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: 8142886
• 负责人: PAUL R PENTEL
• 金额: $ 59.35万
• 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/8142886
• 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）：本申请是根据PAS-08 - 061 "阿片类药物成瘾的长效、可持续疗法"提交的。一种海洛因/吗啡成瘾治疗候选疫苗已经开发出来，初步研究表明它在大鼠中非常有效。本提案旨在进一步表征该疫苗在大鼠和小鼠中的免疫原性、作用机制和有效性，并评估其临床试验准备情况。尽管有有效的药物治疗海洛因成瘾，但在美国，只有不到五分之一的阿片类药物成瘾者选择使用这些药物。目前可用药物的局限性包括其作用持续时间相对较短、需要严格管制配药、副作用或干扰其他阿片类药物的治疗用途，以及"以一种成瘾性换取另一种成瘾性"的看法。新药物的作用机制与现有药物不同，可以提供额外的治疗选择，长期的作用可以增加其吸引力和易用性。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。这些疫苗减少或减缓了靶向药物在大脑中的分布，减弱了它们的作用。我们（安东实验室）最近开发了一种高免疫原性的第二代疫苗（吗啡结合破伤风类毒素; M-TT），针对海洛因及其活性代谢产物（6-MAM，吗啡，吗啡-6-gluc）。用M-TT疫苗接种激发高浓度的高亲和力抗体，并且在大鼠中稳健地阻断海洛因或吗啡自我施用。我们提出了一个综合系列的（目标1）免疫学，（目标2）药代动力学，（目标3）行为和（目标4）安全性研究，以评估该疫苗在大鼠和小鼠中的临床潜力。由于海洛因的药代动力学是复杂的，将特别注意表征和定量M-TT对海洛因及其活性代谢物的影响。这些数据将使我们能够理解抗体与这些部分中的每一个的结合如何与疫苗效力相关，并将提供可用于在未来临床试验中评估免疫充分性的生物标志物。待检验的一般假设是：1）M-TT免疫原性可进一步增强，并且M-TT即使在海洛因存在下也保持免疫原性，2）M-TT通过涉及海洛因及其每种活性代谢物的多种互补药代动力学机制起作用，3）M-TT减弱海洛因和吗啡自我给药，和在临床相关的阿片剂量范围内阿片诱导的脑奖赏阈值的变化，和4）M-TT是安全的，并且本身不促使阿片戒断。 公共卫生相关性：据估计，全世界有1500万阿片类药物成瘾者，美国有120万海洛因成瘾者。海洛因成瘾与犯罪中断、社会破坏和严重的健康后果有关，包括艾滋病毒和丙型肝炎的传播。有几种药物已经可用或治疗海洛因成瘾，包括美沙酮，丁丙诺啡和纳洛酮。尽管这些药物都被证明是有效的，但在美国，只有不到五分之一的成瘾者选择使用它们，因为它们存在真实的或可感知的缺点，导致可接受性低。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，可能会增加选择和坚持治疗的成瘾者数量。特别令人感兴趣的是一种不成瘾和长效的药物，它消除了每天门诊的需要。已经开发出用于治疗尼古丁和可卡因成瘾的疫苗，并处于早期临床试验阶段。这些疫苗刺激抗体的产生，这些抗体结合药物并减少到达大脑的药物量，从而减少其成瘾作用。用于成瘾治疗的疫苗的优点是它们是安全的，非成瘾性的，并且具有非常长的作用持续时间（数月），可以根据需要通过额外的加强剂量来延长。我们已经开发出一种海洛因疫苗，它可以刺激产生高水平的抗体，并可以阻断海洛因或吗啡在大鼠中的一些关键成瘾作用。拟议的研究将在广泛的临床相关海洛因剂量范围内进一步表征该疫苗，以评估其是否适合推进临床试验。这项工作的重要性在于为那些认为现有选择不可接受的阿片类药物成瘾者或滥用者提供另一种药物，或可能在现有药物之外使用，以提高其疗效。