Modular Biomaterials for Targeted Anti-Cytokine Immunotherapies

描述（由申请人提供）：细胞因子阻断是一种很有前途的方法，可以减少急性和慢性炎症，如风湿性关节炎或结肠炎的炎症和痛苦。被动保护，例如分别注射抗体或受体拮抗剂来阻断细胞因子TNF-¿或IL-1¿，是治疗这些疾病的一种行之有效的治疗方法，但需要频繁的患者监测和每天或每周注射大量昂贵的生物制剂，并且由于患者免疫系统对治疗蛋白的敏感化，它最终可能失败。另外，产生针对细胞因子的中和抗体反应的免疫疗法作为更有效的保护策略正在被追求，但一直具有挑战性，因为抗体必须在不破坏T细胞对细胞因子的耐受性的情况下提高，这可能导致细胞因子产生组织的不可逆反应和持续炎症。该项目的目标是开发一种新型的、模块化的、化学定义的生物材料，这种材料可以在不引起炎症或破坏T细胞对这些细胞因子的耐受性的情况下，原位产生针对特定细胞因子的中和抗体反应。该策略采用自组装肽，可以结合感兴趣的表位的精确比例，并在没有炎症的情况下产生靶向抗体反应。这一提议将验证这样一种假设，即在免疫过程中，将显示炎性细胞因子TNF-或IL-1的B细胞表位的共组装肽纤维与非细胞因子T细胞表位结合，将产生针对细胞因子的治疗性抗体反应，而不会诱导炎症或T细胞对细胞因子的反应。使用模型抗原的初步数据支持这一假设。细胞因子肽表位的自组装将被合成，测试其与已建立的通用T细胞表位的共组装，并测试其在健康小鼠中提高高滴度抗体反应的能力（目的1）。接下来，将对材料的有效性进行优化，首先使用免疫小鼠血清中和细胞因子生物活性的体外实验，然后使用细胞因子介导的内毒素休克的体内保护实验（目的2）。这种基于材料的细胞因子免疫治疗策略是一种管理炎症条件的创新方法，利用肽自组装的能力来提高靶向抗体反应而不伴有炎症。这个R21项目将作为一个关键的概念证明，通过化学定义的肽材料可以诱导持久和治疗性的抗细胞因子反应，从而为进一步开发类风湿性关节炎、结肠炎或其他炎症性疾病的疾病特异性背景建立一个通用平台。

DESCRIPTION (provided by applicant): Cytokine blockade is a promising way to reduce inflammation and suffering in acute and chronic inflammatory conditions such as rheumatoid arthritis or colitis. Passive protection, e.g. injection of antibodies or receptor antagonists to bock the cytokines TNF-¿ or IL-1¿, respectively, is a well-established treatment for these conditions, but requires frequent patient monitoring and daily or weekly injections of large quantities of expensive biologics, and it can eventually fail due to sensitization of the patient's immune system to the therapeutic protein. Alternatively, immunotherapies that generate neutralizing antibody responses against cytokines are being pursued as more efficient strategies for protection, but have been challenging because the antibodies must be raised without breaking T cell tolerance to the cytokines, which could cause an irreversible response and ongoing inflammation in cytokine-producing tissues. The goal of this project is to develop a novel, modular, chemically defined biomaterial that can generate neutralizing antibody responses in situ against specific cytokines without inflammation or breaking T cell tolerance to those cytokines. The strategy employs self-assembling peptides that can incorporate precise ratios of epitopes of interest and generate targeted antibody responses in the absence of inflammation. This proposal will test the hypothesis that immunization with co-assembled peptide fibers displaying B cell epitopes from an inflammatory cytokine, TNF- ¿ or IL-1¿, alongside a non-cytokine T cell epitope will generate therapeutic antibody responses against the cytokine without inducing inflammation or T cell responses to the cytokine. Preliminary data using model antigens support this hypothesis. Self-assemblies of cytokine peptide epitopes will be synthesized, tested for co-assembly with an established universal T cell epitope, and tested for their ability to raise high-titer antibody responses in healthy mice (Aim 1). Next, the materials wll be optimized for effectiveness, first using an in vitro assay of neutralization of cytokine bioactivity by sera collected from immunized mice, then using an in vivo assay of protection against cytokine-mediated endotoxic shock (Aim 2). This materials-based strategy for cytokine immunotherapy is an innovative approach for managing inflammatory conditions, exploiting the ability of peptide-self-assemblies to raise targeted antibody responses without associated inflammation. This R21 project will serve as a critical proof-of-concept that durable and therapeutic anti-cytokine responses can be induced via chemically defined peptide materials, thus establishing a versatile platform for further development within disease-specific contexts of rheumatoid arthritis, colitis, or other inflammatory diseases.