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，过敏反应年度为180亿 该国的医疗成本和生产力损失。 IgE的调节 B细胞的生产由Th2细胞因子策划。这个范式决定了 IgE介导的超敏疾病的治疗方式，可减少 内源性IL-4水平，从而由IgE-Commant-Commant B细胞产生IgE。 另外，PI发起的研究表明，遵循IgE 免疫，CD8 T细胞在抑制IgE产生中起重要作用 通过IgE commanted B细胞，随之而来的深度缺乏并保持 在IgE免疫的小鼠中。该观察结果导致当前的被动抗IGE 治疗产品概念。但是，这种治疗方式遭受了缺点 无法抑制IgE合成并去除循环 与 治疗之前的水平。而且尚待确定患者是否 可以给予第二次重剂量，而不会引起中和抗体， 包括可能导致桅杆的抗体的内部图像类型 细胞脱粒。必须设计替代性治疗方式 基于具有更高安全标准的主动IgE免疫。这里，我们 提供长期通过主动免疫来降低IgE水平的长期策略 IgE细胞毒性肽（ECP），与要求无关 构象。由于表现出IgE谱系的B细胞和浆细胞 自然ECP到MHC I类的绑定位点袋中，这些目标是 由于主动疫苗接种，由ECP特异性CTL iys。这个优点 商业疫苗是：（i）ECP是序列依赖性的，并且不引起 反英; （ii）ECP是经济的，其效果长期持久。实现这一目标 直接目标，我们的两个目标是：目标I：确定自然的结构 人IgE（Huige）CTL表位仅限于HLA-A2.1并确定其 产生Huige细胞的功效。 AIM II：确定是否 主动免疫引起的ECP特异性CTL抑制了人IgE的产生 在Huige/HLA-A2.1转基因小鼠的临床前模型中。 拟议的商业应用： IgE细胞毒性肽（ECP）疫苗的目标是主动过敏免疫的开放市场。与常规的过敏原脱敏性不同，基于通用IgE表位的ECP技术可以使由于无数过敏原引起的过敏综合征脱敏，并用振动剂量降低过敏性综合征。此外，与当前的被动抗IGE疗法不同，ECP是一两次注射的经济性；与当前的抗IgE疗法相比，由于抗IGE治疗实际上可能导致由于抗IDIOTYPE的诱导而导致肥大细胞脱粒，因此无风险的线性序列无法通过抗IGE识别。