Anti-Flavivirus Immunotherapeutics

描述(申请人提供)：本港共有1亿宗登革热个案 每年有25万人感染危及生命的登革热 出血热/登革休克综合征(DHS/DSS)。治疗方案包括 仅限于症状管理。被动免疫预防和免疫治疗是 一些病毒性疾病的标准治疗方法。然而，未定义的 高免血清的性质不适合登革热病毒病的治疗。 为了为严重疾病提供一种明确的试剂治疗，我们建议 检测使用眼镜蛇毒因子连接的病毒抗体的有效性 结构膜蛋白(E)和病毒第一非结构蛋白(NS1)AS 免疫治疗剂。在第一阶段中，人类Fab组合文库将 构建，识别E或NS1蛋白的Fab片段将被 已确认身份。这些碎片将被评估交叉反应， 非重叠表位识别和亲和力。所有FAB片段都将 与眼镜蛇毒素因子的偶联及补体介导的评价 用于降低病毒感染性的细胞溶解和抗-E结合物。为了进一步 评价这些结合物在小鼠体内的免疫预防作用 还将进行挑战研究。在第二阶段，F(Ab)2-人源化CVF 结合物将在哺乳动物细胞中表达，并在 老鼠和非人灵长类动物。 建议的商业应用： I期鉴定的登革病毒复合体特异性抗E和NS1 Fab片段 研究有可能缓解严重的登革热症状。多过 每年报告的严重登革热病例为25万例。

DESCRIPTION (provided by the applicant): There are 100 million cases of dengue infection each year with 250,000 cases of the life-threatening Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHS/DSS). Treatment options are limited to symptoms management. Passive immunoprophylaxis and immunotherapy are standard treatments for a number of viral diseases. However, the undefined nature of hyperimmune serum is unsuitable for dengue virus disease treatment. To provide a defined reagent treatment for severe disease, we propose to examine the efficacy of using cobra venom factor linked antibodies to the viral structural envelope (E) and the viral first non-structural (NS1) proteins as immunotherapeutic agents. In Phase I a combinatorial human Fab library will be constructed, and Fab fragments which recognize either E or NS1 proteins will be identified. These fragments will be evaluated for cross-reactivity, non-overlapping epitope recognition and affinity. All Fab fragments will be conjugated to cobra venom factor and evaluated for complement mediated cytolysis and anti-E conjugates for reduction in virus infectivity. To further evaluate the immunoprophylaxis potential of the conjugates, in vivo mouse challenge studies will also be performed. In Phase II, F(ab)2-humanized CVF conjugates will be expressed in mammalian cells and their efficacy evaluated in mice and non-human primates. PROPOSED COMMERCIAL APPLICATION: The dengue virus complex specific anti-E and NS1 Fab fragments identified in Phase I research have the potential to relieve severe dengue disease symptoms. More than 250,000 annual cases of severe dengue disease are reported each year.