Decoy receptors are potential new pharmaceuticals to treat brain diseases, such as brain injury, spinal cord injury, stroke, or neurodegeneration. However, decoy receptor drugs are large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) bind human tumor necrosis factor (TNF)-1, to block cytoxic effects of this inflammatory cytokine. A new approach to the BBB delivery of large molecules such decoy receptors is the molecular Trojan horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the decoy receptor extracellular domain (ECD) is fused to a BBB molecular Trojan horse. The latter is a genetically engineered monoclonal antibody (MAb) that is able to cross the human BBB by receptor-mediated transcytosis on endogenous BBB peptide transport systems. The present work will produce a novel fusion gene encoding the ECD of the human TNF receptor type II and a genetically engineered MAB molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-110. The fusion protein genes will be incorporated in a eukaryotic expression vector followed by permanent transfection of host cells. These phase I SBIR studies will enable production of a permanently transfected host cell line for future manufacturing of AGT-110.
Decoy receptors are potential new pharmaceuticals to treat brain diseases, such as brain injury, spinal cord injury, stroke, or neurodegeneration. However, decoy receptor drugs are large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) bind human tumor necrosis factor-alpha, to block cytoxic effects of this inflammatory cytokine.
| Boado, Ruben J; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang et al. (2010) Selective targeting of a TNFR decoy receptor pharmaceutical to the primate brain as a receptor-specific IgG fusion protein. J Biotechnol 146:84-91 |
