A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix

• Published in: Science translational medicine Vol. 11; no. 489
• Main Authors: Seeherman, Howard J, Berasi, Stephen P, Brown, Christopher T, Martinez, Robert X, Juo, Z Sean, Jelinsky, Scott, Cain, Michael J, Grode, Jaclyn, Tumelty, Kathleen E, Bohner, Marc, Grinberg, Orly, Orr, Nadav, Shoseyov, Oded, Eyckmans, Jeroen, Chen, Christopher, Morales, Pablo R, Wilson, Christopher G, Vanderploeg, Eric J, Wozney, John M
• Format: Journal Article
• Language: English
• Published: United States 24.04.2019
• Subjects: Activins - chemistry; Activins - pharmacology; Animals; Bone Morphogenetic Protein 2 - metabolism; Bone Morphogenetic Protein 6 - metabolism; Bone Morphogenetic Protein 6 - pharmacology; Bone Morphogenetic Proteins - metabolism; Bone Morphogenetic Proteins - pharmacology; Cell Differentiation - drug effects; Humans; Osteogenesis - drug effects; Signal Transduction - drug effects
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aar4953

Bone morphogenetic protein (BMP)/carriers approved for orthopedic procedures achieve efficacy superior or equivalent to autograft bone. However, required supraphysiological BMP concentrations have been associated with potential local and systemic adverse events. Suboptimal BMP/receptor binding and rapid BMP release from approved carriers may contribute to these outcomes. To address these issues and improve efficacy, we engineered chimeras with increased receptor binding by substituting BMP-6 and activin A receptor binding domains into BMP-2 and optimized a carrier for chimera retention and tissue ingrowth. BV-265, a BMP-2/BMP-6/activin A chimera, demonstrated increased binding affinity to BMP receptors, including activin-like kinase-2 (ALK2) critical for bone formation in people. BV-265 increased BMP intracellular signaling, osteogenic activity, and expression of bone-related genes in murine and human cells to a greater extent than BMP-2 and was not inhibited by BMP antagonist noggin or gremlin. BV-265 induced larger ectopic bone nodules in rats compared to BMP-2 and was superior to BMP-2, BMP-2/6, and other chimeras in nonhuman primate bone repair models. A composite matrix (CM) containing calcium-deficient hydroxyapatite granules suspended in a macroporous, fenestrated, polymer mesh-reinforced recombinant human type I collagen matrix demonstrated improved BV-265 retention, minimal inflammation, and enhanced handling. BV-265/CM was efficacious in nonhuman primate bone repair models at concentrations ranging from / to / of the BMP-2/absorbable collagen sponge (ACS) concentration approved for clinical use. Initial toxicology studies were negative. These results support evaluations of BV-265/CM as an alternative to BMP-2/ACS in clinical trials for orthopedic conditions requiring augmented healing.