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.

性状（由申请方提供）：IgE介导的过敏性哮喘， 鼻炎、食物过敏、特应性皮炎、过敏反应每年花费180亿 医疗费用和生产力的损失。IgE的调节 B细胞的产生是由Th 2细胞因子协调的。这种模式决定了 IgE介导的过敏性疾病的治疗方式， IL-4的内源性水平，从而通过IgE定型B细胞产生IgE。 或者，PI发起的研究表明，在IgE 免疫后，CD 8 T细胞在抑制IgE产生中起重要作用 由IgE定型B细胞，和深刻的IgE缺乏症随之而来，并保持 在IgE免疫的小鼠中。这一观察结果导致目前的被动抗IgE 治疗产品概念。然而，这种治疗方式具有缺点， 在不能抑制IgE合成以及去除循环中的 IgE-抗IgE复合物，其累积水平比 治疗前的水平。目前还不确定患者是否 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内部图像类型抗体 细胞脱颗粒设计替代治疗模式势在必行 基于更高安全标准的主动IgE免疫。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）是独立的要求， 构象由于IgE谱系的B细胞和浆细胞表现出 将天然的ECP结合到MHC I类的结合位点口袋上，这些靶点是 由于主动接种，被ECP特异性CTL裂解。的优点 （i）ECP是序列依赖性的，并且不引起 抗IgE抗体;（ii）ECP经济有效，作用持久。实现这一 近期目标，我们的两个目标是：目标一：确定自然界的结构 HLA-A2.1限制性人IgE（huIgE）CTL表位及其确定 与huIgE产生细胞的功效。目标二：确定是否 主动免疫诱导的ECP特异性CTL抑制人IgE的产生 在huIgE/HLA-A2.1转基因小鼠的临床前模型中。 拟定商业应用： IgE细胞毒性肽（ECP）疫苗旨在打开主动过敏免疫市场。与传统的过敏原脱敏不同，基于靶向通用IgE表位的ECP技术可以以更大剂量脱敏由无数过敏原引起的过敏综合征。此外，与目前的被动抗IgE治疗不同，ECP对于一次或两次注射是经济的;无风险的，因为它针对的是不被抗IgE识别的线性序列，与目前的抗IgE治疗相比，目前的抗IgE治疗实际上可能由于诱导抗独特型而导致肥大细胞脱粒。