Disrupted Adenovirus Serotype 5-based Anti-cocaine Vaccine

描述（由申请人提供）：可卡因成瘾是一个主要问题，没有有效的治疗方法。由于成瘾是一种慢性复发性疾病，其特征是吸毒和戒断的循环，因此接种可卡因疫苗可能是终身治疗。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连接到蛋白质载体上的成功有限，可能是因为蛋白质载体没有足够的免疫原性来引起足以阻断可卡因到达其在大脑中的受体的高亲和力、高滴度抗体。我们开发了一种新的策略来唤起对可卡因的免疫力，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。我们假设将可卡因类似物与Ad衣壳蛋白连接将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偶联到破坏的衣壳蛋白的疫苗将保留完整Ad的免疫佐剂性质。基于这些概念，我们开发了dAd 5GNE，一种破坏的E1- E3-血清型5 Ad与GNE，一种稳定的可卡因类似物，共价连接到Ad衣壳蛋白。在小鼠、大鼠和非人灵长类动物中，dAd 5GNE诱发持久的、高滴度、高亲和力IgG抗可卡因抗体。在重复静脉内剂量的可卡因之后，dAd 5GNE疫苗接种在消除小鼠中可卡因诱导的活动过度方面是高度有效的，限制大鼠中的活动过度和可卡因自我施用行为，并且阻断可卡因接近非人灵长类动物中的其同源CNS受体。该提案的重点是将dAd 5GNE转化为临床研究，生产GMP级疫苗，在实验动物中证明安全性，获得监管批准并进行I期临床研究，以评估安全性和有效性的初步措施。为了实现这一目标，我们制定了以下具体目标。目标1.开发扩大规模的工艺并优化dAd 5GNE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dAd 5GNE疫苗。目标2.对dAd 5GNE产品进行IND使能临床前有效性和安全性测试。目标3。准备并提交IND包，并获得FDA和其他监管机构的批准，以启动I期临床试验。目标4。进行I期试验，以评估dAd 5GNE疫苗在人体中的安全性和初步疗效。

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.