Preclinical studies of a heroin/morphine vaccine for opiate addiction

海洛因/吗啡疫苗治疗阿片成瘾的临床前研究

• 批准号: 8310238
• 负责人: PAUL R PENTEL
• 金额: $ 59.68万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310238
• 关键词: 6-O-monoacetylmorphine; Address; Adverse effects; Agonist; Antibodies; Antibody Affinity; Antibody Formation; Asses; Attention; Attenuated; Behavior; Behavioral; Binding; Biological Markers; Brain; Buprenorphine; Clinic Visits; Clinical; Clinical Trials; Cocaine Dependence; Complement; Complex; Conjugate Vaccines; Crime; Data; Data Set; Dependence; Developing Countries; Dose; Drug Delivery Systems; Drug Kinetics; Endorphins; Future; Generations; Goals; HIV; Health; Hepatitis C; Heroin; Heroin Dependence; Immunization; Immunologics; Immunology; Leucine Enkephalin; Measures; Methadone; Morphine; Morphine Dependence; Mus; Naltrexone; Nicotine Dependence; Opiate Addiction; Opiates; Perception; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Prodrugs; Production; Property; Psychological reinforcement; Public Health; Rattus; Readiness; Regimen; Regulation; Rewards; Role; Safety; Self Administration; Series; Specificity; Supervision; Testing; Tetanus Toxoid; Therapeutic; Therapeutic Uses; Toxicology; Vaccinated; Vaccination; Vaccines; Withdrawal; Work; addiction; clinically relevant; drug distribution; immunogenic; immunogenicity; interest; morphine-6-glucuronide; novel; preclinical study; public health relevance; response; safety study; social; vaccination schedule; vaccine candidate; vaccine efficacy

DESCRIPTION (provided by applicant): This application is submitted in response to PAS-08-061 "Long-acting, sustainable therapies for opiate addiction". A heroin/morphine addiction treatment vaccine candidate has been developed which appears in preliminary studies to be highly effective in rats. The purpose of this proposal is to further characterize the immunogenicity, mechanism of action and efficacy of this vaccine in rats and mice and assess its readiness for clinical trials. Despite the availability of effective pharmacotherapies for treating heroin addiction, fewer than 1 in 5 opiate addicts in the U.S. choose to use these. Among the limitations of currently available medications are their relatively short duration of action, the need for tight regulation of dispensing, side effects or interference with the therapeutic use of other opiates, and the perception of "trading one addiction for another". New medications with mechanisms of action distinct from those already available could provide additional treatment options, and a long duration of action could increase their appeal and ease of use. Vaccines for nicotine and cocaine addictions are in clinical trials and preliminary data suggest efficacy. These vaccines reduce or slow the distribution of the target drug to brain, attenuating their effects. We (Anton lab) recently developed a highly immunogenic second-generation vaccine (morphine conjugated to tetanus toxoid; M-TT) directed against heroin and each of its active metabolites (6-MAM, morphine, morphine-6- gluc). Vaccination with M-TT elicits high concentrations of high affinity antibodies, and robustly blocks heroin or morphine self- administration in rats. We propose an integrated series of (Aim 1) immunologic, (Aim 2) pharmacokinetic, (Aim 3) behavioral and (Aim 4) safety studies to evaluate the clinical potential of this vaccine in rats and mice. Because heroin pharmacokinetics is complex, particular attention will be paid to characterizing and quantitating M-TT effects on heroin and each of its active metabolites. These data will allow us to understand how the binding of each of these moieties by antibody relates to vaccine efficacy, and will provide biomarkers that can be used to asses the adequacy of immunization in future clinical trials. The general hypotheses to be tested are that 1) M-TT immunogenicity can be further enhanced, and that M-TT remains immunogenic even in the presence of heroin, 2) M-TT acts through multiple complementary pharmacokinetic mechanisms involving heroin and each of its active metabolites, 3) M-TT attenuates heroin and morphine self-administration, and opiate-induced changes in brain reward thresholds over a range of clinically relevant opiate doses, and 4) M- TT is safe and does not itself precipitate opiate withdrawal. PUBLIC HEALTH RELEVANCE: There are an estimated 15 million opiate addicts worldwide and 1.2 million heroin addicts in the U.S. Heroin addiction is associated with disruption of crime, social disruption, and severe health consequences including the spread of HIV and hepatitis C. There are several medications already available or the treatment of heroin addiction, including methadone, buprenorphine and naltrexone. Although these have all been shown to be effective, fewer than 1 in 5 addicts in the U.S. choose to use them because of real or perceived drawbacks that result in low acceptability. The vast majority of heroin addicts are therefore not receiving treatment. Alternative medications, which could provide a greater choice of therapeutic options, might increase the number of addicts electing and staying in treatment. A non-addictive and long-acting medication which obviates the need for daily clinic visits would be of particular interest. Vaccines have been developed for the treatment of nicotine and cocaine addiction, and are in early clinical trials. These vaccines stimulate the production of antibodies that bind the drug and reduce the amount of drug reaching the brain, thereby reducing its addictive effects. Advantages of vaccines for addiction treatment are that they are safe, non-addictive, and have a very long duration of action (months) which can be extended as needed with additional booster doses. We have developed a heroin vaccine that stimulates production of high levels of antibodies and that can block some of the key addictive effects of heroin or morphine in rats. The proposed study will further characterize this vaccine, over a wide range of clinically relevant heroin doses, to assess whether it is suitable for advancement to clinical trials. The importance of this work is in providing an additional type of medication for those opiate addicts or abusers who find the currently available options unacceptable, or possibly for use in addition to existing medications to enhance their efficacy.

