Development of a Next Generation Vaccine for Smoking Cessation and Relapse Preven

描述(申请人提供)：该项目的目标是开发一种卓越的戒烟抗尼古丁疫苗。吸烟的高发病率使与吸烟有关的疾病成为可预防的死亡和发病的主要原因。尽管每年有70%的吸烟者渴望戒烟，40%的吸烟者试图戒烟，但这些尝试成功的不到10%。显然，全球迫切需要更有效的戒烟疗法。一种有希望的方法是接种尼古丁疫苗，诱导尼古丁特异性抗体捕获血液中的尼古丁，抑制尼古丁进入大脑，从而消除其成瘾增强活性。来自两个独立的II期临床试验的支持性数据表明，抗尼古丁抗体效价与戒烟之间存在相关性。然而，在发表的研究中，只有三分之一的研究组达到了足以增加戒烟次数的抗尼古丁效价，而不是安慰剂。这两项试验都使用了将尼古丁与蛋白质联系起来的传统疫苗设计策略(半抗原载体方法)。我们假设，需要一种全新的技术战略来提高抗尼古丁效价。基于罗伯特·兰格(麻省理工学院)、奥米德·法罗克扎德(布里格姆妇女医院和哈佛医学院)和乌尔里希·冯·安德里安(哈佛医学院)实验室的突破性靶向纳米颗粒和免疫学技术，Selecta Biosciences开发了一种全新的疫苗设计方法，以提高免疫反应，远远超出传统技术。Selecta的技术由合成的免疫调节纳米颗粒组成，这些纳米颗粒寄生在抗原呈递细胞(树突状细胞和B细胞)中，以驱动聚焦和高度繁殖的抗原特异性免疫反应。这种纳米颗粒可以经过精确的设计，并包含优化免疫反应所需的所有关键要素：1)靶向抗原提呈细胞，以提高疗效并减少偏离靶标的影响；2)高表面密度的B细胞抗原(尼古丁)呈递，以刺激快速的B细胞反应；3)用于T辅助细胞激活和诱导高效免疫记忆的T细胞抗原；4)用于细胞特异性免疫激活的佐剂(Toll样受体激动剂)，以及5)用于活性成分时间释放的生物相容性聚合物。这些纳米粒子是在一种专利的、可扩展的、一步自组装过程中从合成构件中生产出来的。Selecta的尼古丁疫苗原型纳米颗粒已经在小鼠中诱导了显著的尼古丁血清抗体水平。这项工作将作为优化工作的基础，以实现远远超过传统疫苗技术的抗体滴度。在这个拟议的项目中，我们的最终目标是完成一种高级戒烟治疗性疫苗的临床前开发，准备好提交IND，然后进行第一阶段临床试验。该项目将集中于四个具体目标：1)优化纳米颗粒；2)完成CMC开发活动；3)完成适合支持IND备案的GLP毒理学研究；4)完成第一阶段人类临床安全性测试。 与公共健康相关：Selecta生物科学公司正在应用免疫学和纳米颗粒技术的进步来开发一种基于纳米颗粒技术的新型疫苗，这种疫苗将在希望戒烟的吸烟者中诱导高水平的尼古丁循环抗体。诱导抗体通过与血液中的尼古丁结合，防止尼古丁穿过血脑屏障，从而阻止尼古丁在大脑中的成瘾作用，从而促进戒烟。该项目寻求支持，通过在人体上进行第一阶段临床试验来开发纳米疫苗。

DESCRIPTION (provided by applicant): The goal of this project is to develop a superior anti-nicotine vaccine for smoking cessation. A high incidence of smoking makes smoking-related diseases the leading cause of preventable death and morbidity. Even though 70% of smokers desire to quit and 40% of smokers attempt to stop smoking each year, less than 10% of these attempts are successful. Clearly, an urgent global need exists for more efficacious approaches to smoking cessation therapy. A promising approach is to vaccinate against nicotine, inducing nicotine specific antibodies to capture nicotine in the blood and inhibit passage to the brain, thus eliminating its addiction reinforcing activities. Supportive data from two independent phase II clinical trials indicate a correlation between anti-nicotine antibody titers and smoking cessation. However, in the published study, only one third of the study group achieved anti-nicotine titers sufficient to increase smoking cessation above placebo. Both trials used the conventional vaccine design strategy of linking the nicotine to a protein (a hapten-carrier approach). We postulate that a fundamentally new technological strategy to increase anti-nicotine titers is needed. Based on ground breaking targeted nanoparticle and immunology technologies from the laboratories of Robert Langer (MIT), Omid Farokhzad (Brigham & Women's Hospital and Harvard Medical School) and Ulrich von Andrian (Harvard Medical School), Selecta Biosciences has developed an entirely new approach to vaccine design to boost immune responses well beyond conventional technologies. Selecta's technology consists of synthetic immunomodulatory nanoparticles that home to antigen presenting cells (dendritic cells and B cells) to drive focused and highly prolific antigen-specific immune responses. The nanoparticles can be precisely engineered and comprise all of the key elements required to optimize an immune response: 1) Targeting to antigen presenting cells to enhance efficacy and reduce off target impact; 2) B-cell antigen (nicotine) presentation at high surface density to stimulate rapid B-cell responses; 3) T-cell antigen for T helper cell activation and the induction of efficient immune memory; 4) Adjuvant (Toll-like receptor agonist) for cell specific immune activation, and 5) Biocompatible polymers for the time release of active components. The nanoparticles are produced in a proprietary, scalable, one-step self-assembly process from synthetic building blocks. Selecta's prototype nicotine vaccine nanoparticle has induced significant nicotine serum-antibody levels in mice. This work will serve as a basis for optimization efforts to achieve antibody titers well in excess of conventional vaccine technologies. Our ultimate goal in this proposed project is to complete the preclinical development of a superior smoking cessation therapeutic vaccine ready for IND submission followed by a phase 1 clinical trial. The project will focus on four specific aims: 1) to optimize the nanoparticle; 2) to complete CMC development activities; 3) to complete GLP toxicology studies suitable to support filing of an IND; 4) to complete phase I human clinical safety testing. PUBLIC HEALTH RELEVANCE: Selecta Biosciences, Inc. is applying advances in immunology and nanoparticle technology to develop a novel class of vaccines based on nanoparticle technology which will induce high levels of circulating antibodies against nicotine in smokers who desire to quit. The induced antibodies promote smoking cessation by binding to nicotine in the blood and preventing it from crossing the blood brain barrier and thus preventing the addictive effects of nicotine in the brain. This project seeks support to develop the nanoparticle vaccine through an initial Phase 1 clinical trial in people.