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: 10581630
• 负责人: ROBERT A WOOD
• 金额: $ 744万
• 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/10581630
• 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; Placebo Control; 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.

总结 尽管在食物过敏的潜在治疗方法的开发方面取得了重大进展，但研究的方法 迄今为止，由于临床反应不足和/或不良反应率高而受到限制。而 舌下和表皮免疫疗法（SLIT和EPIT）似乎相对安全，临床反应 令人失望，而口服免疫疗法（OIT）更强大的临床反应是以 更频繁和更严重的不良反应。此外，很明显，这些治疗所获得的益处 通常不持久，反映了短暂的脱敏，而不是任何形式的长期耐受， 使得它们很可能需要无限期地使用以维持保护。 理想的治疗将具有低的不良反应风险，高的脱敏率，高水平的抗过敏性。 保护，并将真正持续的效果。在目前研究的新模式中， 实现这些目标的候选是ASP 0892（ARA-LAMP-vax）。这种新型化合物是一种单一的质粒 多价（Ara h1、h2、h3）溶酶体相关膜（LAMP）DNA疫苗，其被设计为从根本上 改变致敏患者对花生过敏原的免疫反应。简而言之，编码花生过敏原的DNA Ara h1、h2和h3串联插入含有LAMP编码序列的单个质粒中。后 皮内或肌内给药时，抗原呈递细胞对质粒的摄取导致 变应原-LAMP融合蛋白的合成。LAMP组分将融合蛋白引导至细胞内， 溶酶体，其中过敏原被加工并添加到主要组织相容性复合物（MHC）-II抗原， 然后刺激CD 4+辅助T细胞反应。鉴于肽过敏原不是从皮肤中释放的， 抗原提呈细胞，预期这些免疫调节作用可以在最小或不存在抗原提呈细胞的情况下实现。 对疫苗有全身过敏反应的风险。 该方案的中心假设是，这种利用LAMP的新型免疫方法 相关质粒DNA疫苗，将提供一种安全，有效和持久的治疗花生过敏， 长期目标是开发下一代花生和其他食物过敏的免疫疗法。