Preclinical studies of a heroin/morphine vaccine for opiate addiction

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，在初步研究中显示对大鼠非常有效。本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，但在美国，只有不到五分之一的鸦片成瘾者选择使用这些药物。现有药物的局限性包括作用时间相对较短、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“以一种成瘾换另一种成瘾”的观念。具有不同于现有药物的作用机制的新药物可以提供额外的治疗选择，而长时间的作用可以增加它们的吸引力和易用性。针对尼古丁和可卡因成瘾的疫苗正在进行临床试验，初步数据显示效果良好。这些疫苗减少或减缓目标药物向大脑的分布，减弱其作用。我们（Anton实验室）最近开发了一种高度免疫原性的第二代疫苗（吗啡结合破伤风类毒素；M-TT），针对海洛因及其每一种活性代谢物（6-MAM，吗啡，吗啡-6-葡聚糖）。接种M-TT疫苗可引起高浓度的高亲和力抗体，并能有效地阻断大鼠对海洛因或吗啡的自我给药。我们建议进行一系列综合研究（目的1）免疫学，（目的2）药代动力学，（目的3）行为学和（目的4）安全性，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，因此将特别注意对M-TT对海洛因及其每一种活性代谢物的影响进行表征和定量。这些数据将使我们了解抗体结合这些片段与疫苗效力的关系，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。需要测试的一般假设是：1)M-TT的免疫原性可以进一步增强，即使在海洛因存在的情况下，M-TT仍保持免疫原性；2)M-TT通过多种互补的药代动力学机制起作用，涉及海洛因及其每一种活性代谢物；3)M-TT减弱海洛因和吗啡的自我给药，以及阿片类药物引起的大脑奖励阈值在临床相关阿片类药物剂量范围内的变化。4) M- TT是安全的，本身不会引起阿片类药物的戒断。

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.