Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

类风湿性关节炎、牛皮癣和克罗恩病等慢性炎症性疾病目前 使用生物制剂治疗，如单抗和其他炎性蛋白抑制剂 细胞因子。这些被动免疫疗法，其中外源产生的抗体被重复 注入以中和感兴趣的目标，近年来不仅在 炎症状况，但涉及广泛的疾病，包括癌症、糖尿病、心血管疾病 疾病，以及其他。然而，被动免疫疗法有许多缺点，包括需要 用于频繁和重复注射人造蛋白质，密切患者监测，高产量 成本，以及因重复给药而加剧的敏感风险。作为解决方案，主动 诱导患者产生治疗性抗体反应的免疫疗法代表着一种 有吸引力的替代方案。然而，抗细胞因子主动免疫疗法的发展受到以下挑战 缺乏能够提高狭义免疫反应的可用免疫治疗平台 必要的，避免自动反应的。在这个项目中，我们将通过设计 可诱导表位特异性B细胞/抗体反应的超分子多肽材料 三种关键的炎性细胞因子在慢性炎症性疾病的发病机制中起关键作用。 这项工作是通过以前对该项目的资助实现的，在该项目中，自我调整、非煽动性、 模块化超分子多肽纳米纤维已经被开发出来。在目标1中，多肽组件将是 旨在提高抗体反应，但可以忽略T细胞对炎性细胞因子的反应 肿瘤坏死因子、白介素1b和白介素17。在目标2中，调节力量、表型、亲和力和持久性的策略 将开发一系列抗细胞因子免疫反应，并在体内分布和清除 将对纳米材料进行研究。在目标3中，单表位和多表位主动免疫疗法将是 用于治疗类风湿性关节炎的小鼠模型，临床前安全性将进行评估。这个 预期结果是1)概念验证，即持久的、治疗性抗体反应可以 在小鼠中产生的针对几种关键的炎症细胞因子，2)优化的多种辅助剂的配方 最大限度提高治疗性抗体反应的组装肽，以及3)有关节的设计规则 用于控制所产生的免疫反应的强度、亲和力、持续时间和免疫表型。这个 这项工作将由一个在生物材料、免疫学和 炎症过程。

Chronic inflammatory conditions such as rheumatoid arthritis, psoriasis, and Crohn’s disease are currently treated using biologics such as monoclonal antibodies and other protein inhibitors of inflammatory cytokines. These passive immunotherapies, where exogenously produced antibodies are repeatedly injected to neutralize a target of interest, have seen considerable success in recent years not only towards inflammatory conditions but across a broad range of diseases including cancer, diabetes, cardiovascular disease, and others. However, passive immunotherapies possess many shortcomings, including the need for frequent and repeated injections of manufactured proteins, close patient monitoring, high production costs, and a risk of sensitization that is heightened by repetitive administration. As a solution, active immunotherapies that elicit the production of therapeutic antibody responses by the patient represent an attractive alternative. However, the development of anti-cytokine active immunotherapies is challenged by a lack of available immunotherapy platforms capable of raising the narrowly defined immune responses necessary and avoiding autoreactivity. In this project we will address this challenge by designing supramolecular peptide materials capable of eliciting epitope-specific B cell/antibody responses against three key inflammatory cytokines pivotally involved in the pathogenesis of chronic inflammatory diseases. The work is enabled by previous funding of this project, in which self-adjuvanting, non-inflammatory, modular supramolecular peptide nanofibers have been developed. In Aim 1, peptide assemblies will be designed that raise antibody responses but negligible T-cell responses against the inflammatory cytokines TNF, IL-1b, and IL-17. In Aim 2, strategies for modulating the strength, phenotype, affinity, and persistence of anti-cytokine immune responses will be developed, and the biodistribution and clearance of the nanomaterials will be investigated. In Aim 3, single- and multi-epitope active immunotherapies will be developed for treating rheumatoid arthritis in a mouse model, and preclinical safety will be assessed. The expected outcomes are 1) a proof-of-concept that durable, therapeutic antibody responses can be generated in mice against several key inflammatory cytokines, 2) optimized formulations of multiple co- assembled peptides that raise maximally therapeutic antibody responses, and 3) articulated design rules for controlling the strength, affinity, duration, and immune phenotype of the immune responses raised. The work will be conducted by a research team with broad expertise in biomaterials, immunology, and inflammatory processes.