Preclinical Development and Clinical Proof of Concept of a Synthetic Nanoparticle

合成纳米粒子概念的临床前开发和临床证明

基本信息

批准号：
8846090
负责人：
Lloyd Patrick Johnston
金额：
$ 374.85万
依托单位：
SELECTA BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8846090
关键词：
Adjuvant Adverse event Affinity Agonist Agreement Animals Antibodies Antibody Response Antigen-Presenting Cells Antigens Applications Grants B-Lymphocytes Binding Biological Markers Blood Blood - brain barrier anatomy Bolus Infusion Brain CD4 Positive T Lymphocytes Centers for Disease Control and Prevention (U.S.)Cessation of life Chemistry Clinic Clinical Clinical Data Clinical Protocols Clinical Research Clinical Trials Clinical Trials Design Data Dendritic Cells Development Dialysis procedure Disease Dose Drug Formulations Elements Engineering Equilibrium Equipment Excipients Fever Generations Goals Grant Haptens Health Health Care Costs Helper-Inducer T-Lymphocyte Home environment Human Immune Immune response Immunology Individual Inferior Injection Site Reaction Link MHC Class II Genes Macaca fascicularis Measurement Measures Memory Methods Monitor Morbidity - disease rate Mus Nicotine Oligonucleotides Particle Size Peptides Pharmaceutical Preparations Phase Phase I Clinical Trials Phase III Clinical Trials Placebos Production Productivity Proteins Research Contracts Safety Smoker Smoking Surface Surrogate Markers T-Lymphocyte TLR7 gene Technology Testing Time Toll-like receptors Toxicology Translating Translations United States Vaccinated Vaccine Design Vaccines Work addiction authority base biocompatible polymer clinical toxicology cytokine density design disorder prevention drug candidate flexibility in vivo manufacturing scale-up meetings nanoparticle new technology nonhuman primate novel novel strategies particle pre-clinical preclinical study prevent programs response safety testing scale up smoking cessation success vaccine candidate vaccine development vaccine trial

项目摘要

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.

描述（由申请人提供）：该项目的目的是开发一种用于戒烟的抗雪Nicotine疫苗。与吸烟有关的疾病是可预防死亡和发病率的主要原因。尽管有70％的吸烟者希望戒烟，而40％的吸烟者试图每年停止吸烟，但不到10％的尝试成功。疾病控制与预防中心估计，吸烟是每年的直接医疗保健费用960亿美元，在美国，每年额外的970亿美元的生产力损失。显然，全球需要更有效的戒烟方法。一种有前途的方法是对尼古丁进行疫苗接种，诱导尼古丁特定的抗体捕获血液中的尼古丁并抑制对大脑的传递，从而消除其成瘾强化活性。来自独立阶段2和3阶段临床试验的支持性数据表明，高抗雪Nicotine抗体水平与戒烟之间的相关性。但是，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联系起来的常规疫苗策略（一种抗甲携带者方法）。我们假设需要从根本上进行新技术来增加抗雪Nicotine滴度。 Selecta Biosciences已开发出一种新型的疫苗设计方法，以增强免疫反应，远远超出了传统技术。 Selecta的技术由抗原呈递细胞（树突状细胞和B细胞）的合成免疫调节纳米颗粒组成，以驱动聚焦和高度多产抗原特异性免疫反应。纳米颗粒可以精确地设计，并构成优化免疫反应所需的所有关键要素：1）靶向抗原呈递细胞（APC）以提高功效并降低目标影响； 2）B细胞抗原（尼古丁）在高表面密度下表现，以刺激稳健和快速的B细胞反应； 3）T细胞抗原（TCHP）提供T细胞帮助，以使B细胞反应的亲和力成熟和有效产生免疫记忆； 4）用于APC激活的辅助（TOLL样受体激动剂）和5）活性成分的时间释放的生物相容性聚合物。 Selecta进行了第一代尼古丁疫苗（SEL-068）的1期临床试验，该试验由包含所有三个活性成分（TLR激动剂，TCHP和Nicotine）的单个颗粒配方组成。 SEL-068的耐受性良好并产生了尼古丁特异性抗体。在这笔赠款中，我们建议测试其他尼古丁纳米颗粒制剂，以进一步增加使用两种颗粒尼古丁疫苗的人类抗脱氧蛋白抗体水平，其中TLR激动剂和TCHP将在含尼古丁尼古丁的纳米颗粒中配制。这两个颗粒可以在诊所中以各种比率和剂量水平进行混合和剂量，以优化人类抗雪Nicotine抗体反应。赠款提案的范围是配方，临床前研究，扩展和制造以及自适应设计阶段1临床试验。