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， 通过严格避免过敏原，这会增加焦虑并降低生活质量。在目前的 临床或研究治疗，花生口服免疫疗法（OIT）和舌下免疫疗法 （SLIT）已经显示出有效性，但这两种策略都需要终生的日常管理， 患者的依从性和成本。此外，SLIT方案显示出更好的安全性 在临床试验中，它们比OIT更有效，但它们在诱导过敏原脱敏方面效果较差。相反地， OIT表现出更大的疗效，但具有更大的不良反应风险，包括过敏反应。 OIT和SLIT的治疗效果均与T细胞表型从Th 2向Th 3的转变有关。 Th 1和抗体同种型从IgE到IgG和伊加的转变，尽管这些的相对贡献 免疫学变化尚未完全阐明。理想情况下，舌下给药的仔细 从过敏原中选择肽B细胞表位可以提高过敏的安全性 免疫疗法，但舌下提高针对肽表位的抗体应答已被证明是一种有效的免疫疗法。 重大挑战。该项目旨在利用最近设计的一个平台， 基于超分子肽-聚合物纳米材料的免疫，已经显示出非常 最近，当以片剂形式或液体形式舌下递送时， 制剂。这些材料将被设计成使得合理选择的线性B细胞表位和 舌下递送联合收割机产生能够提高保护性抗体新疗法 针对花生抗原中的选定表位的免疫应答，同时将过敏反应的风险降至最低。后 从主要花生过敏原中选择线性B细胞表位，使舌下免疫原性最大化， 为了最大限度地减少体外反应原性，将在小鼠中研究多表位纳米材料疫苗 过敏原脱敏和花生攻击模型。该项目利用多学科 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Joel Collier的研究小组）和过敏，疫苗接种， 和佐剂（病理学系赫尔曼Staats研究小组）。结束时 这个为期两年的高风险/高回报R21项目，我们希望已经证明了一个关键的证明， 建立超分子舌下肽纳米材料作为潜在免疫疗法的概念 可在后续工作中进行全面研究。