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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。

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

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

DOI：
10.1111/adb.13179
发表时间：
2022-07
期刊：
Addiction biology
影响因子：
3.4
作者：
通讯作者：

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

Cocaine hydrolase blocks cocaine-induced dopamine transporter trafficking to the plasma membrane.