Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse

可卡因滥用是直接或间接影响大多数社区和 家人。目前还没有FDA批准的针对可卡因依赖或过量治疗的药物。 可卡因滥用造成的灾难性的医学和社会后果使一种反可卡因的发展 药物治疗是高度优先的。加速可卡因代谢，通过以下途径产生生物活性代谢产物 最有利的可卡因代谢途径--人类催化的可卡因水解酶 血浆中丁酰胆碱酯酶(BChE)被认为是治疗可卡因最有效的策略 吸毒过量和依赖。由于野生型BChE对自然产生的(-)-的催化效率- 可卡因含量低，我们设计并发现了一组BChE突变体，称为可卡因水解酶 (COCHS)，与野生型BChE相比，对(-)-可卡因的催化效率至少提高了1000倍。 我们之前发现的第一个CocH的临床前和临床数据已经证明了这一前景 探讨了酶疗法治疗可卡因依赖的方法。我们的最新设计和 发现了新的Coch实体，记为CocH5-FC(M6)，它不仅进一步改进了催化 对可卡因的效率，但也相当长的生物半衰期。事实证明， 单剂量的CocH5-FC(M6)可用于完全阻断可卡因诱导的生理，行为， 在动物模型上有较长时间的增强作用。此外，稳定的CHO细胞系能够 已开发出高效表达CocH5-Fc(M6)和相应的主细胞库(MCB) 随着强大的上下游蛋白质生产工艺的建立，为 大规模生产CocH5-Fc(M6)蛋白。建立在我们合理设计令人鼓舞的进步的基础上， 发现和开发高效、长效的COCH实体CocH5-FC(M6)，拟议的新 该项目的重点是进一步开发CocH5-FC(M6)作为可卡因的新候选治疗药物 依赖治疗，包括大规模生产CocH5-Fc(M6)蛋白质材料 开发了MCB并建立了强大的上下游蛋白质生产工艺， 研究性新药(IND)使能研究，以及首例人类(FIH)临床试验。获得的临床应用 有关CocH5-FC(M6)在人体内的安全性、药代动力学和体外药效学的数据将 使我们能够合理地设计最合适的剂量方案，为未来的进一步临床试验确定 CocH5-FC(M6)治疗可卡因依赖的临床疗效观察因此，这项调查将使 极有希望的酶疗法候选药物更接近FDA批准的可卡因 依赖治疗。

Cocaine abuse is a major public health problem that directly or indirectly affects most communities and families. There is still no FDA-approved medication specific for treatment of cocaine dependence or overdose. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via the most favorable cocaine-metabolizing pathway—cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma—is recognized as the most efficient treatment strategy for cocaine overdose and dependence. Since the catalytic efficiency of wild-type BChE against the naturally occurring (-)- cocaine is low, we have designed and discovered a set of BChE mutants, known as cocaine hydrolases (CocHs), with at least 1,000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE. Preclinical and clinical data for the first one of our previously discovered CocHs has demonstrated the promise of enzyme therapy approach to the treatment of cocaine dependence. Our more recently designed and discovered novel CocH entity, denoted as CocH5-Fc(M6), which has not only further improved catalytic efficiency against cocaine, but also a considerably prolonged biological half-life. It has been demonstrated that a single dose of CocH5-Fc(M6) can be used to completely block cocaine-induced physiological, behavioral, and reinforcing effects for a long period of time in animal models. In addition, a stable CHO cell line capable of efficiently expressing CocH5-Fc(M6) and the corresponding master cell bank (MCB) have been developed along with establishment of the robust upstream and downstream protein production processes, ready for large-scale CocH5-Fc(M6) protein production. Built on the encouraging progress of our rational design, discovery, and development of the highly efficient, long-acting CocH entity CocH5-Fc(M6), the proposed new project is focused on further development of CocH5-Fc(M6) as a novel therapeutic candidate for cocaine dependence treatment, including large-scale production of the CocH5-Fc(M6) protein material using the developed MCB and established robust upstream and downstream protein production processes, investigational new drug (IND)-enabling studies, and first-in-human (FIH) clinical trials. The obtained clinical data about the safety, pharmacokinetics, and ex vivo pharmacodynamics of CocH5-Fc(M6) in humans will enable us to rationally design the most appropriate dosage regimen for future further clinical trials to determine the clinical efficacy of CocH5-Fc(M6) in cocaine-dependent patients. Thus, this investigation will move a promising candidate of the highly desired enzyme therapy closer toward FDA approval for cocaine dependence treatment.