Design of second generation therapeutic recombinant bone morphogenetic proteins

Bone morphogenetic proteins (BMPs) are growth factors belonging to the TGF beta super family. To date, more than twenty human BMPs have been identified. Of these, BMP-2 and BMP-7 (also known as osteogenic protein 1 or OP-1) are the only BMPs used clinically. Recombinant forms of both proteins are currently being implanted surgically to induce spinal fusion and to treat long bone non-union fractures. However, in both indications, large quantities of recombinant proteins are needed to induce new bone formation. This translates to higher costs and potential safety risks. Various genetic engineering approaches are being considered to produce second generation BMPs with improved safety and efficacy profiles. Modified BMPs with one or more of the following characteristics are being considered: (i) improved binding affinity to specific target cell surface BMP receptors, (ii) decreased sensitivity to natural BMP inhibitors, (iii) better immunogenicity profile, and (iv) increased solubility and stability, to cite a few. This review summarizes the progress made so far in this field and gives a perspective on what the next generation BMPs could look like.