描述（由申请人提供）：该申请是针对PAS-08-061“长效，可持续的阿片类药物成瘾疗法”提交的。已经开发了海洛因/吗啡成瘾治疗疫苗的候选疫苗，在初步研究中似乎在大鼠中非常有效。该提案的目的是进一步表征该疫苗在大鼠和小鼠中的免疫原性，作用机理和功效，并评估其对临床试验的准备。尽管可用于治疗海洛因成瘾的有效药物疗法，但在美国，五分之一的阿片类瘾君子中只有不到1个选择使用这些。当前可用药物的局限性包括它们相对较短的作用时间，需要严格调节分配，副作用或干扰其他阿片类药物的治疗方法，以及对“将一种成瘾交易为另一种成瘾交易”的看法。具有与已经可用的药物不同的作用机制的新药物可以提供其他治疗选择，并且长时间的行动可以提高其吸引力和易用性。尼古丁和可卡因成瘾的疫苗正在临床试验中，初步数据表明有效。这些疫苗减少或减慢靶药对大脑的分布，从而减轻其作用。我们（Anton Lab）最近开发了一种高度免疫原性的第二代疫苗（吗啡偶联到针对双毒素; M-TT），该疫苗针对海洛因及其每种活性代谢产物（6-MAM，吗啡，吗啡，6- gluc）。使用M-TT的疫苗接种会引起高浓度的高亲和力抗体，并牢固地阻断大鼠海洛因或吗啡自我给药。我们提出了一系列一系列（AIM 1）免疫学，（AIM 2）药代动力学，（AIM 3）行为和（AIM 4）安全研究，以评估大鼠和小鼠中该疫苗的临床潜力。由于海洛因药代动力学很复杂，因此将特别注意表征和定量对海洛因及其活性代谢产物的影响。这些数据将使我们能够通过抗体与疫苗功效有关这些部分的结合如何，并提供可用于评估未来临床试验中免疫足够的生物标志物。 The general hypotheses to be tested are that 1) M-TT immunogenicity can be further enhanced, and that M-TT remains immunogenic even in the presence of heroin, 2) M-TT acts through multiple complementary pharmacokinetic mechanisms involving heroin and each of its active metabolites, 3) M-TT attenuates heroin and morphine self-administration, and opiate-induced changes in brain reward thresholds over a临床上相关的阿片类剂量范围，4）M- TT是安全的，并且本身不会沉淀鸦片戒断。 公共卫生相关性：全球估计有1500万鸦片瘾君子，在美国海洛因成瘾中有120万海洛因瘾君子与犯罪，社会中断和严重的健康后果的破坏有关，包括HIV和HIV和肝炎C的传播。已经有几种药物可用，或者有几种药物治疗，或治疗了海洛因成瘾，包括美甲酮，buprenorphine和Naltrtrtrentrexon和Naltrtrtrtrexon。尽管所有这些都被证明是有效的，但在美国，五分之一的成瘾者中只有不到1个，因为实际或可感知的缺点会导致可接受性较低，因此选择使用它们。因此，绝大多数海洛因成瘾者没有接受治疗。替代药物可以提供更多的治疗选择，可能会增加选举和继续治疗的吸毒者数量。一种非副作用和长效药物，可以尤其令人兴奋，以消除对日常诊所的需求。已经开发出用于治疗尼古丁和可卡因成瘾的疫苗，并且正在早期临床试验中。这些疫苗刺激结合药物并减少到达大脑的药物量的抗体的产生，从而降低其上瘾的作用。成瘾治疗的疫苗的优势是它们是安全的，不添加的，并且行动持续时间很长（月），可以根据需要扩大额外的助推器剂量。我们已经开发了一种海洛因疫苗，可刺激高水平的抗体产生，并且可以阻止大鼠海洛因或吗啡的一些关键上瘾作用。拟议的研究将进一步表征这种疫苗，以广泛的临床相关海洛因剂量，以评估它是否适合于临床试验的发展。这项工作的重要性在于为那些鸦片瘾君子或施虐者提供另一种类型的药物，这些药物发现当前可用的选项不可接受，或者除了现有药物以增强其疗效外，可能还可以使用。