Treatment of Peanut Allergy with Intradermal Administration of ASP0892 (ARA-LAMP-vax): A Randomized, Double-Blind, Placebo-Controlled, Phase I/II Study

皮内注射 ASP0892 (ARA-LAMP-vax) 治疗花生过敏：一项随机、双盲、安慰剂对照的 I/II 期研究

• 批准号: 10398332
• 负责人: ROBERT A WOOD
• 金额: $ 577.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398332
• 关键词: Address; Adverse reactions; Age-Years; Allergens; Allergic Disease; Allergic Reaction; Allergy to peanuts; Antigen-Presenting Cells; Antigens; CD4 Positive T Lymphocytes; Chimeric Proteins; Clinical; Clinical Trials; Code; Complex; DNA; DNA Vaccines; Development; Dose; Double-Blind Method; Exhibits; Food Hypersensitivity; Goals; Histamine; IgE; Immune; Immune response; Immunologic Markers; Immunologics; Immunotherapeutic agent; Immunotherapy; Intramuscular; Lysosomes; Membrane; Membrane Fusion; Modality; Mus; Oral; Outcome; Patients; Peptides; Phase; Phase II Clinical Trials; Placebos; Plasmids; Prevention; Price; Process; Protocols documentation; Randomized; Risk; Safety; T cell response; Time; Vaccines; clinical efficacy; clinical predictors; clinically relevant; comparative efficacy; desensitization; design; food allergen; immunoregulation; improved; intradermal injection; mouse model; next generation; novel; novel vaccines; oral immunotherapy; plasmid DNA; reduce symptoms; response; safety study; uptake

Summary Despite significant advances in the development of potential treatments for food allergy, the approaches studied thus far have been limited by insufficient clinical responses and/or high rates of adverse reactions. While sublingual and epicutaneous immunotherapy (SLIT and EPIT) appear relatively safe, clinical responses have been disappointing, whereas with oral immunotherapy (OIT) more robust clinical responses come at the price of more frequent and severe adverse reactions. Further, it is clear that the benefits achieved with these treatments are usually not long lasting, reflecting a transient desensitization rather than any form of longer term tolerance, such that they will in all likelihood need to be used indefinitely to maintain protection. The ideal treatment will have a low risk of adverse reactions, a high rate of desensitization, a substantial level of protection, AND effects that will be truly sustained. Of the new modalities under current study, the most promising candidate to achieve these goals is ASP0892 (ARA-LAMP-vax). This novel compound is a single plasmid multivalent (Ara h1, h2, h3) lysosomal associated membrane (LAMP) DNA vaccine that is designed to radically shift the immune response to peanut allergens in sensitized patients. In brief, DNA encoding the peanut allergens Ara h1, h2 and h3 are inserted in tandem in a single plasmid containing the coding sequence for LAMP. Upon intradermal or intramuscular administration, uptake of the plasmid by antigen presenting cells results in the synthesis of an allergen-LAMP fusion protein. The LAMP component directs the fusion protein to cellular lysosomes where the allergen is processed and added to major histocompatability complex (MHC)-II antigens, which then stimulate a CD4+ helper T-cell response. Given that the peptide allergen is not released from the antigen presenting cells, it is anticipated that these immunoregulatory effects can be achieved with minimal or no risk of systemic allergic reactions to the vaccine. The central hypothesis of this protocol is that this novel immunotherapeutic approach, utilizing the LAMP associated plasmid DNA vaccine, will provide a safe, effective and long-lasting treatment for peanut allergy, with a long term goal of developing the next generation of immunotherapy for peanut and other food allergies.

摘要 尽管食物过敏的潜在治疗方法的开发取得了重大进展，但所研究的方法 到目前为止，由于临床反应不足和/或不良反应发生率较高，这些药物的应用受到了限制。而当 舌下和皮下免疫疗法(SILT和EPIT)似乎相对安全，临床反应有 令人失望，而口服免疫疗法(OIT)更强劲的临床反应是以 更频繁更严重的不良反应。此外，很明显，通过这些治疗所获得的好处 通常不会持续很长时间，反映的是短暂的脱敏，而不是任何形式的长期耐受， 因此，它们很可能需要无限期地使用以维持保护。 理想的治疗方法将具有低风险的不良反应，高脱敏率，相当程度的 保护，以及将真正持久的影响。在目前研究的新模式中，最有希望的 实现这些目标的候选方案是ASP0892(ARA-LAMP-VAX)。这种新型化合物是一种单质粒 多价(Ara H1、H2、H3)溶酶体相关膜(LAMP)DNA疫苗，旨在从根本上 使致敏患者的免疫反应转向花生过敏原。简而言之，编码花生过敏原的DNA 将ara h1、h2和h3串联插入包含LAMP编码序列的单个质粒中。vt.在.的基础上 皮内或肌肉内给药，抗原提呈细胞摄取质粒会导致 变应原-LAMP融合蛋白的合成。LAMP组件将融合蛋白定向到细胞 处理变应原并将其加入主要组织相容性复合体(MHC)-II抗原的溶酶体， 然后刺激CD4+辅助性T细胞反应。鉴于多肽过敏原不是从 抗原提呈细胞，预计这些免疫调节作用可以在最小或没有的情况下实现 对疫苗发生全身过敏反应的风险。 该方案的中心假设是，这种新的免疫治疗方法，利用LAMP 相关的质粒DNA疫苗将为花生过敏提供一种安全、有效和持久的治疗方法， 为花生和其他食物过敏开发下一代免疫疗法的长期目标。