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Protein Engineering of a Biologic Drug Candidate

候选生物药物的蛋白质工程

基本信息

批准号：
9347908
负责人：
Matthew W Kalnik
金额：
$ 20.08万
依托单位：
ANTIDOTE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347908
关键词：
Abstinence Animals Antibody Response Antibody titer measurement Antidotes Architecture Attenuated Award Behavioral Behavioral Model Biological Biological Assay Blood Circulation Brain Businesses Cessation of life Chantix Chemicals Cigarette Clinical Clinical Research Clinical assessments Cocaine Computer Simulation Coupled Dependency Development Dose Drug Kinetics Engineering Ensure Enzymes Epitopes Evaluation Filtration Future Generations Goals Gold Half-Life Health Care Costs Human In Vitro Intention Investments Kidney Label Lead Masks Medical Molecular Weight Monoclonal Antibodies Mus National Institute of Drug Abuse Nicotine Nicotine Dependence Pegaspargase Pharmaceutical Preparations Pharmacotherapy Phase Placebos Plasma Polyethylene Glycols Privatization Program Development Property Protein Engineering Proteins Pseudomonas putida Radial Rattus Relapse Renal clearance function Roentgen Rays Sales Series Serum Site Small Business Innovation Research Grant Smoker Smoking Structure Substance Use Disorder Surface T-Lymphocyte Epitopes Testing Therapeutic Tobacco use Treatment Efficacy Variant Withdrawal Withholding Treatment addiction cigarette smoking craving drug candidate drug development drug of abuse immunogenic immunogenicity improved in vitro activity in vivo in vivo Model novel novel strategies novel therapeutics patient safety pharmacokinetic model pre-clinical preclinical development prevent smoking cessation standard of care success therapeutic protein

项目摘要

Project Summary/Abstract Cigarette smoking is responsible for nearly one-half million deaths/yr. in the U.S. where direct healthcare costs to treat smoking and smoking-attributable illness exceed $170 billion/year. Only ~20-25% smokers achieve long- term abstinence using standard of care pharmacotherapies leaving the majority still smoking and seeking alternatives. The focus of this project is to further assess the protein properties of a novel nicotine-degrading enzyme and its suitability for use as a smoking cessation treatment. Enzymatic degradation of nicotine is a new approach for treating smoking cessation. Clinical “proof-of-principle” has already been established for in vivo enzymatic degradation of drugs of abuse: two cocaine-degrading enzymes have demonstrated encouraging phase 1/2 results. Engineering of the biological properties of this enzyme is needed to reduce potential immunogenicity and to extend serum half-life, in order to ensure patient safety, sufficient stability and duration of enzymatic action. To this end we will investigate the effect of PEGylation, the chemical conjugation of large non-toxic polyethylene glycol (PEG) moieties to the surface of the enzyme, which provide steric masking of potential epitopes and enhanced hydrodynamic radius of the protein, decreasing its rate of renal clearance. PEGylated lead candidates will be progressed through a series of in vitro enzyme and serum stability assays, as well as in vivo models to assess PEGylation’s effects on immunogenic potential and pharmacokinetic properties. The goal of this project is to reduce the immunogenic potential and increase the serum stability of this novel enzyme though optimization of various PEGylation strategies, while maintaining its potent nicotine-degrading activity. Achieving these goals will provide supportive pre-clinical evidence to conduct further lead optimization efforts and multiple-dose studies in animal behavioral models of addiction (Phase II proposal); thereby progressing this novel nicotine degrading enzyme approach for smoking cessation into pre-clinical development.

项目总结/文摘

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optimization of a nicotine degrading enzyme for potential use in treatment of nicotine addiction.

优化尼古丁降解酶，用于治疗尼古丁成瘾。

DOI：
10.1186/s12896-019-0551-5
发表时间：
2019
期刊：
BMC biotechnology
影响因子：
3.5
作者：
Thisted,Thomas;Biesova,Zuzana;Walmacq,Celine;Stone,Everett;Rodnick-Smith,Max;Ahmed,ShahedaS;Horrigan,StephenK;VanEngelen,Bo;Reed,Charles;Kalnik,MatthewW
通讯作者：
Kalnik,MatthewW