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

• 批准号: 10538770
• 负责人: Joel H Collier
• 金额: $ 19.74万
• 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: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538770
• 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 Products; CD4 Positive T Lymphocytes; Cells; Characteristics; Chronic; Colitis; Complement; Crohn' s disease; Development; Disease; Dose; Engineering; Epithelial; Epitopes; Equilibrium; Exhibits; Family; Formulation; Immune response; Immunotherapy; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-17; Intestinal Mucosa; Lead; Listeria; Measures; Mediating; Mediator of activation protein; 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; base; beta pleated sheet; combinatorial; comparative efficacy; compliance behavior; cytokine; design; dextran sulfate sodium induced colitis; epithelium regeneration; experience; experimental study; high reward; high risk; improved; innovation; interleukin-22; intestinal barrier; intestinal epithelium; member; mouse model; murine colitis; nanofiber; nanomaterials; neutralizing antibody; novel strategies; novel therapeutics; pathogenic bacteria; patient population; patient response; pre-clinical; predicting response; regenerative; response; screening; tissue regeneration; treatment comparison

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，通常用以下药物治疗： 针对炎性细胞因子的单克隆抗体。然而，很大一部分患者没有 对这种生物制剂有反应或随着时间的推移经历功效递减。此外，间歇性给药可 加剧抗药抗体的产生。即使在有反应的患者中， 治疗可以改善疾病症状，但它们往往不能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关键的未满足的需求 通过减少和降低患者的死亡率， 炎症和促进组织再生。主动免疫疗法，其中抗炎免疫 使用工程免疫原在患者体内产生反应，是一种替代方法，但仍处于起步阶段。 可以提供改善的治疗效果的策略。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-22 BP）。细胞因子， IL-22是IL-10家族的成员，在调节肠屏障中起着重要作用。 健康组织和上皮再生期间;因此，中和IL-22 BP有望促进促增殖， IL-22用于改善IBD的再生特性。主动免疫疗法将使用 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-22 BP和TNF的中和应答，沿着设计为 提供CD 4 + T细胞帮助，而不破坏T细胞对天然细胞因子的耐受性。有效性评估期 在葡聚糖硫酸钠诱导的结肠炎的小鼠模型中。如果成功，这个高风险/高回报的项目 将为联合主动免疫疗法建立一个概念验证， 和再生的背景下，IBD，构成了这一战略的第一个示范， 更广泛地应用于其他炎性疾病和细胞因子。