登革病毒 (Dengue virus; DENV) 屬於黃熱病毒科、黃熱病毒屬，並且具有四種血清型。DENV主要傳播到人類的方式是藉由被感染的斑蚊所叮咬而造成，主要盛行在熱帶以及亞熱帶地區。所有四種血清型的DENV都會在人類造成疾病，可以從較輕微的登革熱到嚴重危及生命的登革出血熱以及登革休克症候群。有效的疫苗或者是治療性的藥物仍需要被開發。實驗室先前的研究顯示，抗登革病毒非結構性蛋白1 (NS1) 抗體會交叉反應到人類的內皮細胞以及血小板，分析顯示NS1蛋白C端序列與此交叉反應有關。因此我們將登革病毒NS1的C端序列去除或置換為日本腦炎病毒NS1的C端，分別產生C NS1及DJ NS1蛋白。研究顯示，抗修飾過的蛋白抗體可以在DENV感染的小鼠模式提供保護效果。此外，在抗NS1單株抗體2E8的研究也顯示，此單株抗體不僅可以辨識四種血清型且不會辨識到NS1的C端序列。此單株抗體可以結合到DENV感染的內皮細胞，並導致補體的活化而造成細胞裂解而死亡。另外在DENV感染的小鼠模式上，此單株抗體提供很好的治療效果。本論文依據先前單株抗體2E8的研究，進一步探討嵌合性單株抗體2E8的治療效果。結果顯示，嵌合性單株抗體2E8會結合到DENV感染的內皮細胞，並導致補體的活化而造成細胞死亡。另外在小鼠的研究模式中，給予嵌合性單株抗體2E8可以減少DENV感染所造成的小鼠尾部出血時間延長、局部皮膚的出血嚴重度、以及病毒NS3蛋白的表現量。因此，嵌合性單株抗體2E8是一個在未來對抗DENV的使用上具有潛力的抗體候選者。另外我們也進一步比較單株抗體33D2和2E8的保護效果，實驗顯示單株抗體33D2也不會辨識到NS1的C端序列，並且和單株抗體2E8一樣可以結合到DENV感染的內皮細胞並導致補體的活化而造成細胞死亡。除了DENV2外，單株抗體33D2和單株抗體2E8一樣可以結合到DENV1和DENV3感染的內皮細胞，且在補體的存在之下導致補體的活化而造成細胞死亡。另外在小鼠的研究模式中，給予單株抗體33D2或者單株抗體2E8一樣都可以減少DENV感染所造成的小鼠尾部出血時間延長、以及局部皮膚的出血嚴重度。總括這些結果，單株抗體33D2和2E8不管在細胞研究或者是小鼠研究模式中都具有相似的保護效果。

Dengue virus (DENV) belongs to the Flaviviridae family, Flavivirus genus and consists of four serotypes. DENV is transmitted to humans by infected mosquitoes of the genus Aedes, particularly in tropical and subtropical countries. All four DENV serotypes can cause a wide range of diseases from classical dengue fever to the life-threatening dengue hemorrhagic fever and dengue shock syndrome. Effective vaccine and therapeutic agents still need to be developed. Our previous studies indicated that antibodies against DENV nonstructural protein 1 (NS1) cross-react with endothelial cells and platelets, and the cross-reactive epitopes reside in the C-terminal region of DENV NS1. We therefore generated a modified DENV NS1 by deleting the C-terminal region of NS1 protein (C NS1) or replacing the C-terminal region with JEV NS1 protein (DJ NS1). Anti-modified DENV NS1 antibodies provided protection in DENV-infected mice. In addition, anti-DENV NS1 monoclonal antibody (mAb) 2E8 recognizes all four serotypes of DENV but not the C-terminal region of DENV NS1. The mAb 2E8 also binds to DENV-infected endothelial cells and causes complement-mediated cytolysis. Furthermore, mAb 2E8 showed therapeutic effect in a DENV-infected mouse model. In this study, we evaluate the therapeutic effect of chimeric mAb 2E8 based on previous studies. The results showed that chimeric mAb 2E8 binds to DENV-infected endothelial cells and induces complement-mediated cytolysis. Treatment with chimeric mAb 2E8 can reduce prolonged bleeding time, hemorrhage severity, and viral NS3 antigen expression in DENV-infected mice. Therefore, chimeric 2E8 is a potential candidate for future dengue therapeutic application. We further compared the protective effects of mAb 33D2 and mAb 2E8 both in vitro and in vivo. MAb 33D2, similar to mAb 2E8, does not recognize the C-terminal region of DENV NS1. In addition to DENV2, mAb 33D2 and mAb 2E8 bound to DENV1 and DENV3-infected endothelial cells and caused cytolysis in the presence of complement. Furthermore, treatment with mAb 33D2 or mAb 2E8 reduced prolonged mouse tail bleeding time and hemorrhage severity at similar levels. In summary, mAb 33D2 possesses similar protective effects as mAb 2E8 both in a DENV-infected mouse model and in cell culture studies.

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