Catalytic Bioscavengers Human Butyrylcholinesterase and Paraoxonase Sequestered to the Center for CNS

The purpose of this research was 2-fold. The first specific aim was to genetically engineer, express, and validate 2 novel biopharmaceutical fusion proteins, designated AGT-185 and AGT-186. Both proteins are fusion proteins of human paraoxonase PON-1 variants and a genetically engineered monoclonal antibody MAb against the human insulin receptor HIR. The 2 proteins are intended for development as new treatments of the brain in organophosphate chemical nerve gas attacks. The second specific aim is the performance of a plasma pharmacokinetics PK and brain uptake study of AGT-185 in the adult Rhesus monkey. Both specific aims were accomplished. Both AGT-185 and AGT-186 were engineered, expressed, and shown to retain high binding to the HIR and high PON1 enzyme activity, and the proteins were shipped to the Institute for Chemical Defense for testing against nerve gas agents. The PK study in the primate was the first PK study performed for a variant of human PON1 and showed the IgG-PON1 fusion protein is rapidly cleared from blood following intravenous injection, and is rapidly taken up by all organs including brain. The blood-brain barrier permeation constant for AGT-185 was high compared to a blood volume marker and comparable to the permeation constant for the HIRMAb alone without the fused PON1. AGT-185 is the first stable, field-deployable formulation of human PON1. AGT-185 is the first brain penetrating form of human PON1.