calcification, Physiologic / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D017354:Point Mutation / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012886:Skull / Q000187:drug effects / Q000473:pathology; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C000597022:AB204; D055396:Bone Morphogenetic Protein 2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C422405:activin A; C499469:recombinant human bone morphogenetic protein-2; D028341:Activins; D030201:Activin Receptors, Type I; D000469:Alkaline Phosphatase
keywords: AB204; ACTIVIN A/BMP2 CHIMERA; BONE HEALING; CRITICAL SIZE DEFECT; OSTEOGENESIS