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