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（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（目标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。要测试的一般假设是1）M-TT免疫原性可以进一步增强，即使在存在海洛因的情况下，M-TT也可以保持免疫原性，2）M-TT通过多种涉及海洛因及其每个互补的药物机制及其每种互补的药物机制起作用。活性代谢产物，3）M-TT减弱了海洛因和吗啡自我给药，并且在一系列临床相关的阿片剂量上，鸦片诱导的脑奖励阈值变化，而4）M- TT是安全的，并且本身并不降低阿片类药片的戒断。