Supramolecular biomaterials for tuning the inflammatory properties of the complement system

用于调节补体系统炎症特性的超分子生物材料

• 批准号: 10631187
• 负责人: Joel H Collier
• 金额: $ 54.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631187
• 关键词: Active Immunotherapy; Acute; Anti-Inflammatory Agents; Antibodies; Antibody Response; Arthritis; Autoimmune Diseases; B-Lymphocyte Epitopes; B-Lymphocytes; Biocompatible Materials; Biological; Biological Assay; Biological Products; CD4 Positive T Lymphocytes; Chronic; Collaborations; Complement; Complement 5a; Complement Activation; Complement Inactivators; Degenerative Disorder; Development; Dimensions; Disease; Dose; Flow Cytometry; Functional disorder; Future; Immune response; Immunotherapeutic agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Infusion procedures; Injections; Ischemia; Listeria monocytogenes; Malignant Neoplasms; Measures; Mediating; Modeling; Monoclonal Antibodies; Mus; Natural Immunity; Non-Steroidal Anti-Inflammatory Agents; Outcome; Passive Immunization; Passive Transfer of Immunity; Pathogenesis; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pre-Clinical Model; Property; Proteins; Renal glomerular disease; Reperfusion Therapy; Research; Resistance to infection; Rheumatoid Arthritis; Role; Route; Safety; Sodium Dextran Sulfate; Structure; T cell response; T-Cell Depletion; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Tissues; Transgenic Mice; Treatment Efficacy; Vertebral column; Work; chronic inflammatory disease; collagen antibody induced arthritis; complement C3d,g; complement system; compliance behavior; cytokine; design; experimental study; falls; inhibitor; innovation; interest; manufacture; mouse model; nanofiber; nanomaterials; patient population; preservation; protein complex; receptor; response; self assembly; tool

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.

补体抑制剂目前正受到针对炎性疾病的显著关注， 类风湿性关节炎和炎症性肠病，主要以单克隆抗体的形式， 补体激活的终末产物是有害炎症的主要原因。然而，在这方面， 单克隆抗体治疗在很大程度上未能提供广泛有用的炎症治疗工具， 疾病，因为它们被迅速清除，在广泛的患者人群中具有可变的疗效， 昂贵，并且需要定期输注以维持治疗浓度。循环给药进一步 诱导抗药抗体的形成，而单克隆抗体治疗错过了机会， 为了同时可控地接合多个补充成分以特别地减少有害的 炎症由于这些挑战，补体抑制剂仅被批准用于有限的用途。 数量或补体介导的疾病，并且仍然迫切需要能够 选择性和稳定地中和多种精确靶向的补体蛋白， 慢性炎症本项目主要研究超分子（自组装） 含有末端补体蛋白C3dg或C5a的纳米材料，在以前的工作中， 显示出在小鼠中提高治疗性抗炎B细胞和T细胞应答。与被动相比 用单克隆抗体免疫，这种主动免疫治疗方法具有优点， 耐用性和大大简化的剂量要求。这项工作的中心目标是设计 针对两种重要的炎性疾病，类风湿性疾病， 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， 用于治疗关节炎的生物材料和炎性肠病的病理生理学。成果 预计这一项目的成果将证明， 使用超分子组装产生，并且这些反应在小鼠中具有治疗功效。 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 基于生物材料的主动免疫治疗策略，从而提供了单克隆抗体的替代方案。 抗体和其他蛋白质生物制剂不仅用于治疗炎性疾病， 未来的其他目标。