Efficacy and Safety of an Aerosolized Recombinant Butyrylcholinesterase Pretreatm

描述（由申请人提供）：有机磷（OPs）化合物是强效神经毒性化学物质，广泛应用于医药、工业和农业；最引人注目的是作为杀虫剂。主要由 AChE 抑制引起的神经毒性可能会因急性暴露或精神症状而表现为胆碱能危象和死亡，并且可能会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治疗和特定治疗，例如药物治疗。阿托品和肟通常无法预防发病或死亡。目前，重组 (r) BChE 因其强大的生物清除能力而成为 OP 毒性的主要暴露前治疗候选者，但由于其与 OP 的化学计量为 1:1，因此需要大剂量，并且未经转换后修饰，rBChRE 在肌内、静脉内或皮下给药时表现出较差的循环稳定性。为了克服与肠外递送相关的潜在挑战，PlantVax 利用 BChE 分子的大尺寸，并开发了一种使用雾化 (aer) 形式的 rBChE 的创新递送方法。因此，BChE 以气溶胶形式递送，覆盖肺部气道，形成“肺生物屏障”，可以原位清除传入（吸入）的 OP：防止它们进入体循环并抑制 AChE 红细胞和神经肌肉接头。这种给药途径是高度相关的，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，并且由于 OP 快速进入血液而成为中毒的主要方式。在 I 期可行性研究中，aer-rBChE 被证明可以保护小鼠免受对氧磷 (Px) 毒性，而在 II 期研究中，未经修饰的 aer-rMaBChE 和 aer-rHuBChE 被证明几乎可以完全保护猕猴，即使在预处理后 40 小时发生 aer-Px 暴露时也是如此。由于在这些实验中，aer-rBChE 和 aer-Px 是使用微喷雾器递送的，因此拟议的 IIB 期研究将扩展这些发现，并将使用气雾吸入（雾化器）装置进行功效和早期非 GLP 安全性测试，以直接评估吸入的“肺生物盾”是否能有效预防 OP 毒性以及是否安全。这些研究首次证明 BChE 可以抵御杀虫剂，并且对于人类吸入 OP 的 aer-rHuBChE 暴露前治疗来说是个好兆头，即使重新用于对抗神经毒剂和吸入可卡因毒性。

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.