ApoVax104-TB as a Novel Vaccine for Tuberculosis

ApoVax104-TB 作为结核病新型疫苗

• 批准号: 7538154
• 负责人: Kathryn J MacLeod
• 金额: $ 39.17万
• 依托单位: APOVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538154
• 关键词: Adjuvant; Animal Disease Models; Animal Model; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Bacteria; Binding; Biotin; C57BL/6 Mouse; CD8B1 gene; Cells; Chimeric Proteins; Chronic; Clinical; Clonal Anergy; Communicable Diseases; Data; Dendritic Cells; Development; Dose; Down-Regulation; Drug Formulations; Effector Cell; Extracellular Domain; Figs - dietary; Generations; Head; Histocompatibility Antigens; Immune; Immune response; Immune system; Immunity; Immunology; Immunotherapy; Infection; Knockout Mice; Lead; Ligands; Lipopolysaccharides; Lung; Malignant neoplasm of cervix uteri; Marketing; Memory; Modeling; Mus; Mycobacterium tuberculosis; N-terminal; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Phase; Preventive; Process; Protein Biochemistry; Proteins; Public Health; Published Comment; Recombinants; Research Personnel; Resources; Signal Transduction; Small Business Technology Transfer Research; Staging; Standards of Weights and Measures; Streptavidin; Structure; Subunit Vaccines; T-Cell Proliferation; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tuberculosis; Tuberculosis Vaccines; United States Food and Drug Administration; Up-Regulation; Upper arm; Ursidae Family; Vaccinated; Vaccination; Vaccines; Work; base; chemokine; clinical application; concept; crosslink; cytokine; cytotoxicity; design; in vivo; innovation; interest; macrophage; monophosphoryl lipid A; mouse model; novel; novel vaccines; prevent; prophylactic; receptor; response; therapeutic vaccine; tumor; uptake; vaccine development; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): The objective of this NIAID Advanced STTR Phase I proposal is to combine the strengths of academic investigators from the fields of immunology and animal disease modeling with the resources of ApoImmune Inc. to develop a novel vaccine, ApoVax104-TB" targeting both active and latent Tuberculosis (TB) infections. ApoVax104-TB" uses a novel proprietary vaccine based on ApoImmune's chimeric protein consisting of streptavidin and the costimulatory ligand, 4-1BBL, conjugated with known Mycobacterium tuberculosis T-cell antigens. This vaccine concept bears significant potential as a preventive and therapeutic vaccine against TB since the 4-1BBL component of the vaccine has been shown to induce adaptive (CD4+ and CD8+ T cell responses) and innate (dendritic cells, macrophages, and NK cells) immunity and overcome various immune evasion mechanisms (CD4+CD25+FoxP3+ Treg cells and clonal anergy). This application proposes to develop a subunit vaccine against TB based on a triple antigen strategy consisting of recombinant Ag85B, ESAT-6, and Mpt83 TB proteins. Ag85B and ESAT-6 are expressed by actively growing bacteria, and Mpt83 is expressed in non-dividing bacteria, thereby targeting both subpopulations in the lung. These antigens will be biotinylated and conjugated to chimeric 4-1BBL via biotin- streptavidin interaction and delivered in vivo specifically to dendritic cells constitutively expressing the 4-1BB receptor. The underlying hypothesis is that 4-1BBL interaction with 4-1BB on dendritic cells will activate these cells for antigen uptake, processing, and presentation to T cells, thereby generating potent adaptive immunity. At a second stage, 4-1BBL may directly work on activated CD4+ and CD8+ T cells with upregulated 4-1BB receptor to expand these cells and augment the memory response. At a third stage, 4-1BBL may overcome various immune evasion mechanisms, such as clonal anergy and CD4+CD25+FoxP3+ Treg cells, implicated in persistent TB. These combined effects are expected to result in protective as well as therapeutic effects against TB. This hypothesis is supported by our strong preliminary data demonstrating better efficacy of ApoVax104 than two bench-mark adjuvants, Monophosphoryl Lipid A and CpG, as components of a therapeutic vaccine against cervical cancer. The efficacy of ApoVax104-TBTM will be tested in preventive and therapeutic settings of TB in an animal model. If proven effective, these studies will be followed by a Phase II STTR application to further develop the vaccine for testing in a Phase I clinical trail. The development of a vaccine against TB will have tremendous societal benefits as well as target a global market in the billions of dollars. PUBLIC HEALTH RELEVANCE: This project will establish the necessary fundamental parameters to develop a novel vaccine against tuberculosis (TB). Using ApoImmune's lead vaccine, ApoVax104", we will develop a vaccine that will suppress the spread of TB by acting as a preventative as well as a therapeutic vaccine. ApoImmune's novel immunotherapy, ApoVax104 TM vaccine, is a new innovative approach to treating infectious diseases.

描述(申请人提供)：NIAID Advanced STTR第一阶段提案的目标是将免疫学和动物疾病建模领域的学术研究人员的力量与ApoImmune Inc.的资源结合起来，开发一种新型疫苗ApoVax104-TB“针对活动性和潜伏性结核病(TB)感染。ApoVax104-TB”使用一种新型专利疫苗，该疫苗基于Apo免疫e的嵌合蛋白，包括链霉亲和素和共刺激配体4-1BBL，与已知的结核分枝杆菌T细胞抗原结合。这种疫苗概念具有作为预防和治疗结核病疫苗的巨大潜力，因为疫苗的4-1BBL成分已被证明能诱导适应性(CD4+和CD8+T细胞反应)和天然(树突状细胞、巨噬细胞和NK细胞)免疫，并克服各种免疫逃避机制(CD4+CD25+FoxP3+Treg细胞和克隆无能)。本申请建议基于由重组的Ag85B、ESAT-6和Mpt83结核蛋白组成的三抗原策略开发一种针对结核病的亚单位疫苗。Ag85B和ESAT-6由活跃生长的细菌表达，Mpt83在非分裂细菌中表达，从而针对肺中的这两个亚群。这些抗原将被生物素化，通过生物素-链霉亲和素相互作用连接到嵌合的4-1BBL上，并在体内特异性地输送到组成4-1BB受体的树突状细胞。潜在的假设是，4-1BBL与树突状细胞上的4-1BB相互作用将激活这些细胞，使其摄取、处理抗原并呈递给T细胞，从而产生强大的获得性免疫。在第二阶段，4-1BBL可能直接作用于具有上调的4-1BB受体的活化的CD4+和CD8+T细胞，以扩大这些细胞并增强记忆反应。在第三阶段，4-1BBL可能克服与持续性结核病有关的各种免疫逃避机制，如克隆性无能和CD4+CD25+FoxP3+Treg细胞。这些综合作用预计将产生预防和治疗结核病的效果。这一假设得到了我们强有力的初步数据的支持，这些数据表明，作为宫颈癌治疗性疫苗的组成部分，ApoVax104比两种基准佐剂--单磷脂A和CpG--更有效。ApoVax104-TBTM的有效性将在动物模型的结核病预防和治疗环境中进行测试。如果证明有效，将在这些研究之后进行第二阶段STTR应用，以进一步开发疫苗，在第一阶段临床试验中进行测试。结核病疫苗的开发将产生巨大的社会效益，并瞄准数十亿美元的全球市场。公共卫生相关性：该项目将建立必要的基本参数，以开发一种新的结核病疫苗。利用ApoImmune的主导疫苗ApoVax104“，我们将开发一种既是预防疫苗又是治疗性疫苗的疫苗，它将抑制结核病的传播。Apo免疫的新型免疫疗法ApoVax104 TM疫苗是治疗传染病的新的创新方法。