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: 8534845
• 负责人: PAUL R PENTEL
• 金额: $ 55.21万
• 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/8534845
• 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 Kinetics; Drug Targeting; 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）：本申请是为了响应 PAS-08-061“阿片成瘾的长效、可持续疗法”而提交的。一种海洛因/吗啡成瘾治疗候选疫苗已经开发出来，初步研究表明该疫苗对大鼠非常有效。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、作用机制和功效，并评估其临床试验的准备情况。尽管有治疗海洛因成瘾的有效药物疗法，但美国只有不到五分之一的阿片类成瘾者选择使用这些疗法。目前可用药物的局限性包括其作用持续时间相对较短、需要严格监管配药、副作用或干扰其他阿片类药物的治疗用途，以及“以一种成瘾换成另一种成瘾”的看法。作用机制与现有药物不同的新药物可以提供额外的治疗选择，并且作用持续时间长可以增加其吸引力和易用性。针对尼古丁和可卡因成瘾的疫苗正在进行临床试验，初步数据表明其疗效。这些疫苗减少或减缓了目标药物在大脑中的分布，从而减弱了它们的作用。我们（Anton 实验室）最近开发了一种高免疫原性的第二代疫苗（与破伤风类毒素结合的吗啡；M-TT），针对海洛因及其每种活性代谢物（6-MAM、吗啡、吗啡-6-gluc）。 M-TT 疫苗接种可引发高浓度的高亲和力抗体，并强力阻断大鼠体内海洛因或吗啡的自我给药。我们提出了一系列综合的（目标 1）免疫学、（目标 2）药代动力学、（目标 3）行为学和（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。由于海洛因药代动力学很复杂，因此将特别关注 M-TT 对海洛因及其每种活性代谢物的影响的表征和定量。这些数据将使我们能够了解抗体与这些部分的结合如何与疫苗功效相关，并将提供可用于评估未来临床试验中免疫充分性的生物标志物。要测试的一般假设是 1) M-TT 免疫原性可以进一步增强，并且即使在海洛因存在下，M-TT 仍保持免疫原性，2) M-TT 通过涉及海洛因及其每种成分的多种互补药代动力学机制发挥作用。活性代谢物，3) M-TT 减弱海洛因和吗啡的自我给药，以及在一系列临床相关阿片剂量范围内阿片引起的大脑奖励阈值的变化，以及 4) M-TT 是安全的，本身不会导致阿片戒断。 公共卫生相关性：全球估计有 1500 万鸦片成瘾者，美国有 120 万海洛因成瘾者。海洛因成瘾与犯罪破坏、社会混乱和严重的健康后果（包括艾滋病毒和丙型肝炎的传播）有关。有多种药物已经可用或治疗海洛因成瘾的药物包括美沙酮、丁丙诺啡和纳曲酮。尽管这些药物都已被证明是有效的，但在美国，只有不到五分之一的成瘾者选择使用它们，因为实际或感知到的缺点导致可接受性较低。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，可能会增加选择并继续接受治疗的成瘾者数量。一种无需每天去诊所就诊的非成瘾性长效药物将特别令人感兴趣。已经开发出用于治疗尼古丁和可卡因成瘾的疫苗，并正在进行早期临床试验。这些疫苗刺激结合药物的抗体的产生，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安全、不会成瘾，并且作用持续时间很长（数月），可以根据需要通过额外的加强剂量来延长作用时间。我们开发了一种海洛因疫苗，可以刺激高水平抗体的产生，并可以阻止海洛因或吗啡对大鼠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下进一步表征该疫苗，以评估其是否适合进入临床试验。这项工作的重要性在于为那些认为目前可用的选择不可接受的阿片类成瘾者或滥用者提供一种额外类型的药物，或者可能在现有药物的基础上使用以增强其疗效。