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

基本信息

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
项目类别：
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

项目摘要

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）：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。