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研究生:黃麗如
研究生(外文):Li-Ju Huang
論文名稱:製備用於開發癌症疫苗之異元二價醣抗原
論文名稱(外文):Preparation of a hetero-divalent glycan epitope for cancer vaccine development
指導教授:翁啟惠翁啟惠引用關係
指導教授(外文):Chi-Huey Wong
口試委員:吳宗益謝俊結
口試委員(外文):Chung-Yi WuJiun-Jie Shie
口試日期:2018-01-18
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:99
中文關鍵詞:醣抗原Globo HSSEA-4癌症疫苗異元二價
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大部分的癌症細胞表面會表現多量的特定醣抗原,先前研究顯示出Globo H, SSEA-4, SSEA-3等三種醣抗原會大量表現在至少16種不同類型的癌症細胞表面上而且在正常細胞中未被發現。此三種醣抗原之任一種在這16種癌症細胞中,出現的比例高達70%以上。因此,Globo H, SSEA-4, SSEA-3適合並有潛力做為抗癌疫苗之候選物。目前的臨床研究大多都是針對單一抗原所發展出來的疫苗,雖然本實驗室先前研發出的Globo H-DT疫苗可同時誘發針對Globo H, SSEA-3及SSEA-4此三種醣抗原之抗體,但其主要還是針對Globo H及SSEA-3的醣抗原。因此,在本篇研究中,我們想設計出一個多價的治療型抗癌疫苗,使其誘發出的抗體能夠對此三種醣抗原都具有高度的結合力,這種疫苗極有可能能夠同時對抗多種癌症。
此篇研究的目的在於將兩種或以上的醣抗原連接在一起,並將其接上載體蛋白以形成抗癌疫苗候選物。為了使不同的醣抗原能夠平均接在載體蛋白上,我們將Globo H和SSEA-4這兩種抗原接在一段短胜肽鍵上,使這兩種醣抗原的比例相同,最後和載體蛋白CRM-197(DT)接合,提升此多價抗癌疫苗的免疫性。藉由此合成策略,我們期望能設計出一組多價的抗癌疫苗,能夠有效率的治療不同的癌症。
Most cancer cell lines overexpress specific glycan antigens. Particularly, Globo H, SSEA-3, SSEA-4 of Globo series epitopes are found in at least 16 different types of cancer cell lines but not found in normal ones. The probability of finding one of the three Globo series epitopes in the 16 different types of cancer cell lines is up to 70%. Therefore, they are regarded as potential anticancer vaccine candidates. Most vaccine-associated studies were designed to elicit immune response to a single therapeutic target based on the uniqueness of each antigen. In 2013, our group published a Globo H-DT anticancer vaccine, which could simultaneously induce antibodies against Globo H, SSEA-4, and SSEA-3 antigens, but mostly against Globo H and SSEA-3. To have a universal anti-cancer vaccine, we designed a multivalent vaccine and hope it can induce immune response to all three specific glycan antigens with significantly binding. This multivalent anticancer vaccine can be used to simultaneously target different types of cancer.
In this study, we combined two glycan antigens and conjugated the combined antigens with carrier protein to form our target product. In order to evenly attach Globo H and SSEA-4 glycan antigens on the carrier protein, we connected Globo H and SSEA-4 with a short peptide to ensure equal proportions of both antigens. Finally, the glycopeptides were conjugated with the carrier protein CRM-197 (DT) to increase the immunity of this cancer vaccine candidate. We anticipate that this vaccine will be used for early stage treatment and even preventive application.
中文摘要 ………………………………………………………………………….......i
ABSTRACT …………………………………………………………………………........ii
ABBREVIATIONS …………………………………………….……………………….iii
CONTENTS ………………………………………………………………………...….....v
LIST OF FIGURES …………………………………………………………...………..vii
LIST OF TABLES ……………………………………………………………...……..viii
LIST OF SCHEMES ………………………………………………………….…...........ix
Chapter 1 Introduction ………...……………………………………............…....1
1.1. Background …………………………………………………………………...1
1.2. Biological roles of carbohydrates ……………………………………...…..…1
1.3. Major classes of glycans ……………………………………………...………2
1.4. Tumor-associated carbohydrate antigens (TACAs) …………………………...3
1.5. Immunological response of carbohydrate antigens ……………………….......7
1.6. Carbohydrate-based anticancer vaccine development ………………...……...8
1.6.1. Challenges of carbohydrate-based anticancer vaccine development .....10
1.6.2. Development of monovalent vaccine ……………….….…….……......11
1.6.3. Development of multivalent vaccine …………………...……………...15
1.6.4. Development of Globo-H anticancer vaccine ………...…...………......19
1.7. Objection …………………………...……………………………………......21
Chapter 2 Result and discussion ………………………………………………..23
2.1. Chemoenzymatic synthesis of Globo H and SSEA-4 with sugar nucleotide regeneration ……………………………………………………………………………...23
2.2. Retro-synthesis of GH-DT-SSEA4 < 1st Generation > ………………………25
2.2.1. Retro-synthesis of GH-DT-SSEA4 < 2nd Generation > ………………28
2.2.2. Synthesis of modified SSEA3 (8) ……………………………..…......30
2.2.3. Strategies of detritylation …………......………………………...……33
2.2.4. Synthesis of modified GH (18) …………………………...………….34
2.2.5. Strategies of synthesis target compound 18 …………………….........37
2.3. Retro-synthesis of GH-DT-SSEA4 < 3rd Generation > ………………….......38
2.3.1. Synthesis of GH-DT-SSEA3 < 3rd Generation > ……………...…...…40
2.3.2. The possibility of the compound 35 formation …………………...….41
Chapter 3 Conclusion and Future perspective ...…………………………...….43
Chapter 4 Experiment section ……………………......…………………………45
4.1. General methods …………..……………………………………...………….45
4.2. Experiment section ………………………………………...…...……………46
References ………………………………………………………………………….…...65
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