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

Abstract

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 1/10 to 1/30 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.

• Authors: Howard J Seeherman, Stephen P Berasi, Christopher T Brown, Robert X Martinez, Z Sean Juo, Scott Jelinsky, Michael J Cain, Jaclyn Grode, Kathleen E Tumelty, Marc Bohner, Orly Grinberg, Nadav Orr, Oded Shoseyov, Jeroen Eyckmans, Christopher Chen, Pablo R Morales, Christopher G Wilson, Eric J Vanderploeg, John M Wozney
• Journal: Science translational medicine (Sci Transl Med) Vol. 11 Issue 489 (04 24 2019) ISSN: 1946-6242 [Electronic] United States
• PMID: 31019025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Bone Morphogenetic Protein 2
• Bone Morphogenetic Protein 6
• Bone Morphogenetic Proteins
• activin A
• Activins

Topics

• Activins (chemistry, pharmacology)
• Animals
• Bone Morphogenetic Protein 2 (metabolism)
• Bone Morphogenetic Protein 6 (metabolism, pharmacology)
• Bone Morphogenetic Proteins (metabolism, pharmacology)
• Cell Differentiation (drug effects)
• Humans
• Osteogenesis (drug effects)
• Signal Transduction (drug effects)