Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

描述（由申请人提供）：有机磷化合物是一种强效的神经毒性化学物质，广泛应用于医药、工业和农业；最明显的是杀虫剂。神经毒性主要是乙酰胆碱酯抑制的结果，急性暴露或精神症状可能导致胆碱能危机和死亡，并可能导致慢性暴露后的迟发性神经病变。通常，杀虫剂中毒的治疗包括支持性护理和特异性治疗，如阿托品和肟，但往往不能预防发病或死亡。目前，重组(r) BChE由于其强大的生物清除能力，是OP毒性暴露前治疗的主要候选药物，但由于其与OP的1:1化学计量，需要大剂量，并且没有转移后修饰，rBChRE在给药、静脉注射或皮下注射时表现出较差的循环稳定性。PlantVax利用了BChE分子的大尺寸优势，并开发了一种使用雾化（aer）形式的rBChE的创新递送方法。因此，BChE以气溶胶的形式包裹在肺部的气道上，形成一个“肺生物屏障”，可以就地清除进入（吸入）的OPs：既防止它们进入体循环，又防止它们对乙酰胆碱酯酶的抑制

DESCRIPTION (provided by applicant): Organophosphorus (OPs) compound are potent neurotoxic chemicals that are widely used in medicine, industry and agriculture; most notably as insecticides. The neurotoxicity which is primarily a result of AChE inhibition, may take the form of cholinergic crisis and death as a consequence of acute exposure or psychiatric symptoms and may lead to delayed neuropathy following chronic exposure. Usually, treatment of insecticide poisoning consists of supportive care and specific therapy e.g. atropine and oximes, which often fail to prevent morbidity or death. Currently, recombinant (r) BChE is a leading pre-exposure treatment candidate for OP toxicity due to its potent bioscavenging ability but because of its 1:1 stoichiometry with OP, large doses will be required and without post-transitional modification, rBChRE exhibits poor circulatory stability when administered im, iv or sc. To overcome the potential challenges associated with parenteral delivery, PlantVax has taken advantage of the large size of the BChE molecules and has developed an innovative delivery approach using an aerosolized (aer) form of rBChE. Thus BChE delivered as an aerosol coats the airways of the lungs forming a "pulmomary bioshield" that can scavenge incoming (inhaled) OPs in situ: preventing both their entry into the systemic circulation and their inhibition of AChE on RBC and in neuromuscular junctions. This route of administration is highly relevant since inhalation of vapors and particles is the predominant form of exposure to insecticides and G-type nerve agents and serves as a major means of intoxication because of rapid accesses of the OP to the blood. In Phase I Phase I feasibility studies, aer-rBChE was shown to protect against paraoxon (Px) toxicity in mice while in Phase II, unmodified aer-rMaBChE and aer-rHuBChE were shown to almost totally protect macaques even when aer-Px exposure occurred 40 hr following pretreatment. Since, in these experiments, aer-rBChE and aer-Px were delivered using a microsprayer, the proposed Phase IIB studies will extend these findings and will perform efficacy and early non-GLP safety testing using aerosl inhalation (nebulizer) devices to directly assess whether an inhaled "pulmonary bioshield" is efficacious in preventing OP toxicity and whether it is safe. These studies represent the first time BChE has been shown to protect against an insecticide and bode well for an aer-rHuBChE pre-exposure treatment against inhaled OPs in humans even when repurposed for use against nerve agents and inhaled cocaine toxicity.