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: 8721384
• 负责人: PAUL R PENTEL
• 金额: $ 56.93万
• 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/8721384
• 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.

描述(申请人提供)：本申请是根据PAS-08-061“阿片成瘾的长效、可持续疗法”提交的。一种治疗海洛因/吗啡成瘾的候选疫苗已经开发出来，在初步研究中似乎对大鼠非常有效。这项建议的目的是进一步表征这种疫苗在大鼠和小鼠身上的免疫原性、作用机制和有效性，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，但在美国，只有不到五分之一的阿片成瘾者选择使用这些药物。目前可用的药物的局限性包括作用时间相对较短，需要对配药进行严格监管，副作用或干扰其他阿片类药物的治疗使用，以及“用一种上瘾换取另一种上瘾”的看法。作用机制与现有药物不同的新药可以提供额外的治疗选择，长期的作用可能会增加它们的吸引力和易用性。尼古丁和可卡因成瘾疫苗正在进行临床试验，初步数据显示效果良好。这些疫苗减少或减缓了靶向药物在大脑中的分布，减弱了它们的效果。我们(Anton Lab)最近开发了一种针对海洛因及其活性代谢产物(6-MAM、吗啡、吗啡-6-Gluc)的高免疫原性第二代疫苗(吗啡与破伤风类毒素结合；M-TT)。接种M-TT疫苗可诱导高浓度的高亲和力抗体，并有力地阻断海洛因或吗啡的自我给药。我们提出了一系列完整的(AIM 1)免疫学、(AIM 2)药代动力学、(AIM 3)行为学和(AIM 4)安全性研究，以评估该疫苗在大鼠和小鼠中的临床潜力。由于海洛因的药动学是复杂的，将特别注意表征和量化M-TT对海洛因及其每种活性代谢物的影响。这些数据将使我们了解抗体与这些部分的结合如何与疫苗效力相关，并将提供生物标志物，可用于在未来的临床试验中评估免疫的充分性。要检验的一般假设是：1)M-TT的免疫原性可以进一步增强，并且M-TT即使在海洛因存在的情况下也保持免疫原性，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减轻海洛因和吗啡的自我给药，并在临床相关的阿片类药物剂量范围内引起阿片类药物引起的大脑奖赏阈值的变化，4)M-TT是安全的，本身不会促使阿片类药物戒断。