Immunopharmacotherapy for Mitigating Opioid Addiction

减轻阿片类药物成瘾的免疫药物疗法

基本信息

批准号：
9754087
负责人：
Kim Janda
金额：
$ 147.01万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754087
关键词：
6-O-monoacetylmorphine Adjuvant Adverse reactions Affect Affinity Agonist Amides Animals Antibodies Antibody Affinity Attenuated Behavioral Behavioral Model Benchmarking Benzylisoquinolines Biodistribution Biological Assay Blood Carrier Proteins Cerebrospinal Fluid Clinical Clinical Trials Conjugate Vaccines Coupling Development Dose Drug Kinetics Elements Epidemic Extinction (Psychology)Fentanyl Food Formulation Future Goals Grant Haptens Heroin Heroin Dependence Human Hydrocodone Immunize Immunoconjugates Intake Laboratories Lead Macaca mulatta Measures Mediating Metabolism Methadone Methods Modeling Monitor Monkeys Mus Naltrexone Nature Nitrogen Nociception Opiate Addiction Opioid Oxycodone Pharmaceutical Preparations Pharmacological Treatment Phase Pilot Projects Preparation Primates Procedures Protocols documentation Rattus Readiness Relapse Research Safety Saline Schedule Self Administration Series Site Societies Structure Sum Testing Tetanus Toxoid Therapeutic Toxicology Translating Vaccine Design Vaccines Vicodin addiction aluminum sulfate behavior test booster vaccine combat dosage drug addict economic cost effective therapy experience experimental study falls heroin use illicit opioid nonhuman primate novel therapeutics opioid abuse prescription opioid prevent public health relevance scaffold side effect social vaccination strategy vaccine candidate vaccine development vaccine trial

项目摘要

DESCRIPTION (provided by applicant): Within the past decade, opioid drug abuse has dramatically increased to unprecedented levels. The illicit opioid heroin as well as the prescription opioids oxycodone (Oxycotin) and hydrocodone (Vicodin) are the most commonly abused opioids, and they incur a large social and economic cost to society. More than ever before, effective therapies are needed to combat the destructive increase in opioid abuse. Because these drugs are highly addictive, traditional pharmacological treatments such as methadone substitution fall short at preventing relapse. Fortunately, great strides have been made in identifying active vaccination strategies for opioid abuse. Drug-conjugate vaccines can elicit long-lasting, high-affinity antibodies which selectively neutralize administered drug doses without side-effects. The Janda laboratory has developed a heroin conjugate vaccine that can successfully attenuate heroin intake in rat self-administration models. Furthermore, the vaccine shifts the heroin ED50 by greater than 20-fold in mouse antinociceptive testing compared to unvaccinated animals. Lastly, the vaccine remains effective for over 8 months in mice with booster vaccines without producing any observable adverse reactions. Due to the promising nature of this therapeutic approach, additional studies are warranted to uncover the full potential of opioid vaccines. In sum, four aims within two phases will be implemented: UH2 Phase. Aim1. Refine the heroin vaccine formulation to produce optimal efficacy and safety. Aim 2. Adapt heroin vaccine design elements to other opioids. Oxy and hydrocodone share structural features with heroin that beget compatibility with our heroin immunoconjugate scaffold, enabling access to vaccines against these opioids. Aim 3. Non-human primate testing is essential for determining whether the heroin vaccine can be translated to humans. Within this aim we will evaluate the heroin vaccine in a pilot study in rhesus macaques. Heroin schedule controlled responding (SCR) and heroin pharmacokinetics (PK) will be conducted to accurately gauge the efficacy and compatibility of the heroin vaccine in primates. UH3 Phase. Within this phase we will seek to conduct translational opioid vaccine studies. Thus, within Aim 4 we will conduct a series of studies that will be broken into three sub-aims including: 4A. Optimize immunoconjugate preparation protocols, and investigate vaccine toxicology and long-term stability. 4B. Examine the vaccine in self-administration models in rhesus macaques; a heroin versus food choice procedure will employed to determine if the heroin vaccine can attenuate drug intake under a variety of conditions that are representative of what human drug addicts experience. 4C. Perform pilot studies investigating Aim 2 oxy and hydrocodone vaccines in monkey SCR and PK studies. Overall our aims align with the goals of advancing opioid vaccine candidates toward clinical trials, while also establishing new testing paradigms for future addiction therapies.

