Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse

 描述（由申请人提供）：可卡因滥用是一个主要的公共卫生问题，直接或间接影响大多数社区和家庭。目前还没有FDA批准的针对可卡因成瘾或过量的药物。可卡因滥用造成的不利的医疗和社会后果使开发一种抗可卡因药物成为高度优先事项。加速可卡因代谢，通过与可卡因主要代谢途径相似的途径产生生物学上无活性的代谢物-血浆中人丁酰胆碱酯酶（BChE）催化的可卡因水解-被认为是可卡因过量和成瘾的最有效治疗策略。由于野生型BChE对天然存在的（-）-可卡因的催化效率（kcat/KM）较低（kcat = 4.1 min和KM = 4.5 µ M），我们最近设计并发现了一组BChE-1突变体，称为可卡因水解酶（CocHs），与野生型BChE相比，对（-）-可卡因的催化效率提高了至少1，000倍。我们发现并获得专利的第一个CoCh的体内和临床数据证明了酶治疗可卡因滥用的前景。除了改进的功效之外，我们最近设计、发现和获得专利的新CocH实体不仅对（-）-可卡因具有显著更高的催化效率，而且还具有更长的生物半衰期。（LAFs或CocH-LAFs），本研究将重点关注进一步优化、生产工艺开发、处方开发，和临床前测试的最有前途的CocH-LAF作为一种新的治疗候选可卡因成瘾治疗。具体目标是：（1）优化不仅对（-）-可卡因具有高催化效率而且具有长生物半衰期的有希望的CocH-LAF;（2）测试有希望的CocH-LAF实体的大规模表达的可行性;（3）开发目标2中选择的最有希望的CocH-LAF的大规模制造方法;（4）在动物模型中，用目的3中生产的CocH-LAF材料表征最有前途的CocH-LAF的详细药理学和毒理学特征。在这项研究中开发的最有前途的CocH-LAF实体预计是高度有效和安全的，作为一种新的外源性酶，适用于治疗人类可卡因成瘾的每月给药方案。这项研究将使最好的CocH-LAF实体为cGMP（现行药品生产质量管理规范）蛋白质生产、研究性新药（IND）使能研究和后续临床试验做好准备。因此，这项研究将推动一种有前途的治疗方法， 候选人更接近FDA批准可卡因成瘾治疗。

 DESCRIPTION (provided by applicant): 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 cocaine addiction 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 a route similar to the principal cocaine-metabolizing pathway-cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma-is recognized as the most efficient treatment strategy for cocaine overdose and addiction. Since the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-cocaine is low (kcat = 4.1 min and KM = 4.5 µM), we have recently designed and discovered a set of BChE -1 mutants, known as cocaine hydrolases (CocHs), with at least 1,000-fold improved catalytic efficiency against (- )-cocaine compared to wild-type BChE. In vivo and clinical data for the first one of our discovered and patented CocHs demonstrate the promise of enzyme therapy for cocaine abuse. In addition to improved efficacy, our recently designed, discovered, and patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine, but also possess much longer biological half-lives Built on our success in rational design and discovery of the highly efficient CocHs and their long-acting forms (LAFs or CocH-LAFs), this investigation will focus on further optimization, manufacturing process development, formulation development, and preclinical testing of the most promising CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine, but also a long biological half-life; (2) to test feasibility of lage- scale expression of promising CocH-LAF entities; (3) to develop large-scale manufacturing processes for the most promising CocH-LAF selected in Aim 2; (4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in animal models with the CocH-LAF material produced in Aim 3. The most promising CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for a monthly dosing schedule for treatment of cocaine addiction in humans. This investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing Practices) protein manufacturing, Investigational New Drug (IND)-enabling studies, and subsequent clinical trials. Thus, this investigation will move a promising therapeutic candidate closer toward FDA approval for cocaine addiction treatment.