Disrupted Adenovirus Serotype 5-based Anti-cocaine Vaccine

基于破坏腺病毒血清型 5 的抗可卡因疫苗

• 批准号: 8325250
• 负责人: RONALD G CRYSTAL
• 金额: $ 286.87万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325250
• 关键词: Adenoviruses; Adverse event; Affinity; Animals; Antibodies; Behavior; Binding; Brain; Capsid Proteins; Carrier Proteins; Chronic; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Coupled; Data; Development; Dose; Double-Blind Method; Drug usage; Haptens; Health; Human; Human Adenoviruses; Hyperactive behavior; Immune system; Immunity; Immunologic Adjuvants; Intravenous; Knowledge; Link; Measures; Medical; Methods; Mus; Partner in relationship; Patient Self-Report; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Placebo Control; Procedures; Process; Production; Property; Rattus; Records; Relapse; Reporting; Reproducibility; Risk; Safety; Self Administration; Serotyping; Therapeutic; Toxicology; Translating; Urine; Vaccination; Vaccines; Validation; Virus; addiction; analog; anti-IgG; base; cocaine use; design; drug abstinence; effective therapy; efficacy trial; immunogenic; manufacturing process; meetings; nonhuman primate; novel strategies; preclinical efficacy; preclinical safety; preclinical study; receptor; safety testing; scale up; small molecule; social; success

DESCRIPTION (provided by applicant): Cocaine addiction is a major problem for which there is no effective therapy. Because addiction is a chronic relapsing illness, characterized by cycles of drug use and abstinence, vaccination against cocaine could be a lifetime therapeutic. The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Previous linking of cocaine as a hapten to a protein carrier has had limited success, likely because the protein carrier has not been sufficiently immunogenic to evoke high affinity, high titer antibodies sufficient to block cocaine from reaching its receptors in the brai. We developed a novel strategy to evoke immunity to cocaine, leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans. We hypothesized that linking a cocaine analog to Ad capsid proteins would elicit high-affinity, high-titer antibodies against the cocaine, sufficient to sequester systemically administered drug from access to the brain, thus suppressing cocaine-induced behavior. We strategized that we could avoid any risk of the infectious virus by disrupting the Ad, with the concept that a vaccine comprised of the cocaine analog coupled to disrupted capsid proteins would retain the immunologic adjuvant properties of intact Ad. Based on these concepts, we developed dAd5GNE, a disrupted E1- E3- serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In mice, rats and nonhuman pri- mates, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies. dAd5GNE vaccination was highly effective in abrogating cocaine-induced hyperactivity in mice, following repetitive intravenous doses of cocaine, limiting both hyperactivity and cocaine self-administration behavior in rats, and blocked cocaine access to its cognate CNS receptors in nonhuman primates. The focus of this proposal is to translate dAd5GNE to a clinical study, manufacture GMP grade vaccine, demonstrate safety in experimental animals, obtain regulatory approval and carry out phase I clinical studies to evaluate safety and preliminary measures of efficacy. To accomplish this, we have formulated the following specific aims. Aim 1. Develop a scaled-up process and optimize production, purification and characterization of dAd5GNE, transfer the methods to our GMP facility, validate the manufacturing process, and produce a GMP clinical grade dAd5GNE vaccine. Aim 2. Execute IND-enabling preclinical efficacy and safety testing of the dAd5GNE product. Aim 3. Prepare and submit an IND package and gain approval from the FDA and other regulatory groups to initiate a phase I clinical trial. Aim 4. Carry out a phase I trial to assess the safety nd preliminary measure of efficacy of the dAd5GNE vaccine in humans. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a major health problem for which there is no effective therapy. We have devel- oped an anti-cocaine vaccine dAd5GNE, a highly immunogenic disrupted serotype 5 human adenovi- rus to which a cocaine analog is coupled. Based on studies in mice, rats and nonhuman primates demonstrating dAd5GNE is highly effective in evoking anti-cocaine antibodies and suppressing the ability of cocaine to reach the brain, we propose to carry out the preclinical studies obtain regulatory approval and carry out a phase I safety and initial efficacy trial of dAd5GNE in cocaine addicts.

描述（由申请人提供）： 可卡因成瘾是一个主要问题，目前尚无有效的治疗方法。由于成瘾是一种慢性复发性疾病，其特点是吸毒和戒断周期，因此接种可卡因疫苗可能是终生治疗。开发抗可卡因疫苗的挑战在于可卡因是一种小分子，免疫系统看不见。先前将可卡因作为半抗原与蛋白质载体连接的成功有限，可能是因为蛋白质载体没有足够的免疫原性来激发高亲和力、高滴度的抗体，足以阻止可卡因到达大脑中的受体。我们利用腺病毒 (Ad) 衣壳蛋白在人类中具有高度免疫原性的知识，开发了一种激发可卡因免疫力的新策略。我们假设将可卡因类似物与Ad衣壳蛋白连接会引发针对可卡因的高亲和力、高滴度抗体，足以隔离全身给药的药物进入大脑，从而抑制可卡因诱导的行为。我们的策略是，我们可以通过破坏Ad来避免感染病毒的任何风险，其概念是由可卡因类似物与破坏的衣壳蛋白偶联组成的疫苗将保留完整Ad的免疫佐剂特性。基于这些概念，我们开发了 dAd5GNE，一种破坏的 E1-E3-血清型 5 Ad，其中 GNE 是一种稳定的可卡因类似物，与 Ad 衣壳蛋白共价连接。在小鼠、大鼠和非人灵长类动物中，dAd5GNE 诱发持久、高效价、高亲和力 IgG 抗可卡因抗体。重复静脉注射可卡因后，dAd5GNE 疫苗接种可以非常有效地消除可卡因诱导的小鼠多动症，限制大鼠的多动症和可卡因自我给药行为，并阻止可卡因进入非人类灵长类动物的同源中枢神经系统受体。该提案的重点是将 dAd5GNE 转化为临床研究，生产 GMP 级疫苗，在实验动物中证明安全性，获得监管部门批准并开展 I 期临床研究以评估安全性和初步疗效措施。为了实现这一目标，我们制定了以下具体目标。目标 1. 开发放大工艺并优化 dAd5GNE 的生产、纯化和表征，将方法转移到我们的 GMP 设施，验证生产工艺，并生产 GMP 临床级 dAd5GNE 疫苗。目标 2. 对 dAd5GNE 产品执行 IND 临床前功效和安全性测试。目标 3. 准备并提交 IND 包并获得 FDA 和其他监管团体的批准以启动 I 期临床试验。目标 4. 进行 I 期试验，以评估 dAd5GNE 疫苗在人体中的安全性和初步疗效。 公共卫生相关性：可卡因成瘾是一个主要的健康问题，目前尚无有效的治疗方法。我们开发了一种抗可卡因疫苗 dAd5GNE，这是一种高度免疫原性的破坏血清型 5 人类腺病毒，与可卡因类似物偶联。基于对小鼠、大鼠和非人灵长类动物的研究表明 dAd5GNE 在诱发抗可卡因抗体和抑制可卡因到达大脑的能力方面非常有效，我们建议开展临床前研究，获得监管部门的批准并进行 I 期安全性研究以及 dAd5GNE 对可卡因成瘾者的初步疗效试验。