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

描述（由申请人提供）：该项目的目标是开发一种用于戒烟的优质抗尼古丁疫苗。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%的吸烟者尝试戒烟，但这些尝试中只有不到10%是成功的。显然，全球迫切需要更有效的戒烟治疗方法。一种很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并抑制其进入大脑，从而消除其成瘾强化活动。来自两项独立的II期临床试验的支持性数据表明抗尼古丁抗体滴度与戒烟之间存在相关性。然而，在已发表的研究中，只有三分之一的研究组达到了足以比安慰剂更有效地戒烟的抗尼古丁滴度。这两项试验都采用了传统的疫苗设计策略，将尼古丁与蛋白质连接起来（半抗原载体方法）。我们假设需要一种全新的技术策略来增加抗尼古丁滴度。Selecta Biosciences基于Robert Langer（麻省理工学院）、Omid Farokhzad（布里格姆妇女医院和哈佛医学院）和Ulrich von Andrian（哈佛医学院）实验室突破性的靶向纳米粒子和免疫学技术，开发了一种全新的疫苗设计方法，大大超出了传统技术，可以增强免疫反应。Selecta的技术由合成的免疫调节纳米颗粒组成，这些纳米颗粒可容纳抗原呈递细胞（树突状细胞和B细胞），以驱动集中和高度多产的抗原特异性免疫反应。纳米颗粒可以精确地进行工程设计，并包含优化免疫反应所需的所有关键元素：1)靶向抗原呈递细胞，以提高功效并减少脱靶影响；2)高表面密度b细胞抗原（尼古丁）呈递，刺激b细胞快速反应；3) T细胞抗原用于T辅助细胞活化和诱导高效免疫记忆；4)辅助剂（toll样受体激动剂）用于细胞特异性免疫激活，5)生物相容性聚合物用于活性成分的定时释放。纳米颗粒是通过专有的、可扩展的、一步自组装的合成模块生产的。Selecta的原型尼古丁疫苗纳米颗粒在小鼠体内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。我们在这个拟议项目中的最终目标是完成一种优质戒烟治疗性疫苗的临床前开发，准备提交IND，然后进行1期临床试验。该项目将专注于四个具体目标：1)优化纳米颗粒；2)完成CMC开发活动；3)完成GLP毒理学研究，以支持IND的申请；4)完成I期人体临床安全性试验。

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.