Supramolecular peptide immunotherapies for peanut allergy

花生过敏的超分子肽免疫疗法

• 批准号: 10317230
• 负责人: Joel H Collier
• 金额: $ 19.75万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317230
• 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

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，主要是控制 通过严格避免过敏原，这会增加焦虑，降低生活质量。在当前的 临床或研究治疗，花生口服免疫疗法(Oit)和舌下免疫疗法 (Sit)已经显示出有效性，但这两种策略都需要终身的日常管理，从而产生影响 患者依从性和成本。此外，狭缝疗法显示出相对较好的安全性。 在临床试验中，它们比OIT更有效，但在诱导过敏原脱敏方面效果较差。相反， OIT显示出更好的疗效，但有更大的不良反应风险，包括过敏反应。 OIT和SIT的疗效与T细胞表型从Th2向Th2的转变有关 Th1和抗体同型从IgE向IgG和IgA的转变，尽管这些因素的相对贡献 免疫学变化尚未完全阐明。在理想的情况下，舌下给药要小心 从过敏原中选择B细胞表位可以改善过敏的安全性 免疫疗法，但提高多肽表位的抗体反应已被证明是一种 这是一个巨大的挑战。该项目旨在开发一个最近设计的亚语言平台 基于超分子多肽-聚合物纳米材料的免疫，已经被证明是非常 最近，当舌下给药时，无论是片剂还是液体，都会产生强烈的免疫球蛋白G反应 配方。这些材料的设计将使合理选择的线性B细胞表位和 舌下给药结合产生一种能够提高保护性抗体的新疗法 对花生抗原中选定表位的反应，同时将过敏反应的风险降至最低。之后 从花生主要变应原中筛选线性B细胞表位最大限度提高舌下免疫原性和 为了将体外反应原性降至最低，多表位纳米材料疫苗将在小鼠身上进行研究 变应原脱敏模型及花生刺激。该项目利用了一个多学科的 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 (生物医学工程系乔尔·科利尔的研究小组)和过敏，疫苗接种， 和佐剂(病理学系Herman Staats研究组)。在……结束时 这个为期两年的高风险/高回报R21项目，我们希望已经展示了关键的证据- 构筑超分子舌下肽纳米材料作为潜在的免疫治疗 对于花生过敏脱敏，可以在后续工作中进行全面研究。