Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

描述(申请人提供)：有机磷化合物(OPS)是一种强有力的神经毒性化学物质，广泛用于医药、工业和农业；最主要的是作为杀虫剂。神经毒性主要是AChE抑制的结果，可表现为胆碱能危象和死亡的形式，作为急性暴露或精神症状的结果，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殊治疗，如阿托品和肟类药物，但这往往无法防止发病率或死亡。目前，重组(R)BChE因其强大的生物清除能力而成为OP毒性暴露前治疗的领先候选药物，但由于其与OP的化学计量比为1：1，因此需要大剂量，并且没有过渡后修饰，rBChRE在im、iv或sc时表现出较差的循环稳定性。为了克服与非肠道给药相关的潜在挑战，PlantVax利用了BChE分子的大尺寸，并开发了一种使用雾化(Aer)形式的rBChE的创新给药方法。因此，BChE以气雾剂的形式包裹在肺部的呼吸道上，形成了一种“肺生物盾牌”，可以在原位清除传入(吸入)的OP：阻止它们进入体循环，并抑制AChE 在红细胞和神经肌肉交界处。这种给药途径非常重要，因为吸入蒸气和颗粒是接触杀虫剂和G型神经毒剂的主要形式，而且由于OP快速进入血液，因此是中毒的主要手段。在第一阶段第一阶段可行性研究中，Aer-rBChE被证明可以保护小鼠免受对氧磷(Px)的毒性，而在第二阶段，未经修饰的Aer-rMaBChE和Aer-rHuBChE被证明几乎完全保护猕猴，即使Aer-PX暴露在预处理40小时后也是如此。由于在这些实验中，Aer-rBChE和Aer-PX是使用微喷雾器提供的，拟议的IIB阶段研究将扩大这些发现，并将使用气雾剂(雾化器)设备进行有效性和早期非GLP安全测试，以直接评估吸入的“肺生物盾牌”在预防OP中毒方面是否有效以及是否安全。这些研究是BChE首次被证明可以抵御杀虫剂，并预示着Aer-rHuBChE在人类中针对吸入性有机磷农药的预暴露治疗是个好兆头，即使它被重新用于对抗神经毒剂和吸入性可卡因中毒。

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.