A Peptide Nanoparticle Nicotine Vaccine

肽纳米颗粒尼古丁疫苗

• 批准号: 8334593
• 负责人: PETER BURKHARD
• 金额: $ 78.58万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334593
• 关键词: Adjuvant; Adverse effects; Animal Model; Antibodies; B-Lymphocytes; Binding; Blood; Clinical Research; Clinical Trials; Coupled; Drug Formulations; Engineering; Epitopes; Freeze Drying; Goals; Haplotypes; Haptens; Human; Immune response; Immunization; Intramuscular Injections; Mus; Nicotine; Pain; Patients; Price; Property; Proteins; Protocols documentation; Route; Safety; Stream; Toxic effect; Translations; Vaccines; Work; addiction; density; design; immunogenic; immunogenicity; large scale production; nanoparticle; novel; peptide A; phase 1 study; polypeptide; scaffold

We have recently developed a novel type of vaccine platform, so-called self-assembling polypeptide nanoparticles (SAPNs). We have demonstrated that these SAPNs are highly immunogenic and induce a strong B cell immune response characterized by high antibody titers without the ned of adjuvant. We have engineered and biophysically characterized SAPNs to which activated nicotine hapten molecules can be coupled. Antibodies induced upon immunization with these SAPNs will bind nicotine in the blood stream and hence counteract the addiction-causing effect of nicotine. The overarching goal of the project is to demonstrate safety, tolerability and immunogenicity of the SAPN nicotine vaccine in a clinical trials phase I study. To achieve this goal we propose to first establish the immunogenicity of these nicotine-SAPNs in mice and to optimize their design with respect to the density of the hapten molecules, the SAPN concentration, and the route of immunization to obtain the highest possible antibody titer. Next, we will optimize the SAPNs for human use by engineering pan-DR binding epitopes that are specific for the human haplotypes into the SAPN scaffold. The immunogenicity of the SAPNs will then be verified in a second animal model followed by toxicity testings that will establish a safety profile of the SAPNs. The translation path will then include protein formulation and lyophilization studies to optimize the long-term storage properties of the SAPNs. Along with the application for Swissmedic approval for clinical studies we will work on a large-scale production protocol of the final vaccine. The vaccine of the present project is adjuvant-free. This will eliminate all adjuvant induced side effects and reduce the price as it will allow a simple galenic formulation of the vaccine. Since the SAPN-vaccines can be applied intranasally their patient acceptance is expected to be higher than for curent vaccine approaches which require painful intramuscular injections.

我们最近开发了一种新型的疫苗平台，即所谓的自组装多肽 纳米颗粒（SAPNs）。我们已经证明这些SAPN具有高度免疫原性，并诱导强烈的免疫应答。 B细胞免疫应答的特征是高抗体滴度，无需佐剂。我们有 活化的尼古丁半抗原分子可以与之结合， 耦合。用这些SAPN免疫后诱导的抗体将结合血流中的尼古丁， 从而抵消尼古丁的致瘾作用。 该项目的总体目标是证明SAPN的安全性、耐受性和免疫原性 尼古丁疫苗处于临床试验第一阶段研究中。为了实现这一目标，我们建议首先建立 这些尼古丁-SAPN在小鼠中的免疫原性，并优化它们的设计方面的密度， 半抗原分子、SAPN浓度和免疫途径，以获得最高可能的免疫应答。 抗体滴度接下来，我们将通过工程化泛DR结合表位来优化用于人类的SAPN， 对人单倍型具有特异性。然后，将测定SAPN的免疫原性。 在第二个动物模型中进行验证，然后进行毒性测试，以确定SAPN的安全性。 翻译路径将包括蛋白质制剂和冻干研究，以优化长期的 SAP的存储特性。沿着Swissmedic临床研究批准申请，我们将 研究最终疫苗的大规模生产方案。 本项目的疫苗不含杀虫剂。这将消除所有佐剂诱导的副作用， 降低价格，因为它将允许疫苗的简单盖伦制剂。由于SAP疫苗可以 鼻内应用，其患者接受度预期高于当前的疫苗方法 需要痛苦的肌肉注射