Clinical Assessment of Anti-cocaine Vaccine dAdGNE in Cocaine Addicts

抽象的。可卡因成瘾是一个主要问题，目前还没有有效的治疗方法。因为 上瘾是一种慢性复发性疾病，特征是反复使用药物和戒毒， 接种可卡因疫苗可能是一种有效的治疗方法。开发反病毒药物的挑战是 可卡因疫苗是指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足以阻断的高亲和力、高滴度的抗体 可卡因到达大脑中的感受器。我们开发了一种新的战略，利用 了解腺病毒(Ad)衣壳蛋白在人类中具有高度的免疫原性。我们 假设将可卡因类似物与Ad衣壳蛋白联系起来会引起高亲和力， 针对可卡因的高滴度抗体，足以隔离全身给药 通过进入大脑，从而减少可卡因诱导的行为。我们 我们的战略是，我们可以通过扰乱广告来避免任何传染性病毒的风险， 一种由可卡因类似物偶联到被破坏的衣壳蛋白的疫苗将保留 完整Ad.免疫佐剂特性。基于这些概念，我们开发了dAd5GNE，一个 干扰的E1‾E3‾5型Ad与Gne，一种稳定的可卡因类似物，共价连接到Ad 凯西德。在小鼠、大鼠和非人灵长类动物中，dAd5GNE可诱导持久、高滴度、高亲和力的免疫球蛋白 抗可卡因抗体。DAd5GNE疫苗在以下方面非常有效：消除可卡因诱导的 小鼠的多动；限制大鼠的多动和可卡因自我给药行为；以及 阻断可卡因进入其同源中枢神经系统受体并抑制可卡因的自我给药 非人灵长类动物。在NIDA授权的U01 DA033835的帮助下，我们开发了制造 DAd5GNE疫苗在我们的GMP设施中，生产了临床级dAd5GNE用于临床研究，执行 启用IND的dAd5GNE产品的临床前疗效和安全性测试，提交了IND 一揽子计划，获得了FDA和其他监管机构的批准，可以启动I期临床试验， 并进行了低剂量(100μg，每月6次)可卡因的初步临床试验 瘾君子。来自该队列的数据表明，在这个低剂量下，dAd5GNE疫苗是安全的 并引起持续的血清可卡因特异性抗体，范围接近 要有效率。本提案的重点是完成FDA和IRB批准的临床 两个更高剂量的试验(队列2：316微克/剂，队列3：1,000微克/剂；各6个月 剂量)。明确目标。启动和完成临床试验的队列2和3，以评估 可卡因依赖者应用dAd5GNE疫苗的安全性及初步疗效评价

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.