Preclinical Development and Clinical Proof of Concept of a Synthetic Nanoparticle

描述(申请人提供)：该项目的目标是开发一种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。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%。美国疾病控制和预防中心估计，在美国，吸烟每年造成960亿美元的直接医疗费用，以及970亿美元的生产力损失。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，并抑制尼古丁进入大脑，从而消除其增强成瘾的活性。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的是将尼古丁与蛋白质联系起来的传统疫苗策略(半抗原载体方法)。我们假设，需要一种根本性的新技术来提高抗尼古丁效价。SELECTA生物科学公司开发了一种新的疫苗设计方法，以提高免疫反应，远远超过传统技术。Selecta的技术由合成的免疫调节纳米颗粒组成，这些纳米颗粒聚集在抗原呈递细胞(树突状细胞和B细胞)上，以驱动聚焦和高产量 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(APC)，以增强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)递呈，以刺激强劲而快速的B细胞反应；3)T细胞抗原(TCHP)，为B细胞反应的亲和力成熟和高效产生免疫记忆提供帮助；4)佐剂(Toll样受体激动剂)用于APC激活，以及5)生物相容性聚合物，用于活性成分的时间释放。Selecta进行了第一代尼古丁疫苗(SEL-068)的第一阶段临床试验，该疫苗由包含所有三种活性成分(TLR激动剂、TCHP和尼古丁)的单颗粒配方组成。SEL-068耐受性良好，可产生尼古丁特异性抗体。在这笔拨款中，我们建议测试更多的尼古丁纳米颗粒配方，以进一步增加 使用双颗粒尼古丁疫苗的人的抗尼古丁抗体水平，在该疫苗中，TLR激动剂和TCHP将在单独的含尼古丁纳米颗粒中配制。这两种颗粒可以在临床上以不同的比例和剂量水平混合和剂量，以优化人类抗尼古丁抗体的反应。拨款建议的范围包括配方、临床前研究、扩大和制造以及适应性设计第一阶段临床试验。

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.