Virus-Like Nanoparticles for Non-Capsid Antigen Delivery with Virus Structure/Functional Mimicry to Activate B Cell Immunity

用于非衣壳抗原递送的病毒样纳米颗粒，具有病毒结构/功能拟态以激活 B 细胞免疫

• 批准号: 10436200
• 负责人: DUXIN SUN
• 金额: $ 51.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436200
• 关键词: Affect; Affinity; Animals; Anthrax disease; Antibodies; Antibody Formation; Antibody Response; Antibody Specificity; Antibody titer measurement; Antigens; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Bacterial Infections; Bacterial Toxins; Binding; Botulinum Toxins; Capsid Proteins; Clinical; Development; ERBB2 gene; Engineering; Exhibits; Haptens; Helper-Inducer T-Lymphocyte; Immunity; Immunization; Malignant Neoplasms; Memory B-Lymphocyte; Oncogenic; Pattern; Peptides; Plasma Cells; Prevention; Specificity; Structure; Structure of germinal center of lymph node; Supporting Cell; System; T-Lymphocyte; Testing; Vaccines; Viral; Virus; Virus-like particle; anthrax toxin; botulinum; cancer therapy; crosslink; density; draining lymph node; improved; lymph nodes; mimicry; nanoparticle; nanoparticle delivery; prevent; response; small molecule; virus characteristic

Various nanoparticles (NPs) have been used for delivery of small antigens, which have limited viral mimic features and are more efficacious than soluble antigens in stimulating B-cell immunity. However, these traditional NPs lack characteristics of virus “spiky capsid protein peplomer”, e.g. spiky antigen clusters on the peplomers, optimal distance between antigen clusters, and highly localized antigen density on the spike. It is unknown how the lack of virus-like features of traditional NPs affect B cell immunity and durable antibody responses. Although virus-like features of B cell vaccine for durable B cell immunity are clinically validated using virus-like particles (VLPs) of viral capsid proteins, VLPs are not suitable for delivery of non-capsid small antigens (such as bacterial toxins, small molecules, and oncogenic peptides) since these non-capsid small antigens are not able to self-assemble to VLPs. There is a need to develop virus-like nanoparticles for small antigens to activate B cell immunity against deadly bacterial toxins (Anthrax, Botulinum), small molecules, and oncogenic peptides. Three components of B cell immunity are critical for durable antibody response: (A) Efficient antigen delivery/retention and unique antigen distribution patterns for B cell acquisition in the draining lymph nodes (dLNs), (B) Activation of antigen-specific B cells through multivalent binding/crosslink with B cell receptor (BCR), (C) Activation of follicular T Helper cells (Tfh) that support Germinal Center (GC) B cells and their differentiation to long-lived plasma cells (LLPCs). However, it is unknown how the lack of virus-like features of NPs antigen delivery systems affect these three critical components of B cell immunity for durable antibody response. In this proposal, we will generate inorganic virus like nanoparticles (IVLNs) with three features of spiky peplomers of virus' using four types of small antigens (peptides of anthrax and botulinum toxins, small molecule 4-hydroxy- 3-nitrophenyl acetyl-hapten, HER2 peptides) to test our hypothesis. We hypothesize that: (A) Virus-like features of IVLNs enhance efficient delivery/retention with unique antigen distribution patterns for B cell acquisition in the lymph node, (B) Virus-like features of IVLNs enhance B cell activation via multivalent bind/crosslink with B cell receptor, promote follicular T (Tfh) cell-dependent B-cell activation, enhance formation of long-lived plasma cells (LLPCs) in the Germinal Center (GC), and generate antibodies with high specificity/affinity, (C) Virus-like features of IVLNs induce durable antibody response against bacterial toxins (anthrax and botulinum) and oncogenic antigens. Aim 1 Determine virus-like features of IVLNs to improve antigen delivery/retention with unique antigen distribution patterns for B cell acquisition in the lymph nodes vs. traditional NPs Aim 2 Identify the stages of B cell responses by the virus-like features of IVLNs vs. traditional NPs Aim 3 Investigate IVLNs-antigen immunizations to induce more durable antibody response against Anthrax and Botulinum toxins and oncogenic HER2 in animals vs. traditional NPs

各种纳米颗粒（NPs）已被用于递送小抗原，其具有有限的病毒模拟物， 特征，并且在刺激B细胞免疫方面比可溶性抗原更有效。然而，这些传统 NP缺乏病毒“刺状衣壳蛋白peplomer”的特征，例如peplomer上的刺状抗原簇， 抗原簇之间的最佳距离，以及刺突上高度局部化的抗原密度。不知道是怎么回事 传统NP缺乏病毒样特征影响B细胞免疫和持久的抗体应答。 尽管用于持久B细胞免疫的B细胞疫苗的病毒样特征在临床上使用病毒样抗体进行了验证， 由于VLP不适合递送病毒衣壳蛋白的非衣壳小抗原（例如， 细菌毒素、小分子和致癌肽），因为这些非衣壳小抗原不能 自我组装成VLP需要开发用于小抗原的病毒样纳米颗粒以激活B细胞 对致命细菌毒素（炭疽，肉毒杆菌），小分子和致癌肽的免疫力。 B细胞免疫的三个组成部分对于持久的抗体应答至关重要：（A）有效的抗原 引流淋巴结中B细胞获取的递送/保留和独特的抗原分布模式 （dLN），（B）通过与B细胞受体（BCR）的多价结合/交联活化抗原特异性B细胞， (C)支持生殖中心（GC）B细胞的滤泡T辅助细胞（Tfh）的活化及其分化 长寿命浆细胞（LLPC）然而，目前尚不清楚NPs抗原的病毒样特征的缺乏如何影响NPs的免疫应答。 递送系统影响持久抗体应答的B细胞免疫的这三个关键组分。 在这个提议中，我们将产生具有三个特征的无机病毒样纳米颗粒（IVLN 使用四种类型的小抗原（炭疽和肉毒杆菌毒素的肽，小分子4-羟基- 3-硝基苯基乙酰半抗原，HER 2肽）来检验我们的假设。我们假设：（A）病毒样特征 IVLN的使用增强了有效的递送/保留，具有独特的抗原分布模式，用于B细胞的获得， 淋巴结，（B）IVLN病毒样特征通过与B细胞的多价结合/交联增强B细胞活化 受体，促进滤泡T（Tfh）细胞依赖性B细胞活化，增强长寿浆细胞的形成 （C）病毒样特征 的IVLN诱导针对细菌毒素（炭疽和肉毒杆菌）和致癌性的持久抗体应答 抗原 目的1确定IVLN的病毒样特征，以改善具有独特抗原的抗原递送/保留 淋巴结中B细胞采集与传统NP的分布模式 目的2通过IVLN与传统NP的病毒样特征识别B细胞应答的阶段 目的3研究IVLN抗原免疫诱导更持久的抗炭疽抗体应答， 动物中的肉毒杆菌毒素和致癌HER 2与传统NP