The emergence of biological therapeutics, including cells, peptides, and proteins, has allowed medical science to address a number of unmet clinical needs. Often these agents are extremely potent, specifically activating endogenous signaling cascades to promote well-characterized biochemical and physiological responses. For example, bone morphogenetic protein-2 (BMP-2) was identified almost 20 years ago as a powerful initiator of osteogenic activity, and has since become part of a leading orthopedic product used for spinal fusion procedures (InFuse from Medtronic). Despite annual sales of nearly $1B, BMP-2 has been shown to trigger bone formation at ectopic sites, such as the trachea or esophagus, when not used precisely as directed by its labeling. So-called off-label use of BMP-2 in cervical spinal fusion procedures has led to numerous patient complications, culminating in an FDA-issued warning to physicians advising against off-label use. Two major issues have led to these complications: 1) large doses of BMP-2 are used in these procedures and 2) the drug is added to a collagen sponge for which BMP-2 has only limited passive affinity. These factors are inextricably linked, in that large doses are applied to ensure that a therapeutic dose is retained over time as the protein diffuses away from the delivery site. Due to these safety concerns, BMP is used in approximately 7-10% of the 237,000 cervical fusion procedures performed annually, as opposed to over 60% of lumbar fusion procedures. Enabling the use of BMP-2 in cervical procedures would result in the near doubling of the $1B market for orthobiologics. Using our core technology, Affinergy has developed a number of peptide-based linker motifs, capable of binding to a range of biomaterials with high affinity. Targets for available peptide linkers include bone substitute materials such as collagen and tricalcium phosphate. Here, we propose the development of a novel transgene for the recombinant production of a BMP-2 protein containing a peptide linker. The resulting molecule will both retain BMP-2 activity and exhibit improved affinity for bone grafting materials over unmodified BMP-2. We believe this product will address both currently unmet needs for BMP-2 delivery by ensuring a therapeutic concentration of protein remains bound to the delivery matrix over time, thereby reducing the initial dosage required. This program is also well-timed, with the impending expiration of considerable intellectual property surrounding BMP-2 within the next 2-3 years. The proposed research program will require: 1) the construction of a BMP-2 expression vector containing the peptide-linker domains within the coding sequence;2) the establishment of an expression clone to ensure the reproducible production of the protein and 3) in vitro testing to determine the activity of peptide-tagged BMP-2 as well as its affinity for bone substitute materials. When successful, Phase II work would include large-scale culture optimization, testing the modified BMP-2 in a critical-sized defect animal model, and a range of preclinical testing. Affinergy believes that partners, such as large orthopedics companies, would seize the opportunity to market this product.
The use of osteogenic proteins in spinal fusion has given rise to a $1B market in spine orthobiologics. While the use of these products continues to grow, certain indications are not able to employ these products due to a range of safety concerns. Here, we propose the incorporation of a peptide tag into the widely used orthobiologic, BMP-2. This peptide will contain a high affinity binding site for bone void filler materials currently used as carriers for BMP-2 in spinal fusion. We believe this product will (1) be restricted to the implantation site, and (2) allow for a smaller dose of BMP-2;these improvements mitigate BMP-2 safety issues such as ectopic bone formation. In addition, this product would enable a more wide-spread and safer use of BMP-2 in cervical spinal fusions, an indication in which orthobiologics are used in only 7-10% of cases because of the known increased incidence of adverse events when used in the cervical spine fusions. The use of Affinergy's proprietary peptides therefore provides effective leverage toward the near doubling of the orthobiologics market.