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

开发长效可卡因水解酶来治疗可卡因滥用

• 批准号: 9754089
• 负责人: CHANG-GUO ZHAN
• 金额: $ 81.18万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754089
• 关键词: Affect; Albumins; Animal Model; Animals; Antibodies; Binding; Binding Sites; Biological; Biological Assay; Butyrylcholinesterase; Cell Line; Clinical Data; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Communities; Computer Simulation; Data; Development; Dose; Drug Kinetics; Enzymes; Evaluation; FDA approved; Family; Formulation; Half-Life; Human; Hydrolase; Hydrolysis; Immunoglobulins; In Vitro; Injections; Investigation; Investigational Drugs; Legal patent; Medical; Metabolic; Metabolism; Monkeys; Monoclonal Antibodies; Neuraxis; Neurons; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Plasma; Preclinical Testing; Process; Production; Proteins; Public Health; Rattus; Route; Self Administration; Serum Albumin; Technology; Testing; Toxic effect; Treatment Protocols; Vaccines; Work; base; cell bank; clinical development; cocaine overdose; design; drug of abuse; enzyme therapy; expression cloning; immunogenicity; improved; in vivo; innovation; manufacturing process; manufacturing process development; mutant; novel; novel therapeutics; off-patent; public health relevance; small molecule; social; success; therapeutic candidate; treatment strategy

 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.

 描述（由适用提供）：可卡因滥用是直接或间接影响大多数社区和家庭的主要公共卫生问题。仍然没有针对可卡因成瘾或过量的FDA批准的药物。可卡因滥用的灾难性医疗和社会后果使抗可卡因药物的发展成为很高的重点。可卡因代谢可通过类似于人丁乙酸酯酶（BCHE）催化的可卡因 - 可卡因催化的主要可卡因 - 替代途径，从而产生生物学上无活性的代谢物，在plasma-the中催化了可卡因过度和加法的最有效的治疗策略。 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野生型Bche。我们发现和专利的科奇的体内和临床数据证明了酶治疗可卡因滥用的希望。除了提高效率外，我们最近设计，发现和专利的新科奇实体不仅显着提高了针对（ - ）可卡因的催化效率，而且可能更长的生物学半衰期是基于我们在我们在高效的COCH上的理性设计和发现的成功中建立的，这将是高效的COCH及其长期效率的测试（LAFS或COCH-LAFS），并制造出来的精确性，并制造了精确的构造，并且制造了构造的构造，并且构成了构造的构造，并且该构造的范围是构成的，并且构成了构造的范围，并且构成了构造的范围，并且构成了构成的构成，并且构成了构造的范围，并且该构造的范围是构成的，并且可以建立一定的效率，并且可以建立一定的效率。最有前途的科奇 - 拉夫（Coch-Laf）是可卡因添加治疗的新型治疗候选者。具体目的是：（1）优化有前途的Coch-LAF，它不仅具有高催化效率（ - ） - 可卡因，而且还具有长长的生物学半衰期； （2）测试有希望的科奇 - 拉夫实体的lage尺度表达的可行性； （3）为AIM 2选择的最有前途的Coch-Laf开发大规模的制造过程； (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.这项投资将使最佳的Coch-LAF实体为CGMP（当前良好的制造实践）蛋白质制造，研究新药（IND）增强研究以及随后的临床试验做好准备。这项投资将推动有希望的疗法。 候选人更接近FDA批准可卡因成瘾治疗。