描述（由适用提供）：在过去的十年中，阿片类药物滥用已大大增加到前所未有的水平。非法的阿片类药物海洛因以及处方阿片类药物氧氧化物（Oxycotin）和氢可酮（vicodin）是最常见的滥用阿片类药物，它们给社会带来了巨大的社会和经济成本。比以往任何时候都需要有效的疗法来打击阿片类药物滥用的破坏性增加。因为这些药物是高度添加剂，所以传统的药物治疗（例如Methodone替代）在防止继电器时缺乏。幸运的是，在确定阿片类药物滥用的主动疫苗策略方面取得了长足的进步。药物偶联的疫苗可以引起持久的高亲和力抗体，这些抗体选择性地中和无副作用的药物剂量。 Janda实验室已经开发了一种海洛因共轭疫苗，该疫苗可以成功地减弱Rat自我管理模型中的海洛因摄入量。此外，与未接种疫苗的动物相比，该疫苗在小鼠抗心动视觉测试中将海洛因ED50移至20倍以上。最后，该疫苗在助推器疫苗的小鼠中保持多8个月以上，而不会产生任何可观察到的不良反应。由于这种治疗方法的承诺性质，需要进行其他研究以揭示全部潜力 Opioid疫苗。总而言之，将在两个阶段内实现四个目标：UH2阶段。 AIM1。优化海洛因疫苗配方，以产生最佳的效率和安全性。目标2。将海洛因疫苗设计元素适应其他opioids。氧气和氢可酮与海洛因共享结构特征，与我们的海洛因免疫偶联脚手架兼容，从而使疫苗能够访问这些卵子。目标3。非人类灵长类动物测试对于确定海洛因疫苗是否可以转化为人类至关重要。在此目标中，我们将在恒河猕猴的试点研究中评估海洛因疫苗。将进行海洛因计划控制的反应（SCR）和海洛因药代动力学（PK），以准确评估海洛因疫苗在私有的效率和兼容性。 UH3阶段。在此阶段，我们将寻求进行翻译阿片类疫苗研究。这是在目标4中，我们将进行一系列研究，这些研究将分为三个亚iam，包括：4a。优化免疫偶联的制备方案，并研究疫苗毒理学和长期稳定性。 4b。在恒河猕猴中的自我管理模型中检查疫苗；将采用海洛因与食物选择程序来确定海洛因疫苗是否可以在多种疾病下衰减药物摄入，这些疾病代表了人类吸毒者的经历。 4C。在猴子SCR和PK研究中进行研究AIM 2氧和氢可酮疫苗的试验研究。总体而言，我们的目标符合将阿片类疫苗候选者推进临床试验的目标，同时还为未来成瘾疗法建立了新的测试范例。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Improvements on a chemically contiguous hapten for a vaccine to address fentanyl-contaminated heroin.

DOI：
10.1016/j.bmc.2021.116225
发表时间：
2021-05
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Hyeri Park;J. Lee;L. M. Eubanks;Beverly Ellis;Bin Zhou;K. Janda
通讯作者：
Hyeri Park;J. Lee;L. M. Eubanks;Beverly Ellis;Bin Zhou;K. Janda

Preclinical Evaluation of Vaccines to Treat Opioid Use Disorders: How Close are We to a Clinically Viable Therapeutic?

DOI：
10.1007/s40263-020-00722-8
发表时间：
2020-04-04
期刊：
CNS DRUGS
影响因子：
6
作者：
Townsend, E. Andrew;Banks, Matthew L.
通讯作者：
Banks, Matthew L.

Lateral Flow Assessment and Unanticipated Toxicity of Kratom.

卡痛的横向流动评估和意外毒性。

DOI：
10.1021/acs.chemrestox.8b00218
发表时间：
2019
期刊：
Chemical research in toxicology
影响因子：
4.1
作者：
Smith,LaurenC;Lin,Lucy;Hwang,CandyS;Zhou,Bin;Kubitz,DianeM;Wang,Huiying;Janda,KimD
通讯作者：
Janda,KimD

Chemical Interventions for the Opioid Crisis: Key Advances and Remaining Challenges.