ApoVax104-TB as a Novel Vaccine for Tuberculosis

描述（由申请人提供）：NIAID高级str I期申请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优势与ApoImmune Inc.的资源相结合，开发一种针对活动性和潜伏性结核病（TB）感染的新型疫苗ApoVax104-TB。ApoVax104-TB”使用了一种新的专利疫苗，该疫苗基于ApoImmune的嵌合蛋白，该嵌合蛋白由链亲和素和共刺激配体4-1BBL组成，与已知的结核分枝杆菌t细胞抗原结合。该疫苗概念具有作为结核病预防和治疗疫苗的巨大潜力，因为疫苗的4-1BBL成分已被证明可诱导适应性（CD4+和CD8+ T细胞反应）和先天（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细胞和克隆能量）。本申请拟开发一种基于重组Ag85B、ESAT-6和Mpt83结核蛋白组成的三抗原策略的抗结核亚单位疫苗。Ag85B和ESAT-6在活跃生长的细菌中表达，而Mpt83在非分裂细菌中表达，从而靶向肺部的这两个亚群。这些抗原将被生物素化并通过生物素-链亲和素相互作用结合到嵌合的4-1BBL上，并在体内特异性地递送到表达4-1BB受体的树突状细胞中。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，使其抗原摄取、加工和呈递给T细胞，从而产生有效的适应性免疫。在第二阶段，4-1BBL可能直接作用于活化的CD4+和CD8+ T细胞，这些细胞具有上调的4-1BB受体，以扩大这些细胞并增强记忆反应。在第三阶段，4-1BBL可能克服各种免疫逃避机制，如克隆能量和CD4+CD25+FoxP3+ Treg细胞，涉及持续性结核病。预计这些综合作用将对结核病产生保护和治疗作用。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酰脂质A和CpG的疗效更好。ApoVax104-TBTM的疗效将在动物模型中进行结核病预防和治疗测试。如果证明有效，这些研究将随后进行II期STTR申请，以进一步开发疫苗，以便在I期临床试验中进行测试。结核病疫苗的开发将带来巨大的社会效益，并瞄准数十亿美元的全球市场。公共卫生相关性：该项目将确定必要的基本参数，以开发一种新型结核病疫苗。利用ApoImmune的先导疫苗“ApoVax104”，我们将开发一种疫苗，既可作为预防疫苗，又可作为治疗疫苗，从而抑制结核病的传播。ApoImmune的新型免疫疗法ApoVax104 TM疫苗是一种治疗传染病的创新方法。

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.