Engineered immunotherapies neutralizing interleukin-22 binding protein

中和白细胞介素 22 结合蛋白的工程免疫疗法

基本信息

批准号：
10688059
负责人：
Joel H Collier
金额：
$ 23.75万
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：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688059
关键词：
Active Immunotherapy Acute Adjuvant Alternative Therapies Anti-Cytokine Therapy Anti-Inflammatory Agents Anti-Tumor Necrosis Factor Therapy Antibodies Antibody Response Antigens B-Lymphocyte Epitopes B-Lymphocytes Binding Proteins Biological Factors Biological Products CD4 Positive T Lymphocytes Characteristics Chronic Colitis Complement Crohn&apos s disease Development Disease Dose Engineering Epithelium Epitopes Equilibrium Exhibits Experimental Designs Family Formulation IL17 gene Immune response Immunotherapy Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Interleukin-10 Intestinal Mucosa Lead Listeria Measures Mediating Mediator Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Mus Natural regeneration Pathogenesis Patients Peptides Pharmaceutical Preparations Phenotype Play Production Property Proteins Psoriasis Recovery Regimen Role Severity of illness Sodium Dextran Sulfate Symptoms System T cell response T-Lymphocyte T-Lymphocyte Epitopes TNF gene Therapeutic antibodies Time Tissues Toxin Treatment Efficacy Tretinoin Ulcerative Colitis Work antagonist antimicrobial beta pleated sheet combinatorial comparative efficacy compliance behavior cytokine design dextran sulfate sodium induced colitis epithelium regeneration experience high reward high risk improved innovation interleukin-22 intestinal barrier intestinal epithelium member mouse model murine colitis nanofiber nanoformulation nanomaterials neutralizing antibody novel strategies novel therapeutics pathogenic bacteria patient population patient response pre-clinical predicting response regenerative response screening tissue regeneration treatment comparison tumor necrosis factor binding protein

项目摘要

Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, are commonly treated with monoclonal antibodies against inflammatory cytokines. However, a large proportion of patients do not respond to such biologics or experience diminishing efficacy over time. Additionally, episodic dosing can exacerbate the production of anti-drug antibodies. Even in responding patients, while anti-cytokine therapies can ameliorate disease symptoms, they often fail to induce adequate intestinal epithelial regeneration. There is therefore a critical unmet need for an alternative therapy for inflammatory bowel disease that generates predictable therapeutic efficacy for broad patient populations by both reducing inflammation and promoting tissue regeneration. Active Immunotherapy, where anti-inflammatory immune responses are generated within the patient using engineered immunogens, is an alternative but nascent strategy that may offer improved therapeutic efficacy. This project aims to design an active immunotherapy against a key mediator of inflammatory bowel disease, IL-22 binding protein (IL-22BP). The cytokine it inhibits, IL-22, is a member of the IL-10 family and plays a central role in regulating the intestinal barrier in healthy tissue and during epithelial regeneration; thus, neutralizing IL-22BP promises to facilitate the pro- regenerative properties of IL-22 for the amelioration of IBD. Active immunotherapies will be designed using innovative supramolecular nanomaterials designed to contain precise quantities of B-cell epitopes raising neutralizing responses against IL-22BP and TNF, along with exogenous T-cell epitopes designed to provide CD4+ T cell help without breaking T-cell tolerance to the native cytokines. Efficacy will be assessed in a murine model of dextran sodium sulfate-induced colitis. If successful, this high risk/high reward project will establish a-proof-of-concept for combinatorial active immunotherapies that are both anti-inflammatory and regenerative in the context of IBD, constituting a first demonstration of this strategy that could have broader application to other inflammatory diseases and cytokines.

炎症性肠病，包括溃疡性结肠炎和克罗恩病，通常采用以下药物治疗抗炎性细胞因子的单克隆抗体。然而，很大一部分患者并不随着时间的推移，对此类生物制剂有反应或疗效逐渐减弱。此外，间歇给药可以加剧抗药物抗体的产生。即使在有反应的患者中，在抗细胞因子治疗的同时治疗可以改善疾病症状，但通常无法诱导足够的肠上皮细胞再生。因此，对于炎症性肠病的替代疗法存在着迫切的未满足需求通过减少疾病，为广大患者群体产生可预测的治疗效果炎症并促进组织再生。主动免疫疗法，抗炎免疫使用工程免疫原在患者体内产生反应，是一种替代方案，但仍处于起步阶段可能会提高治疗效果的策略。该项目旨在设计一种主动免疫疗法对抗炎症性肠病的关键介质 IL-22 结合蛋白 (IL-22BP)。细胞因子它抑制IL-22，是IL-10家族的成员，在调节肠道屏障方面发挥着核心作用健康组织和上皮再生期间；因此，中和 IL-22BP 有望促进亲- IL-22 的再生特性可改善 IBD。主动免疫疗法将设计为使用创新的超分子纳米材料旨在包含精确数量的 B 细胞表位针对 IL-22BP 和 TNF 的中和反应，以及旨在提供 CD4+ T 细胞帮助，而不破坏 T 细胞对天然细胞因子的耐受性。将评估功效在右旋糖酐硫酸钠诱导的结肠炎小鼠模型中。如果成功，这个高风险/高回报的项目将为具有抗炎作用的组合主动免疫疗法建立概念验证和 IBD 背景下的再生，构成了该策略的首次展示，该策略可能会更广泛地应用于其他炎症性疾病和细胞因子。