A Totally Synthetic Immunostimulator that Targets Toll-like Receptor 2 and NOD2: Toward Improved Influenza Vaccines

一种针对 Toll 样受体 2 和 NOD2 的全合成免疫刺激剂：改进流感疫苗

• 批准号: 10254747
• 负责人: Larry C. Blaszczak
• 金额: $ 24.3万
• 依托单位: TEICHOS LABORATORIES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254747
• 关键词: Totally; Synthetic; Immunostimulator; Targets; Toll

Influenza viruses cause seasonal epidemics and occasional pandemics that inflict significant global morbidity and mortality. The threat of emerging influenza infections has stimulated development of vaccines to induce broadly protective and durable immunity. Technology that may boost immunogenicity safely beyond levels afforded by currently used adjuvants is critical to advancing vaccine design and development. While research over several decades has identified broad peptidoglycan (PGN) immunostimulatory properties with potential application as an adjuvant, technical, regulatory, and development challenges have prevented development of native PGN for vaccine applications. Teichos Laboratories, LLC (Teichos) proprietary technology produces a platform of macromolecular immunostimulatory biologics by chemoenzymatic total synthesis of authentic PGN core structure, termed sPGN. Preliminary results with a prototype sPGN, TL-001, support its utility as a vaccine adjuvant. TL-001 is a single-strand, uncrosslinked, macromolecular (ca. 20 – 200 kDa) sPGN produced by robust, scalable, and flexible total synthesis from commercially available small molecules, standard reagents, and a single enzyme. Therefore, TL-001, like all sPGN, is produced free of the adventitious, and often potent, contaminant immune reactive materials that accompany similar macromolecules isolated from microorganisms. In a laboratory vaccination model, low dose TL-001 induces a robust response that is mediated through TLR2 and NOD2 receptors to stimulate coordinated innate and adaptive immune responses through two synergistic layers of signalling that amplify antibody production and T cell activation. Neither toxicity nor reactogenicity were observed when high dose sPGN was administered to laboratory animals. This proposal seeks support to advance TL-001 from discovery (preliminary data) to development phase (application to disease prevention studies) by conducting proof-of- principle experiments to validate development as a human influenza vaccine adjuvant. We will produce a test lot of TL-001 that will be evaluated to define the role of TLR2 and other cellular mechanisms in mediating the immunostimulatory responses in human monocytes and macrophages. We will characterize the antibody and T cell responses to TL-001 using an influenza H1 subunit vaccination model in mice. Anticipated technical success in the proposed studies will help support Phase II assessments of TL-001 safety, protection in lethal influenza challenge models, alternate routes of administration, and formulation development.

流感病毒引起季节性流行病和偶尔的大流行，造成严重的全球发病率和 死亡率。新出现的流感感染的威胁刺激了疫苗的开发，以广泛诱导 保护性和持久的免疫力。可以安全地提高免疫原性的技术，超过了 目前使用的佐剂对推进疫苗设计和开发至关重要。同时研究了几个 几十年来，人们已经确定了广谱肽聚糖(PGN)的免疫刺激特性，并将其作为一种潜在的应用 佐剂、技术、监管和开发方面的挑战阻碍了本机PGN的开发 疫苗应用。Teichos实验室，LLC(Teichos)专有技术生产一个 大分子免疫刺激生物制品通过化学酶全合成真实的PGN核心结构， 称为sPGN。SPGN原型TL-001的初步结果支持其作为疫苗佐剂的用途。TL-001 是一种单链、未交联的大分子(约20-200 kDa)sPGN，由功能强大、可扩展和 由市面上可买到的小分子、标准试剂和单一酶进行灵活的全合成。 因此，tl-001和所有spgn一样，不产生外来的，而且通常是强有力的污染免疫反应。 与从微生物中分离出来的类似大分子伴生的物质。在实验室接种疫苗 模型中，低剂量TL-001通过TLR2和NOD2受体介导的刺激产生强烈反应 通过两个协同层的信号放大协调的先天和获得性免疫反应 抗体产生和T细胞活化。大剂量sPGN未观察到毒性和致反应性 被用在实验动物身上。这项提议寻求支持，以推动TL-001从发现 (初步数据)到开发阶段(应用于疾病预防研究)，通过进行以下证明- 验证作为人类流感疫苗佐剂的开发的原理实验。我们将试生产一批 TL-001，将进行评估，以定义TLR2和其他细胞机制在调节 人单核细胞和巨噬细胞的免疫刺激反应。我们将对抗体和T细胞进行鉴定 小鼠使用流感H1亚单位疫苗模型对TL-001的细胞反应。预期的技术成功 在拟议的研究中将有助于支持TL-001安全性的第二阶段评估，对致命流感的保护 挑战模型、替代给药途径和配方开发。