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.

The effects of a single intravenous injection of novel activin A/BMP-2 (AB204) on toxicity and the respiratory and central nervous systems

“…Activin A/BMP2 (AB204) chimera, AB204 in this study, is known to be more effective in osteoblastic differentiation and in bone healing than rhBMP-2 (Allendorph et al, 2011; Yoon et al, 2014). That is, it can obtain bone healing equal to or better than that of rhBMP-2 even in a significantly lower dose and, consequently, can lead to lower frequency and levels of adverse events.…”

“…Novel activin A/BMP2 (AB2) chimera, AB204 is known to promote osteogenesis and to be more effective in bone healing than rhBMP-2 (Yoon et al, 2014). AB204 even in a 10-fold lower dose was significantly better at bone healing than rhBMP-2 in a mice calvaridal defect model and in a tibial defect model (Yoon et al, 2014).…”

“…AB204 even in a 10-fold lower dose was significantly better at bone healing than rhBMP-2 in a mice calvaridal defect model and in a tibial defect model (Yoon et al, 2014). However, no research has mentioned its toxic effect on the respiratory or CNS.…”

The toxicological evaluation of repetitive 2- and 4-week intravenous injection of Activin A/BMP-2 chimera (AB204) into rats

“…In particular, it was found to be more effective in bone healing in both mice calvaridal and tibial defect models even in a 10-fold lower dose than rhBMP-2 (Yoon et al, 2014). There has been no report on toxicity of AB204.…”

“…It has recently been reported that Activin A/BMP2 chimera, AB204 promotes osteogenesis and is more effective in bone healing than rhBMP-2 (Yoon et al, 2014). In particular, it was found to be more effective in bone healing in both mice calvaridal and tibial defect models even in a 10-fold lower dose than rhBMP-2 (Yoon et al, 2014).…”