Preclinical Development and Clinical Proof of Concept of a Synthetic Nanoparticle

描述（由申请人提供）：本项目的目标是开发用于戒烟的抗尼古丁疫苗。与吸烟有关的疾病是可预防的死亡和发病的主要原因。虽然每年有70%的吸烟者希望戒烟，40%的吸烟者试图戒烟，但这些尝试中只有不到10%是成功的。疾病控制和预防中心估计，吸烟每年造成美国960亿美元的直接医疗保健费用和970亿美元的生产力损失。显然，全球迫切需要更有效的戒烟治疗方法。一种有希望的方法是针对尼古丁接种疫苗，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。来自独立的2期和3期临床试验的支持性数据表明，高抗尼古丁抗体水平与戒烟之间存在相关性。然而，这些疫苗与安慰剂没有区别，因为只有一小部分受试者达到了足够高的尼古丁抗体水平，以帮助戒烟。以前的尼古丁疫苗试验使用了将尼古丁与蛋白质连接的传统疫苗策略（半抗原载体方法）。我们假设需要一种全新的技术来提高抗尼古丁滴度。Selecta Biosciences开发了一种新的疫苗设计方法，以增强免疫反应，远远超过传统技术。Selecta的技术由合成免疫调节纳米颗粒组成，这些纳米颗粒可以归巢抗原呈递细胞（树突状细胞和B细胞），以驱动聚焦和高增殖的 抗原特异性免疫反应。纳米颗粒可以被精确地工程化，并且包含优化免疫应答所需的所有关键要素：1）靶向抗原呈递细胞（APC）以增强功效并减少脱靶影响; 2）B细胞抗原（尼古丁）以高表面密度呈递以刺激稳健和快速的B细胞应答; 3）T细胞抗原（TCHP），为B细胞应答的亲和力成熟和免疫记忆的有效产生提供T细胞帮助; 4）用于APC活化的佐剂（Toll样受体激动剂），和5）用于活性组分的时间释放的生物相容性聚合物。Selecta对第一代尼古丁疫苗（SEL-068）进行了1期临床试验，该疫苗由含有所有三种活性成分（TLR激动剂、TCHP和尼古丁）的单颗粒制剂组成。SEL-068耐受性良好，并产生尼古丁特异性抗体。在这项授权中，我们建议测试额外的尼古丁纳米颗粒制剂，以进一步增加尼古丁的含量。 使用两种颗粒尼古丁疫苗测定人体中的抗尼古丁抗体水平，其中TLR激动剂和TCHP将配制在单独的含尼古丁纳米颗粒中。这两种颗粒可以在临床中以各种比例和剂量水平混合和给药，以优化人抗尼古丁抗体反应。资助范围包括配方、临床前研究、放大和制造以及适应性设计的1期临床试验。

DESCRIPTION (provided by applicant): The goal of this project is to develop an anti-nicotine vaccine for smoking cessation. Smoking-related diseases are the leading cause of preventable death and morbidity. Although 70% of smokers desire to quit and 40% of smokers attempt to stop smoking each year, less than 10% of these attempts are successful. The Centers for Disease Control and Prevention estimates that smoking is responsible for $96 billion a year in direct health care costs and an additional $97 billion a year in lost productivity in the United States. 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 independent phase 2 and phase 3 clinical trials indicate a correlation between high anti-nicotine antibody levels and smoking cessation. However these vaccines were not differentiated from placebo, as only a small portion of subjects achieved high enough nicotine antibody levels to aid in smoking cessation. Previous nicotine vaccine trials used the conventional vaccine strategy of linking the nicotine to a protein (a hapten-carrier approach). We postulate that a fundamentally new technology is needed to increase anti-nicotine titers. Selecta Biosciences has developed a novel approach to vaccine design to boost immune responses well beyond that of 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 (APC) to enhance efficacy and reduce off target impact; 2) B-cell antigen (nicotine) presentation at high surface density to stimulate robust and rapid B-cell responses; 3) T-cell antigen (TCHP) to provide T cell help for affinity maturation of B cell responses and efficient generation of immune memory; 4) Adjuvant (Toll-like receptor agonist) for APC activation, and 5) Biocompatible polymers for the time release of active components. Selecta conducted a Phase 1 clinical trial of a first generation nicotine vaccine (SEL-068) consisting of a single particle formulation containing all three active components (TLR agonist, TCHP, and nicotine). SEL-068 was well tolerated and generated nicotine specific antibodies. In this grant we propose to test additional nicotine nanoparticle formulations to further increase the level of anti-nicotine antibodies in humans using a two particle nicotine vaccine in which the TLR agonist and TCHP will be formulated in separate nicotine-containing nanoparticles. The two particles can be mixed and dosed at various ratios and dose levels in the clinic to optimize the human anti-nicotine antibody response. The scope of the grant proposal is formulation, preclinical studies, scale-up and manufacturing and an adaptive design Phase 1 clinical trial.