ApoVax104-TB as a Novel Vaccine for Tuberculosis

描述（由申请人提供）：NIAID高级STTR I期提案的目的是将免疫学和动物疾病建模领域的学术研究者的优势与ApoImmune Inc.的资源联合收割机结合起来。开发一种新的疫苗，ApoVax 104-TB“针对活动性和潜伏性结核病（TB）感染。ApoVax 104-TB”使用一种基于ApoImmune嵌合蛋白的新型专利疫苗，该嵌合蛋白由链霉亲和素和共刺激配体4-1BBL组成，与已知的结核分枝杆菌T细胞抗原缀合。该疫苗概念具有作为针对TB的预防性和治疗性疫苗的显著潜力，因为疫苗的4-1BBL组分已显示诱导适应性（CD 4+和CD 8 + T细胞应答）和先天性（树突细胞、巨噬细胞和NK细胞）免疫，并克服各种免疫逃避机制（CD 4 + CD 25 + FoxP 3 + Treg细胞和克隆无反应性）。本申请提出了基于由重组Ag 85 B、ESAT-6和Mpt 83 TB蛋白组成的三重抗原策略来开发针对TB的亚单位疫苗。Ag 85 B和ESAT-6由活跃生长的细菌表达，而Mpt 83在非分裂细菌中表达，从而靶向肺中的两个亚群。这些抗原将被生物素化并通过生物素-链霉亲和素相互作用与嵌合4-1BBL缀合，并在体内特异性递送至组成型表达4-1BB受体的树突细胞。基本假设是4-1BBL与树突细胞上的4 -1BB相互作用将激活这些细胞进行抗原摄取、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可以直接作用于具有上调的4-1BB受体的活化的CD 4+和CD 8 + T细胞，以扩增这些细胞并增强记忆反应。在第三阶段，4-1BBL可以克服各种免疫逃避机制，例如涉及持续性TB的克隆无能和CD 4 + CD 25 + FoxP 3 + Treg细胞。预期这些综合作用将产生对结核病的保护和治疗作用。该假设得到了我们强有力的初步数据的支持，这些数据表明ApoVax 104作为针对宫颈癌的治疗性疫苗的组分比两种基准佐剂单磷酰脂质A和CpG的功效更好。将在动物模型中测试ApoVax 104-TBTM在TB的预防和治疗环境中的功效。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，用于I期临床试验。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。使用ApoImmune的主要疫苗ApoVax 104”，我们将开发一种疫苗，通过作为预防和治疗疫苗来抑制结核病的传播。ApoImmune的新型免疫疗法ApoVax 104 TM疫苗是治疗传染病的一种新的创新方法。

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.