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

基本信息

批准号：
10538835
负责人：
Joel H Collier
金额：
$ 56.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10538835
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 Cells 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 Lead 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 Periodicity 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 base chronic inflammatory disease collagen antibody induced arthritis complement C3d,g complement system compliance behavior cytokine design experimental study falls inhibitor innovation interest mouse model nanofiber nanomaterials patient population preservation protein complex receptor response tool

项目摘要

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.

补体抑制剂目前在炎症性疾病方面引起了极大的兴趣，例如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最终产物是造成有害炎症的主要原因。然而，单克隆抗体疗法在很大程度上未能为炎症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功效，价格昂贵，并且需要定期输注以维持治疗浓度。进一步循环给药诱导抗药抗体形成，单克隆抗体疗法错失良机同时可控地参与多种补体成分，以专门减少有害物质炎。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、稳定地中和多种精确靶向的补体蛋白，用于治疗慢性炎症。该项目专注于超分子（自组装）的设计含有末端补体蛋白 C3dg 或 C5a 的纳米材料，在之前的工作中已被显示可提高小鼠的治疗性抗炎 B 细胞和 T 细胞反应。与被动相比单克隆抗体免疫，这种主动免疫治疗方法具有优势耐用性并大大简化了剂量要求。这项工作的中心目标是设计超分子补体组装对抗两种重要的炎症疾病，类风湿病关节炎和炎症性肠病，并阐明它们的保护作用机制。该工作将由具有超分子材料、主动免疫疗法专业知识的协作团队进行，用于治疗关节炎的生物材料以及炎症性肠病的病理生理学。结果该项目预计将证明持久的补体中和反应可以使用超分子组装体产生，并且这些反应对小鼠具有治疗功效关节炎和炎症性肠病模型。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疗法策略，从而提供单克隆疗法的替代方案抗体和其他蛋白质生物制剂不仅可以治疗炎症性疾病，还可以治疗多种疾病未来的其他目标。