Allergy Prevention By lgE Cytotoxic Peptide(ECP)Vaccine

LGE 细胞毒肽 (ECP) 疫苗预防过敏

• 批准号: 6337195
• 负责人: Swey-Shen Chen
• 金额: $ 23.22万
• 依托单位: IGE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337195
• 关键词: MHC class I antigen; active immunization; antiallergic agents; cytotoxicity; genetically modified animals; hypersensitivity; hypersensitivity desensitization; immunoglobulin E; laboratory mouse; peptides; vaccine development

DESCRIPTION (Provided by the applicant): IgE-mediated allergic asthma, rhinitis, food allergy, atopic dermatitis, anaphylaxis cost annual 18 billions in medical costs and loss of productivity in this country. Regulation of IgE production by B cells is orchestrated by Th2 cytokines. This paradigm dictates a treatment modality of IgE-mediated hypersensitive diseases that diminishes endogenous levels of IL-4, thereby IgE production by IgE-committed B cells. Alternatively, studies initiated by PI indicated that following IgE immunization, CD8 T cells play an important role in inhibiting IgE production by IgE-committed B cells, and profound IgE deficiency ensued and is maintained in IgE-immunized mice. This observation leads to the current passive anti-IgE therapeutic product concept. However, this treatment modality suffers drawbacks in failing to inhibit IgE synthesis as well as to remove circulating IgE-anti-IgE complexes, which accumulates to levels 10 fold higher, compared to the levels prior to treatment. And it is yet to be determined whether patients may be given a second heavy dose without eliciting neutralizing antibodies, including internal image-type of antibodies that potentially can cause mast cell degranulation. It is imperative to design alternative therapeutic modality based on active IgE immunization with higher safety standards. Herein, we provide a long-term strategy of reducing IgE levels by active immunization with IgE cytotoxic peptides (ECP) that are independent of requirement of conformation. Since B cells and plasma cells of the IgE lineage exhibiting natural ECP onto the binding site pocket of MHC class I, these targets are Iysed by ECP-specific CTL due to active vaccination. The advantages of this commercial vaccine are: (i) ECP is sequence-dependent, and does not elicit anti-IgE; (ii) ECP is economic and its effect long-lasting. To achieve this immediate goal, our two Aims are: Aim I: To Determine the Structure of Natural Human IgE (huIgE) CTL Epitopes Restricted To HLA-A2.1 and Ascertain Their Efficacies with huIgE-Producing Cells. Aim II: To Determine Whether ECP-specific CTL Elicited By Active Immunization Inhibit Human IgE Production In A Pre-clinical Model of huIgE/HLA-A2.1 Transgenic Mice. PROPOSED COMMERCIAL APPLICATION: IgE cytotoxic peptide (ECP) vaccine aims at an open market of active allergy immunization. Unlike the conventional allergen-desensitization, ECP technology based on targeting the universal IgE epitope can desensitize allergic syndromes caused by a myriad of allergens with a booser dose. Furthernore, unlike the current passive anti-IgE therapy, ECP is economic for one or two injections; risk-free since it is directed to linear sequence not recognize by anti-IgE, as compared to the current anti-IgE therapy that may actually cause mast cell degranulation due to induction of anti-idiotype.

描述（由申请人提供）：IgE介导的过敏性哮喘， 鼻炎、食物过敏、特应性皮炎、过敏反应每年造成 180 亿美元的损失 这个国家的医疗费用和生产力损失。 IgE 的调节 B 细胞的产生是由 Th2 细胞因子协调的。这个范式规定 IgE 介导的过敏性疾病的一种治疗方式，可减少 IL-4 的内源水平，从而由 IgE 定向 B 细胞产生 IgE。 另外，PI 发起的研究表明，IgE 之后 免疫中，CD8 T细胞在抑制IgE产生中发挥重要作用 由 IgE 定向 B 细胞产生，随后发生并维持严重的 IgE 缺乏 在 IgE 免疫小鼠中。这一观察结果导致了目前的被动抗 IgE 治疗产品概念。然而，这种治疗方式也有缺点 未能抑制 IgE 合成以及消除循环 IgE-抗 IgE 复合物，其累积水平比 治疗前的水平。目前尚未确定患者是否 可以给予第二次大剂量而不引发中和抗体， 包括可能导致肥大的抗体的内部图像类型 细胞脱颗粒。设计替代治疗方式势在必行 基于主动IgE免疫，安全标准更高。在此，我们 提供通过主动免疫降低 IgE 水平的长期策略 IgE 细胞毒性肽 (ECP) 独立于 构象。由于 IgE 谱系的 B 细胞和浆细胞表现出 天然 ECP 到 MHC I 类的结合位点口袋上，这些目标是 由于主动接种疫苗，被 ECP 特异性 CTL 裂解。这样做的优点 商业疫苗是： (i) ECP 是序列依赖性的，并且不会引起 抗IgE； (ii) ECP经济且效果持久。为了实现这一目标 近期目标，我们的两个目标是： 目标 I：确定天然物质的结构 人类 IgE (huIgE) CTL 表位限制于 HLA-A2.1 并确定其 产生 huIgE 的细胞的功效。目标二：确定是否 主动免疫引发的 ECP 特异性 CTL 抑制人类 IgE 产生 huIgE/HLA-A2.1 转基因小鼠的临床前模型。 拟议的商业应用： IgE细胞毒性肽（ECP）疫苗旨在开放主动过敏免疫市场。与传统的过敏原脱敏不同，ECP技术基于针对通用IgE表位，可以通过加强剂量使多种过敏原引起的过敏综合征脱敏。此外，与目前的被动抗IgE疗法不同，ECP只需注射一两次即可经济；无风险，因为它针对的是抗IgE不识别的线性序列，而目前的抗IgE疗法实际上可能由于诱导抗独特型而导致肥大细胞脱颗粒。