Supramolecular peptide immunotherapies for peanut allergy

花生过敏的超分子肽免疫疗法

• 批准号: 10416075
• 负责人: Joel H Collier
• 金额: $ 23.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-02 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416075
• 关键词: Adjuvant; Adverse effects; Allergen Immunotherapy; Allergens; Allergic Disease; Allergy to peanuts; Anaphylaxis; Antibodies; Antibody Response; Antigens; Anxiety; B-Cell Activation; B-Lymphocyte Epitopes; B-Lymphocytes; Biological Assay; Biomaterials Research; Biomedical Engineering; Cessation of life; Chemicals; Child; Clinical; Clinical Treatment; Clinical Trials; Dose; Emerging Technologies; Epitopes; Evaluation; Exhibits; Goals; Hypersensitivity; IgE; Immune; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologics; Immunotherapy; In Vitro; Interdisciplinary Study; Investigational Therapies; Modeling; Molecular Conformation; Monoclonal Antibodies; Mucous body substance; Mus; Nature; Outcome; Pathology; Peptides; Pharmaceutical Preparations; Phenotype; Polymers; Proteins; Quality of life; Rapid screening; Regimen; Research; Risk; Route; Safety; Sublingual drug administration; System; T-Lymphocyte; T-Lymphocyte Epitopes; Tablets; Technology; Therapeutic; Therapeutic antibodies; Treatment Efficacy; Vaccination; Vaccine Design; Vaccines; Work; base; clinical translation; compliance behavior; cost; desensitization; design; food allergen; granulocyte; high reward; high risk; immunoengineering; immunogenic; immunogenicity; improved; in vivo; liquid formulation; mouse model; multidisciplinary; nanofiber; nanomaterials; novel strategies; novel therapeutics; oral immunotherapy; peptide B; response; risk minimization; sublingual immunotherapy; vaccine delivery; vaccine platform

Peanut allergy is the leading cause of allergy-related deaths in children and is primarily managed through strict allergen avoidance, which increases anxiety and lowers quality of life. Among current clinical or investigational treatments, peanut oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) have shown efficacy, but both strategies require a lifetime of daily management, impacting patient compliance and cost. Further, SLIT regimens have exhibited comparably better safety profiles than OIT in clinical trials, but they are less effective at inducing allergen desensitization. Conversely, OIT has exhibited greater efficacy but carries a greater risk of adverse effects, including anaphylaxis. The therapeutic efficacy of both OIT and SLIT is associated with a shift in T-cell phenotype from Th2 to Th1 and a shift in antibody isotype from IgE to IgG and IgA, although the relative contributions of these immunological changes have not been fully elucidated. Ideally, the sublingual administration of carefully chosen peptide B-cell epitopes from allergens could improve the safety profile of allergy immunotherapies, but raising antibody responses against peptide epitopes sublingually has proven a significant challenge. This project seeks to exploit a recently designed platform for sublingual immunization based on supramolecular peptide-polymer nanomaterials, which have been shown very recently to raise strong IgG responses when delivered sublingually either in tablet form or in liquid formulations. These materials will be designed such that rationally selected linear B-cell epitopes and sublingual delivery combine to produce a novel therapy capable of raising protective antibody responses against selected epitopes in peanut antigens, while minimizing risks of anaphylaxis. After selecting linear B cell epitopes from major peanut allergens maximizing sublingual immunogenicity and minimizing reactogenicity in vitro, multi-epitope nanomaterial vaccines will be investigated in a mouse model of allergen desensitization and peanut challenge. The project capitalizes on a multi-disciplinary collaboration between research groups with expertise in immune engineering and biomaterials (research group of Joel Collier in the Department of Biomedical Engineering) and allergy, vaccination, and adjuvants (research group of Herman Staats in the Department of Pathology). At the conclusion of this two-year high risk/high reward R21 project, we expect to have demonstrated a critical proof-of- concept establishing supramolecular sublingual peptide nanomaterials as a potential immunotherapy for peanut allergy desensitization that can be comprehensively investigated in follow-on work.

花生过敏是儿童过敏相关死亡的主要原因，主要管理 通过严格的避免过敏原，这会增加焦虑并降低生活质量。当前 临床或研究治疗，花生口服免疫疗法（OIT）和舌下免疫疗法 （缝隙）已显示出功效，但两种策略都需要一生的日常管理，影响 患者合规性和成本。此外，狭缝方案表现出相当更好的安全性概况 在临床试验中，OIT比OIT不如诱导过敏原脱敏的有效性。反过来， OIT表现出更大的功效，但具有更大的不良反应风险，包括过敏反应。 OIT和SLIT的治疗功效都与T细胞表型从TH2转移到 Th1和抗体同种型从IgE转向IgG和IgA，尽管这些相对贡献 免疫变化尚未完全阐明。理想情况下，精心的舌下管理 从过敏原中选择的肽B细胞表位可以提高过敏的安全性 免疫疗法，但提高针对肽表位的抗体反应已证明是 重大挑战。该项目旨在利用最近设计的舌下平台 基于超分子肽聚合物纳米材料的免疫，已显示出非常非常 最近，以平板电脑的形式或液体升舌时提出强烈的IgG响应 配方。这些材料的设计将使理性选择的线性B细胞表位和 舌下递送联合产生一种能够提高保护抗体的新型疗法 对花生抗原中选定表位的反应，同时最大程度地减少过敏反应的风险。后 从主要花生过敏原中选择最大化舌下免疫原性和 将在小鼠中研究体外，多质纳米材料疫苗的反应生成性最小化。 过敏原脱敏和花生挑战的模型。该项目大写以多学科 具有免疫工程和生物材料专业知识的研究小组之间的合作 （生物医学工程系的乔尔·科利尔（Joel Collier）研究小组）和过敏，疫苗接种， 和佐剂（病理学系的Herman Staats研究小组）。结束 这个为期两年的高风险/高奖励R21项目，我们预计将证明至关重要的证明 建立超分子舌下肽纳米材料作为潜在免疫疗法的概念 对于花生过敏脱敏，可以在后续工作中进行全面研究。