Modular Biomaterials for Targeted Anti-Cytokine Immunotherapies

用于靶向抗细胞因子免疫疗法的模块化生物材料

基本信息

批准号：
8682383
负责人：
Joel H Collier
金额：
$ 20.86万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8682383
关键词：
Active Immunotherapy Acute Adjuvant Anti-Cytokine Therapy Antibodies Antibody Affinity Antibody Formation Antigens B-Lymphocyte Epitopes B-Lymphocytes Binding Biocompatible Materials Biological Assay Cells Chronic Colitis Competitive Binding Complex Crohn&apos s disease Cytolysis Data Development Disease Dose Effectiveness Endotoxic Shock Enzyme-Linked Immunosorbent Assay Epitopes Etanercept Fiber Future Goals Guidelines Humira Immune response Immune system Immunization Immunization Schedule Immunoglobulin G Immunosuppressive Agents Immunotherapy In Situ Inflammation Inflammatory Injection of therapeutic agent Interleukin-1 Intraperitoneal Injections Mediating Metric Modeling Mus Nature Passive Immunization Patient Monitoring Patients Peptides Pharmaceutical Preparations Preparation Production Proteins Publishing Research Rheumatoid Arthritis Risk Science Serum Shock System T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Epitopes TNF gene Technology Testing Therapeutic Therapeutic antibodies Time Tissues Treatment Efficacy Work anakinra base cost cytokine density design enzyme linked immunospot assay high reward high risk immunogenicity in vitro Assay in vitro activity in vivo infliximab inhibitor/antagonist innovation interest lymph nodes meetings nanofiber neutralizing antibody novel novel therapeutic intervention prevent public health relevance receptor research study response self assembly synthetic peptide therapeutic protein treatment strategy

项目摘要

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.

描述（通过应用提供）：细胞因子阻断是减少急性和慢性炎症性疾病（例如类风湿关节炎或结肠炎）的注射和痛苦的希望。被动保护，例如注射抗体或受体拮抗剂以分别启动细胞因子TNF- - 或IL-1¿是对这些疾病的完善治疗方法，但需要经常需要患者监测，每天或每周注射大量昂贵的生物学，并且有时由于患者对治疗蛋白的免疫系统的感觉而失败。另外，正在追求对细胞因子产生中和抗体反应的免疫疗法作为更有效的保护策略，但受到了质疑，因为必须提出抗体，而不会在细胞因子上破坏T细胞的耐受性，这可能会导致细胞动物产生的细胞动物的不可逆反应和持续的感染。该项目的目的是开发一种新颖的，模块化的化学定义生物材料，可以在没有炎症或破坏T细胞耐受性的那些细胞因子的情况下产生中和抗体反应的原位中和抗体反应。策略雇员会自组装肽，可以在没有感染的情况下纳入感兴趣的表位并产生靶向抗体反应的比例。该提案将检验以下假设：与非循环因子T细胞表现相同的炎症细胞因子，TNF-€或IL-1？的免疫，表现出来自炎症细胞因子的B细胞表现，将产生针对细胞因子的疗法抗体反应，而无需诱导的细胞反应。使用模型抗原的初步数据支持这一假设。将合成细胞因子肽表位的自组成，并测试与已建立的通用T细胞表位共组装，并测试其在健康小鼠中提高高滴度抗体反应的能力（AIM 1）。接下来，首先使用从免疫抑制的小鼠中收集的血清对细胞因子生物活性的神经元化的体外评估，然后使用对细胞因子介导的内毒性休克进行保护的体内测定法（AIM 2）。这种基于材料的细胞因子免疫疗法的策略是一种用于管理炎症疾病的创新方法，利用了肽自由组装提高靶向抗体反应而没有相关炎症的能力。该R21项目将作为一个关键的概念概念，即可以通过化学定义的肽材料诱导耐用和治疗性抗周期反应，从而建立了一个多功能平台，以在类风湿关节炎，结肠炎，结肠炎，其他炎症性疾病或其他炎症疾病的疾病特异性环境中进一步发展。