Clinical Assessment of Anti-cocaine Vaccine dAdGNE in Cocaine Addicts

抗可卡因疫苗 dAdGNE 对可卡因成瘾者的临床评估

• 批准号: 9750989
• 负责人: RONALD G CRYSTAL
• 金额: $ 53.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750989
• 关键词: Adenoviruses; Affinity; Antibodies; Antibody Specificity; Antibody titer measurement; Behavior; Binding; Blinded; Brain; Capsid; Capsid Proteins; Carrier Proteins; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cocaine; Cocaine Dependence; Coupled; Data; Development; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Enrollment; Funding; Goals; Grant; Haptens; Human; Hyperactive behavior; Immune system; Immunity; Immunologic Adjuvants; Institutional Review Boards; Intravenous; Knowledge; Link; Measures; Medical; Methods; Mus; National Institute of Drug Abuse; Outcome; Patient Self-Report; Pharmaceutical Preparations; Phase I Clinical Trials; Placebos; Property; Randomized; Rattus; Relapse; Research Personnel; Rewards; Risk; Safety; Self Administration; Serotyping; Serum; Site; Specificity; Therapeutic; Toxicology; Treatment Efficacy; Urine; Vaccination; Vaccine Production; Vaccines; Virus; addiction; analog; anti-IgG; base; cocaine receptor; cocaine use; cohort; design; dopamine transporter; drug abstinence; effective therapy; efficacy testing; immunogenic; nonhuman primate; novel strategies; preclinical efficacy; prevent; receptor; safety testing; small molecule; social; success

Abstract. 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 an effective therapeutic. The challenge in developing an anti- cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Attempts to link 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 brain. We have developed a novel strategy 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 cocaine, sufficient to sequester systemically administered drug from access to the brain, with consequent reduction in 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. In mice, rats and nonhuman primates, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies. dAd5GNE vaccination was highly effective in: abrogating cocaine-induced hyperactivity in mice; limiting both hyperactivity and cocaine self-administration behavior in rats; and blocking cocaine access to its cognate CNS receptors and suppressing cocaine self-administration in nonhuman primates. With NIDA grant U01 DA033835, we developed methods to manufacture dAd5GNE vaccine in our GMP facility, produced clinical-grade dAd5GNE for a clinical study, executed IND-enabling preclinical efficacy and safety testing of the dAd5GNE product, submitted an IND package, gained approval from the FDA and other regulatory groups to initiate a phase I clinical trial, and carried out an initial clinical trial of the low dose cohort (100 μg, 6 monthly doses) in cocaine addicts. The data from this cohort demonstrated that at this low dose, the dAd5GNE vaccine is safe and elicits persistent serum cocaine-specific antibodies in the range approaching that which should be efficacious. The focus of the present proposal is to complete the FDA and IRB approved clinical trial with 2 higher doses (cohort 2: 316 µg/dose and cohort 3: 1,000 µg/dose; each for 6 monthly doses). Specific aim. Initiate and complete cohorts 2 and 3 of the clinical trial to assess the safety and preliminary measure of efficacy of the dAd5GNE vaccine in cocaine addicts.

抽象。可卡因成瘾是一个没有有效治疗的主要问题。因为 成瘾是一种慢性复发性疾病，其特征是吸毒和戒毒的循环， 针对可卡因的疫苗接种可能是一种有效的治疗方法。开发抗- 可卡因是一种小分子，免疫系统看不见。尝试链接 可卡因作为蛋白质载体的半抗原取得了有限的成功，可能是因为蛋白质载体 还没有足够的免疫原性来引起高亲和力、高滴度的抗体， 阻止可卡因到达大脑的受体我们已经制定了一项新的战略， 已知腺病毒（Ad）衣壳蛋白在人体内具有高度免疫原性。我们 假设将可卡因类似物与Ad衣壳蛋白连接将引起高亲和力， 抗可卡因的高滴度抗体，足以隔离全身给药药物 从进入大脑，从而减少可卡因引起的行为。我们 我们制定了战略，我们可以通过破坏Ad来避免感染病毒的任何风险， 由可卡因类似物偶联到破坏的衣壳蛋白的疫苗将保留 完整Ad.基于这些概念，我们开发了dAd 5GNE， 用GNE（一种稳定的可卡因类似物）破坏E1-E3 - 5血清型Ad，GNE与Ad共价连接 衣壳。在小鼠、大鼠和非人灵长类动物中，dAd 5GNE诱发持续的、高滴度、高亲和力IgG 抗可卡因抗体dAd 5GNE疫苗接种在以下方面高度有效： 限制大鼠的多动症和可卡因自我给药行为;和 阻断可卡因进入其同源CNS受体并抑制可卡因自我给药， 非人类灵长类动物随着NIDA授予U 01 DA 033835，我们开发了制造 dAd 5GNE疫苗在我们的GMP设施中，生产临床级dAd 5GNE用于临床研究， 已提交IND的dAd 5 GNE产品的IND支持临床前疗效和安全性测试 获得了FDA和其他监管机构的批准，开始了I期临床试验， 并进行了可卡因低剂量队列（100 μg，6个月剂量）的初步临床试验 瘾君子来自该群组的数据表明，在该低剂量下，dAd 5GNE疫苗是安全的。 并使持续的血清可卡因特异性抗体接近应 要有效。本提案的重点是完成FDA和IRB批准的临床 2个较高剂量的试验（队列2：316 µg/剂，队列3：1，000 µg/剂;各6个月 剂量）。具体目标。启动并完成临床试验的队列2和队列3，以评估 dAd 5GNE疫苗在可卡因成瘾者中的安全性和有效性的初步测量。