Re-Engineering Blood-Borne Erythropoietin for Targeted Delivery

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DESCRIPTION (provided by applicant): Erythropoietin (EPO) is a potential new pharmaceutical to treat vascular disease of the brain, including stroke. However, EPO is a large molecule pharmaceutical that does not cross the capillary endothelial wall in brain, which forms the blood-brain barrier (BBB). The present work continues the drug development of a re-engineered form of EPO, wherein the EPO is produced as an IgG fusion protein. The IgG part is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb part of the HIRMAb-EPO fusion protein acts as a molecular Trojan horse to ferry the fused EPO across the BBB via receptor-mediated transport on the endogenous BBB insulin receptor. The pre-SBIR feasibility stage of this research describes the engineering, expression, biochemical validation, and in vivo plasma pharmacokinetics and BBB transport in the Rhesus monkey of the HIRMAb-EPO fusion protein. The proposed phase I SBIR research will develop a manufacturing scheme for production of the HIRMAb-EPO fusion protein. This manufacturing will be designed to produce a therapeutic product that meets FDA specifications with regard to purity, potency, safety, and impurities, so that the manufacturing can be replicated in future GMP production of the fusion protein for clinical trials. The fusion protein produced in phase I will then be used in phase II for in vivo activity and toxicology of the HIRMAb- EPO fusion protein in Rhesus monkeys. The goal of phase II is to produce an efficacy/toxicology data package that can be presented to the FDA for design of future GLP toxicology of this new IgG-EPO fusion protein. PUBLIC HEALTH RELEVANCE: Erythropoietin (EPO) is a tissue-protective agent that could be developed as a new drug for the treatment of vascular disorders of the brain, including stroke. However, EPO cannot penetrate the brain following peripheral administration, because EPO does not cross the endothelial wall in brain, which forms the blood-brain barrier (BBB). This research will develop a new IgG-EPO fusion protein for the treatment of vascular disease of the brain including stroke.