Immunopharmacotherapy for Mitigating Opioid Addiction

 描述（由申请人提供）：在过去十年中，阿片类药物滥用急剧增加到前所未有的水平。非法类阿片海洛因以及处方类阿片羟考酮（Oxycotin）和氢可酮（Vicodin）是最常滥用的类阿片，它们给社会带来了巨大的社会和经济成本。比以往任何时候都更需要有效的治疗方法来对抗阿片类药物滥用的破坏性增加。由于这些药物具有高度成瘾性，传统的药物治疗，如美沙酮替代品，在预防复发方面存在不足。幸运的是，在确定阿片类药物滥用的积极疫苗接种策略方面取得了很大进展。药物缀合物疫苗可以引发持久的、高亲和力的抗体，其选择性地中和施用的药物剂量而没有副作用。Janda实验室开发了一种海洛因结合疫苗，可以成功地减少大鼠自我给药模型中的海洛因摄入量。此外，与未接种疫苗的动物相比，在小鼠抗伤害性试验中，疫苗使海洛因ED 50改变了20倍以上。最后，该疫苗在接种加强疫苗的小鼠中保持有效超过8个月，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前景，需要进行更多的研究来揭示其全部潜力。 阿片类疫苗总之，将在两个阶段内实现四个目标：UH 2阶段。目标1.改进海洛因疫苗的配方，以产生最佳的功效和安全性。目标2.使海洛因疫苗设计要素适应其他阿片类药物。氧和氢可酮与海洛因具有相同的结构特征，这些结构特征与我们的海洛因免疫缀合物支架相容，从而能够获得针对这些阿片类药物的疫苗。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。在此目标下，我们将在恒河猴的试点研究中评估海洛因疫苗。将进行海洛因时间表控制反应（SCR）和海洛因药代动力学（PK），以准确评估海洛因疫苗在灵长类动物中的有效性和相容性。UH 3阶段。在这一阶段，我们将寻求进行翻译阿片类疫苗研究。因此，在目标4中，我们将进行一系列研究，这些研究将分为三个子目标，包括：4A。优化免疫偶联物制备方案，并研究疫苗毒理学和长期稳定性。4B.在恒河猴自我给药模型中检查疫苗;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代表人类药物成瘾者经历的各种条件下减少药物摄入。4C.在猴SCR和PK研究中进行初步研究，调查Aim 2氧和氢可酮疫苗。总的来说，我们的目标与推进阿片类药物候选疫苗临床试验的目标一致，同时也为未来的成瘾治疗建立了新的测试范式。

 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.