Supramolecular biomaterials for tuning the inflammatory properties of the complement system

补体抑制剂目前正受到人们对炎症性疾病的浓厚兴趣，如 类风湿性关节炎和炎症性肠病，主要以抗类风湿性关节炎和炎症性肠病的单抗形式出现 补体激活的最终产物对有害的炎症负有最大责任。然而， 单抗疗法在很大程度上不能为炎症性疾病提供广泛有用的工具 疾病，因为它们被迅速清除，在广泛的患者群体中具有不同的疗效， 价格昂贵，需要定期输液以维持治疗浓度。循环给药进一步 诱导形成抗药物抗体，与单抗治疗错失良机 可控地同时使用多种补体成分，以特别减少有害物质 发炎。由于这些挑战，补体抑制剂仅被批准用于有限的 数量或补体介导的障碍，仍然迫切需要能够 选择性稳定中和多个精确靶向补体蛋白治疗慢性粒细胞白血病 慢性炎症状态。本项目主要研究超分子(自组装)的设计。 含有末端补体蛋白C3dg或C5a的纳米材料，在以前的工作中已经 显示能提高小鼠的治疗性抗炎B细胞和T细胞反应。与被动相反 用单抗免疫，这种主动免疫治疗方法具有优势 经久耐用，大大简化了配药要求。该工作的中心目标是设计 类风湿两种重要炎症性疾病的超分子补体组装 关节炎和炎症性肠病，并阐明其保护作用机制。这项工作将 由一个在超分子材料、主动免疫疗法、 治疗关节炎的生物材料，以及炎症性肠病的病理生理学。结果是 预计这一项目的实施将证明持久的补体中和反应可以 使用超分子组件产生的，这些反应在小鼠身上具有治疗效果 关节炎和炎症性肠病的模型。总的来说，这些结果将进一步支持使用 以生物材料为基础的主动免疫治疗策略，从而提供了一种替代单抗的方法 抗体和其他蛋白质生物制剂不仅用于治疗炎症性疾病，而且用于治疗广泛的 未来的其他目标。

Complement inhibitors are receiving significant interest currently towards inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, primarily in the form of monoclonal antibodies against the terminal products of complement activation most responsible for harmful inflammation. However, monoclonal antibody therapeutics are largely falling short of providing a broadly useful tool for inflammatory disease because they are rapidly cleared, have variable efficacy in broad patient populations, are expensive, and require regular infusions to maintain therapeutic concentrations. Cyclical dosing further induces the formation of anti-drug antibodies, and monoclonal antibody therapeutics miss the opportunity to controllably engage multiple complement components simultaneously to specifically reduce harmful inflammation. Owing to these challenges, complement inhibitors have only been approved for a limited number or complement-mediated disorders, and there remains a critical need for technologies that can selectively and stably neutralize multiple precisely targeted complement proteins for the treatment of chronic inflammatory conditions. This project focuses on the design of supramolecular (self-assembling) nanomaterials containing terminal complement proteins C3dg or C5a, which in previous work have been shown to raise therapeutic anti-inflammatory B-cell and T-cell responses in mice. In contrast to passive immunization with monoclonal antibodies, this active immunotherapy approach has advantageous durability and greatly simplified dosing requirements. The central objectives of the work are to design supramolecular complement assemblies towards two significant inflammatory diseases, rheumatoid arthritis and inflammatory bowel disease, and to clarify their protective mechanism of action. The work will be undertaken by a collaborative team with expertise in supramolecular materials, active immunotherapies, biomaterials for treating arthritis, and the pathophysiology of inflammatory bowel disease. The outcomes of this project are expected to be a demonstration that durable complement-neutralizing responses can be generated using supramolecular assemblies, and that these responses have therapeutic efficacy in mouse models of arthritis and inflammatory bowel disease. Broadly, these results will further champion the use of biomaterials-based strategies for active immunotherapy, thus providing an alternative to monoclonal antibodies and other protein biologics for treating not only inflammatory diseases, but a broad range of other targets in the future.