title: Acetylcholinesterase-Fc Fusion Protein (AChE-Fc): A Novel Potential Organophosphate Bioscavenger with Extended Plasma Half-Life.
abstract: Acetylcholinesterase (AChE) is the physiological target of organophosphate nerve agent compounds. Currently, the development of a formulation for prophylactic administration of cholinesterases as bioscavengers in established risk situations of exposure to nerve agents is the incentive for many efforts. While cholinesterase bioscavengers were found to be highly effective in conferring protection against nerve agent exposure in animal models, their therapeutic use is complicated by short circulatory residence time. To create a bioscavenger with prolonged plasma half-life, compatible with biotechnological production and purification, a chimeric recombinant molecule of HuAChE coupled to the Fc region of human IgG1 was designed. The novel fusion protein, expressed in cultured cells under optimized conditions, maintains its full enzymatic activity, at levels similar to those of the recombinant AChE enzyme. Thus, this novel fusion product retained its binding affinity toward BW284c5 and propidium, and its bioscavenging reactivity toward the organophosphate-AChE inhibitors sarin and VX. Furthermore, when administered to mice, AChE-Fc exhibits exceptional circulatory residence longevity (MRT of 6000 min), superior to any other known cholinesterase-based recombinant bioscavengers. Owing to its optimized pharmacokinetic performance, high reactivity toward nerve agents, and ease of production, AChE-Fc emerges as a promising next-generation organophosphate bioscavenger.
authors.affiliation: †Departments of Biochemistry and Molecular Genetics and ‡Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Noy-Porat
authors.affiliation: †Departments of Biochemistry and Molecular Genetics and ‡Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Cohen
authors.affiliation: †Departments of Biochemistry and Molecular Genetics and ‡Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Ehrlich
authors.affiliation: †Departments of Biochemistry and Molecular Genetics and ‡Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Epstein
authors.affiliation: †Departments of Biochemistry and Molecular Genetics and ‡Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Alcalay
authors.affiliation: †Departments of Biochemistry and Molecular Genetics and ‡Biotechnology, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Mazor
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006207:Half-Life; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D007141:Immunoglobulin Fc Fragments; D009943:Organophosphorus Compounds; D011993:Recombinant Fusion Proteins; D000110:Acetylcholinesterase