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 抗炎性细胞因子的单抗。然而，很大一部分患者并不这样做。 对这样的生物制品做出反应，否则随着时间的推移，疗效会逐渐减弱。此外，间歇性给药可能 加剧了抗药物抗体的产生。即使在有反应的患者中，当抗细胞因子 治疗方法可以改善疾病症状，但往往不能诱导足够的肠道上皮细胞 再生。因此，对炎症性肠炎的替代疗法的迫切需求尚未得到满足。 对广大患者群体产生可预测治疗效果的疾病，通过减少 发炎和促进组织再生。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案，但还处于萌芽阶段 可能提供更好的治疗效果的策略。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-22BP)。细胞因子It 抑制物，IL-22，是IL-10家族的成员，在调节肠道屏障方面发挥核心作用 在健康组织和上皮再生过程中；因此，中和IL-22BP有望促进促进 IL-22的再生特性对IBD的改善作用主动免疫疗法的设计将使用 创新的超分子纳米材料，旨在包含精确数量的B细胞表位提升 针对IL-22BP和肿瘤坏死因子的中和反应，以及设计用于 在不破坏T细胞对天然细胞因子耐受性的情况下，提供CD4+T细胞的帮助。将对疗效进行评估 在葡聚糖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 将为既抗炎又抗炎的组合主动免疫疗法建立概念验证 在IBD的背景下是可再生的，构成了这一战略的第一个演示，可以 更广泛地应用于其他炎症性疾病和细胞因子。