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Allergy Prevention By lgE Cytotoxic Peptide(ECP)Vaccine

LGE 细胞毒肽 (ECP) 疫苗预防过敏

基本信息

批准号：
6511373
负责人：
Swey-Shen Chen
金额：
$ 30.72万
依托单位：
IGE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
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/6511373
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

项目摘要

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(申请人提供)：免疫球蛋白介导的过敏性哮喘，鼻炎、食物过敏、特应性皮炎、过敏反应每年花费180亿美元在这个国家的医疗费用和生产力损失。调节免疫球蛋白E B细胞的产生是由Th2细胞因子调控的。这一范例决定了一种减少IgE介导的过敏性疾病的治疗方式内源性IL-4水平，从而由IgE承诺的B细胞产生IgE。或者，由PI发起的研究表明，以下IgE 免疫后，CD8 T细胞在抑制IgE生成中发挥重要作用由IgE承诺的B细胞和严重的IgE缺乏症接踵而至并维持在免疫的小鼠中。这一观察结果导致了目前被动的抗IgE 治疗性产品概念。然而，这种治疗方式存在缺陷。在未能抑制IgE合成和清除循环的情况下免疫球蛋白-抗-免疫球蛋白E复合体，其累积水平比治疗前的水平。目前还不确定患者是否可能会被给予第二次大剂量，而不会引发中和抗体，包括可能导致肥大的内部图像型抗体细胞脱颗粒。设计替代治疗方式势在必行基于更高安全标准的主动免疫。在此，我们提供通过主动免疫降低IgE水平的长期战略免疫球蛋白E细胞毒肽(ECP)不依赖于构象。由于表现出免疫球蛋白E谱系的B细胞和浆细胞天然ECP结合到MHC I类分子的结合部位口袋上，这些靶点是由于主动接种，被ECP特异性CTL溶解。这样做的好处是商业疫苗是：(I)ECP是序列依赖的，不会诱导抗-IgE；(Ii)ECP经济，疗效持久。要做到这一点近期目标，我们的两个目标是：目标一：确定自然的结构人类免疫球蛋白(惠格)CTL表位与人类白细胞抗原A2.1的关系惠格生产细胞的功效。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。建议的商业应用：免疫球蛋白细胞毒肽(ECP)疫苗旨在开拓主动变态反应免疫市场。与传统的过敏原脱敏不同，基于通用IgE表位的ECP技术可以以更大的剂量脱敏由多种过敏原引起的过敏综合征。此外，与目前被动的抗IgE疗法不同，ECP对于一次或两次注射是经济的；与目前的抗IgE疗法相比，ECP是无风险的，因为它针对的是抗IgE不识别的线性序列，而目前的抗IgE疗法实际上可能会由于诱导抗独特型而导致肥大细胞脱颗粒。