Pre-clinical Development of a Vaccine for the Treatment of Heroin Addiction

治疗海洛因成瘾疫苗的临床前开发

• 批准号: 8981051
• 负责人: Gary Fujii
• 金额: $ 22.5万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981051
• 关键词: Accounting; Achievement; Address; Adjuvant; Affinity; Agreement; Analgesics; Animal Model; Antibodies; Antibody Response; Binding; Blood; Carrier Proteins; Cause of Death; Cessation of life; Chemistry; Clinic; Clinical; Clinical Protocols; Clinical Research; Conjugate Vaccines; Contractor; Crime; Cyclic GMP; Data; Death Rate; Dependence; Development; Disease; Dose; Drug Formulations; Drug abuse; Ensure; Epidemic; Feedback; Guidelines; Haptens; Heroin; Heroin Abuse; Heroin Dependence; Heroin Users; Hydrocodone; Immune response; Immunotherapy; Keyhole Limpet Hemocyanin; Knowledge; Laboratories; Lead; Licensing; Link; Literature; Measures; Mediation; Medical; Methadone; Modeling; Mus; Naloxone; Nature; Opiate Addiction; Opioid; Oryctolagus cuniculus; Overdose; Oxycodone; Pain Measurement; Pamphlets; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Process; Production; Property; Public Health; Qualifying; Rattus; Relapse; Research Design; Research Institute; Research Personnel; Rodent; Safety; Sampling; Schedule; Self Administration; Self-Administered; Series; Small Business Technology Transfer Research; Societies; Solutions; Specificity; Testing; Tetanus Toxoid; Toxic effect; Toxicology; Training; United States; Vaccination; Vaccines; Vicodin; Work; addiction; aluminum sulfate; analytical method; animal efficacy; combat; cost; design; drug of abuse; falls; heroin overdose; immunogenicity; improved; manufacturing process; meetings; novel; overdose death; potency testing; pre-clinical; preference; prescription opioid abuse; prevent; public health relevance; receptor; research clinical testing; response; statistics; vaccination strategy; vaccine candidate; vaccine development

 DESCRIPTION (provided by applicant): Heroin and related opioids are highly addictive drugs known for their analgesic properties. Since 2006, the number of heroin users in the United States has skyrocketed, reaching epidemic levels. Abuse of prescription opioid pain relievers oxycodone (Oxycotin) and hydrocodone (Vicodin) which are known gateway drugs to heroin has also increased dramatically. Because opioids present a significant abuse liability, new therapies are needed to combat the rapid rise in opioid dependence, especially since traditional pharmacological treatments such as methadone fall short at preventing relapse. Immunotherapy, in the form of a conjugate vaccine, is a promising new therapy for opioid addiction. In previous work, we demonstrated that a heroin-keyhole limpet hemocyanin (KLH) conjugate formulated with alum adjuvant generated a high titer antibody response against heroin in mice and rats. Moreover, in rodents we showed that anti-opioid antibodies elicited by this vaccine bound heroin and its metabolites in the blood with high specificity and affinity, thus safely mitigating the psychoactive effects of heroin without binding to endogenous receptors. As a result, our heroin vaccine was able to block heroin self-administration of dependent rats in many addiction models including conditioned-place preference, reinstatement and reacquisition. Dose-response heroin analgesia testing in mice revealed that this vaccine was able to shift EC50 of heroin 5-fold, however, we have since improved our vaccine to produce a massive >20-fold heroin EC50 shift. Furthermore, we tested the long-term performance of our optimized vaccine showing that it retains heroin immunoantagonism up to 2.5 months post-vaccination. Our studies have indicated that this heroin vaccine is safe, effective and long-lasting. The highly promising nature of our vaccine for treating heroin addiction warrants further preclinical development. In this STTR Fast Track application, we propose to select a lead heroin vaccine candidate for advancement to clinical evaluation and conduct the IND- enabling activities necessary to initiate clinical studies.

 描述（由申请人提供）：海洛因和相关阿片类药物是高度成瘾性药物，以其镇痛特性而闻名。自2006年以来，美国的海洛因使用者人数激增，达到了流行病的水平。滥用处方阿片类止痛药羟考酮（Oxycotin）和氢可酮（Vicodin）也急剧增加，这两种药物是已知的海洛因门户药物。由于阿片类药物存在严重的滥用倾向，因此需要新的疗法来对抗阿片类药物依赖性的迅速上升，特别是因为美沙酮等传统药物治疗无法预防复发。结合疫苗形式的免疫治疗是阿片类药物成瘾的一种有前途的新疗法。在以前的工作中，我们证明了海洛因钥孔血蓝蛋白（KLH）结合物与明矾佐剂配制产生高滴度的抗体反应，对海洛因在小鼠和大鼠。此外，在啮齿动物中，我们发现这种疫苗引起的抗阿片抗体以高特异性和亲和力结合血液中的海洛因及其代谢物， 安全地减轻海洛因的精神作用而不与内源性受体结合。结果表明，我们的海洛因疫苗能够阻断海洛因依赖大鼠在多种成瘾模型中的自我给药，包括条件性位置偏爱、复吸和再获取。在小鼠中的剂量反应海洛因镇痛测试显示，该疫苗能够使海洛因的EC50改变5倍，然而，我们已经改进了我们的疫苗以产生>20倍的海洛因EC50改变。此外，我们测试了我们优化的疫苗的长期性能，表明它在接种后2.5个月内保留了海洛因免疫拮抗作用。我们的研究表明，这种海洛因疫苗是安全、有效和持久的。高度 我们的疫苗用于治疗海洛因成瘾的有希望的性质需要进一步的临床前开发。在本STTR快速通道申请中，我们建议选择一种海洛因铅候选疫苗进行临床评价，并开展启动临床研究所需的IND启动活动。