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標題: | 針對攝護腺癌合成相關RM2抗原及其疫苗評估 Synthesis and Vaccine Evaluation of the Tumor Associated Carbohydrate Antigen RM2 from Prostate Cancer |
作者: | Hong-Yang Chuang 莊宏揚 |
指導教授: | 翁啟惠 |
關鍵字: | 攝護腺癌,疫苗,全合成, Prostate Cancer,Vaccine,total synthesis, |
出版年 : | 2013 |
學位: | 博士 |
摘要: | 前列腺癌是一種男生常被檢驗出來的癌症且 RM2 是一種多醣體的抗原,它會高度表現在前列腺癌症細胞表面上面,這種新型的抗原分別是屬於 ganglio-series 和 disialyl lacto-series type 1 chain 系列,且 RM2 抗原目前還沒有被人用化學方法所合成出來。
在本篇論文,我們成功的利用[1+2+3]一鍋化的方法合成出腫瘤相關的RM2抗原,利用NMR和抗體吸附的方法鑑定其結構,此外,我們把合成出的抗原和白喉毒素塗變體DT (CRM197)蛋白質載體結合,得到不同RM2個數的疫苗,再搭配不同的醣脂佐劑,可以引起小鼠的免疫反應,我們利用醣晶片去分析免疫反應,發現一個白喉毒素塗變體DT (CRM197)上有4.7個RM2 抗原所合成的疫苗候選人在搭配醣脂佐劑C34所引起的IgG 得強度是最好的,此外,我們還利用補體有關細胞毒殺實驗去證明所得到的血清是對前列腺癌細胞是有效的。 Prostate cancer is the most commonly diagnosed cancer among men and the RM2 antigen has been discovered as a member of an antigenic carbohydrates family that is highly expressed on prostate cancer cells. The novel antigen RM2 belongs to ‘‘ganglio-series’’and the ‘‘disialyl lacto-series type chain’’ groups. And the RM2 antigen was not been synthesized by chemical method before. In this thesis, we have successfully developed a [1+2+3] one-pot strategy to synthesize the RM2 antigen hexasaccharide that was proposed to be a prostate tumor antigen. The structure of the synthetic product was verified by NMR analysis and antibody binding assay using a glycan microarray. In addition, the synthetic antigen was conjugated to a mutated diphtheria toxin (DT, CRM197) with different copy numbers and adjuvant combination to form the vaccine candidates. After vaccination in mice, we used glycan microarrays to monitor their immune response, and the results indicated that when one molecule of DT was incorporated with 4.7 molecules of RM2 in average (DT-RM4.7) and adjuvanted with the glycolipid C34 exhibited the strongest anti-RM2 IgG titer. Moreover, the induced mouse antibodies mediated effective complement-dependent cytotoxicity (CDC) against the prostate cancer cell line LNCap. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17013 |
全文授權: | 未授權 |
顯示於系所單位: | 化學系 |
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