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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

基本信息

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
项目类别：
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

项目摘要

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.