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

开发治疗可卡因滥用的长效酶疗法

基本信息

批准号：
10405101
负责人：
CHANG-GUO ZHAN
金额：
$ 472.12万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405101
关键词：
Affect Animal Model Antibodies Behavioral Binding Binding Sites Biological Biological Assay Butyrylcholinesterase Cell Line Chinese Hamster Ovary Cell Clinical Data Clinical Research Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Communities Development Dose Double-Blind Method Drug Kinetics Enzymes FDA approved Family Formulation Future Half-Life Human Hydrolase Hydrolysis Immunoglobulins Infusion procedures Intake Investigation Investigational Drugs Legal patent Medical Metabolic Metabolism Monoclonal Antibodies Neuraxis Neurons Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phase II/III Trial Physiological Placebo Control Plasma Process Production Proteins Public Health Randomized Rattus Regimen Safety Schedule Self Administration Serum Albumin Time Vaccines Work base cell bank clinical efficacy cocaine overdose cocaine self-administration design dosage drug of abuse efficacy testing enzyme therapy first-in-human improved in vivo large scale production mutant novel novel therapeutics placebo controlled study placebo group pre-clinical preclinical safety rational design safety testing small molecule social therapeutic candidate treatment group treatment strategy

项目摘要

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.

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。对于可卡因依赖或过量治疗的FDA批准药物仍然没有特定的药物。可卡因滥用的灾难性医疗和社会后果已成为反卡通的发展用药优先。加速可卡因代谢，通过生物学上的非活性代谢物通过最有利的可卡因量代谢途径 - 人类催化的加能力水解血浆中的丁酰胆碱酯酶（BCHE）被认为是可卡因最有效的治疗策略用药过量和依赖性。由于野生型BCHE对天然发生的催化效率（ - ） - 可卡因很低，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1,000倍。我们先前发现的Cochs的临床前和临床数据已经证明了这一承诺酶治疗方法的治疗可卡因依赖性。我们最近设计的发现了新的Coch实体，称为Coch5-FC（M6），它不仅进一步改善了催化性对可卡因的效率，但也是周到的生物半衰期。已经证明单剂量的COCH5-FC（M6）可用于完全阻断可卡因诱导的生理，行为，并在动物模型中长时间增强效果。另外，稳定的CHO细胞系能够已经开发了有效表达COCH5-FC（M6）和相应的主细胞库（MCB）以及建立强大的上游和下游蛋白质生产过程，准备大规模COCH5-FC（M6）蛋白质产生。建立在我们理性设计的令人鼓舞的进步之上发现和开发高效的长效Coch实体Coch5-Fc（M6），拟议的新项目的重点是进一步开发Coch5-FC（M6）作为可卡因的新型治疗候选者依赖性处理，包括使用使用该材料大规模生产COCH5-FC（M6）蛋白质开发了MCB并建立了强大的上游和下游蛋白质生产过程，研究新药（IND）增强研究和首次人类（FIH）临床试验。获得的临床试验有关人类COCH5-FC（M6）的安全性，药代动力学和实体药效学的数据将使我们能够合理设计最合适的剂量方案，以供将来进一步的临床试验以确定 COCH5-FC（M6）在可卡因依赖性患者中的临床效率。那，这项调查将移动高度期望的酶疗法的有前途的候选人更接近FDA批准可卡因依赖治疗。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-lasting blocking of interoceptive effects of cocaine by a highly efficient cocaine hydrolase in rats.

DOI：
10.1038/s41598-023-50678-0
发表时间：
2024-01-09
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Kinetic characterization of an efficient cocaine hydrolase against toxic metabolites of cocaine.

针对可卡因有毒代谢物的有效可卡因水解酶的动力学表征。

DOI：
10.1039/d3ob00374d
发表时间：
2023
期刊：
Organic & biomolecular chemistry
影响因子：
3.2
作者：
Zhan,Max;Hou,Shurong;Shang,Linyue;Chen,Xiabin;Zhan,Chang-Guo;Zheng,Fang
通讯作者：
Zheng,Fang

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism.

开发高效长效可卡因水解酶实体以加速可卡因代谢。

DOI：
10.1021/acs.bioconjchem.2c00210
发表时间：
2022
期刊：
Bioconjugate chemistry
影响因子：
4.7
作者：
Zheng,Fang;Jin,Zhenyu;Deng,Jing;Chen,Xiabin;Zheng,Xirong;Wang,Guojun;Kim,Kyungbo;Shang,Linyue;Zhou,Ziyuan;Zhan,Chang-Guo
通讯作者：
Zhan,Chang-Guo

Recovery of dopaminergic system after cocaine exposure and impact of a long-acting cocaine hydrolase.