A Peptide Nanoparticle Nicotine Vaccine

描述(申请人提供)：我们最近开发了一种新型疫苗平台，即所谓的自组装多肽纳米粒(SAPN)。我们已经证明了这些SAPN具有高度的免疫原性，并诱导了以高抗体效价为特征的强大的B细胞免疫反应，而不需要佐剂。我们已经设计了SAPN，并对其进行了生物物理表征，激活的尼古丁半抗原分子可以偶联到SAPN上。免疫这些SAPN后产生的抗体将结合血液中的尼古丁，从而抵消尼古丁的成瘾效应。该项目的首要目标是在临床试验第一阶段研究中证明SAPN尼古丁疫苗的安全性、耐受性和免疫原性。为了实现这一目标，我们建议首先在小鼠身上建立这些尼古丁SAPN的免疫原性，并根据半抗原分子的密度、SAPN浓度和免疫途径来优化它们的设计，以获得尽可能高的抗体效价。接下来，我们将通过将针对人类单倍型的泛DR结合表位工程引入SAPN支架来优化SAPN供人类使用。然后，将在第二个动物模型中验证SAPN的免疫原性，然后进行毒性测试，以确定SAPN的安全性。翻译后的PAH将包括蛋白质配方和冷冻干燥研究，以优化SAPN的长期储存性能。在申请Swissmedic批准进行临床研究的同时，我们将致力于最终疫苗的大规模生产方案。本项目的疫苗是无佐剂的。这将消除所有佐剂引起的副作用，并降低PRIC，因为它将允许疫苗的简单Galen配方。由于SAPN疫苗可以在鼻腔内应用，预计患者对它们的接受度将高于目前需要痛苦的肌肉注射的疫苗方法

DESCRIPTION (provided by applicant): 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 need 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 pah 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 pric 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 current vaccine approaches which require painful intramuscular