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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 翁啟惠 | |
| dc.contributor.author | Chih-Wei Lin | en |
| dc.contributor.author | 林志偉 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:02:34Z | - |
| dc.date.copyright | 2014-10-01 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-09-29 | |
| dc.identifier.citation | 1. Moon R (2012) Transforming Glycoscience: A Roadmap for the Future.
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(2009) Expression of verotoxin-1 receptor Gb3 in breast cancer tissue and verotoxin-1 signal transduction to apoptosis. BMC cancer 9(1):67. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18385 | - |
| dc.description.abstract | 異常的醣化是癌症的一個特徵。癌細胞其中一個的特點就是細胞表面具異常化的醣脂質，尤其是唾液酸化以及岩藻醣化。SSEA-4長期使用於胚胎幹細胞表面的標記，近來研究指出，在癌症研究中，SSEA-4和相似結構的Globo H和SSEA-3也被發現大量表現於癌細胞上。在這篇論文中，我們建立單株抗體來辨認SSEA-4 (MC45, MC46 and MC48)或同時辨認SSEA-4及Globo H和SSEA-3 (MC607)的抗體。我們並探討這些SSEA-4抗體之特性，並利用這些SSEA-4抗體來做癌細胞治療評估。首先，我們發現SSEA-4皆有表現在胰臟癌細胞。 MC48單株抗體對於SSEA-4表面解離常數約0.46 nM。在細胞實驗顯示，MC48抗體能夠結合於SSES-4抗原表現的胰臟癌細胞與組織，也可藉由細胞毒殺作用在殺死胰臟癌細胞。而在裸鼠動物實驗模式，顯示可抑制胰臟腫瘤的生長。將MC48轉換為嵌合單株抗體chimeric mAb (chi48)來做功能性的探討，chi48 antibody也可藉由補體的細胞毒殺實驗來殺死胰臟癌細胞株BxPC3。因此，本篇研究顯示SSEA-4的抗體具有發展於標靶治療的潛力，可應用於胰臟癌或其他帶有SSEA-4表現的腫瘤上。
另外針對Globo H的結合蛋白尚未報導，明確功能性也仍未被描述。利用蛋白質晶片、ELISA等方法，可初步發現一些Globo H 結合蛋白，利用醣晶片進一步發現Artemin蛋白可與Globo H有作用，而其Artemin/Globo H的相互作用也將探討於此篇論文中。 | zh_TW |
| dc.description.abstract | Aberrant glycolipids, especially the sialylated and fucosylated ones, give the most characteristic patterns of cancers. SSEA-4 (Stage-specific embryonic antigen-4), a sialyl-glycolipid, has long been used as a cell surface marker for pluripotent human embryonic stem cells. In cancer research, SSEA-4 and relative structure Globo H and SSEA-3 (Stage-specific embryonic antigen-3) also found in many cancer cells. In this thesis, we were developing antibodies against SSEA-4 for target validation study. We found SSEA-4 was expressed on pancreatic cancer cells and specimens. From mice immunized with a SSEA-4 synthetic conjugate, two IgG1 (MC45, MC48) and one IgM (MC46) monoclonal antibody were derived that recognizes the SSEA-4 structure. MC48 mAbs were calculated surface dissociation (KD) constant amount to 0.46 nM for SSEA-4 in glycan array assay. We have showed MC48 that is capable of binding to SSES-4 antigen expressed on pancreatic cancer cells and human pancreatic cancer tissue. The MC48 antibody also mediates complement-dependent cytotoxicity in pancreatic cancer cells and it also significantly inhibits pancreatic tumor growth in nude mice. Besides, MC48 convert to human IgG1, the chimeric antibody chi48 also showed that CDC in pancreatic cancer cells. The present studies indicated SSEA-4 mAbs could be explored as an immunotherapy in the treatment of pancreatic cancer patient.
To investigate the glycan binding proteins for glycolipid, we used human protein microarray with biotinylated Globo H glycan epitope (Globo H-biotin). Then the glycan-binding protein candidates of human protein microarray were further analyzed by ELISA and glycan microarray. The Artemin/Globo H interaction was also investigated in this study. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:02:34Z (GMT). No. of bitstreams: 1 ntu-103-D97642008-1.pdf: 7729555 bytes, checksum: 2725fe5a809ee7a88cf2026d41fbdce1 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | Table of Contents
誌謝 ii 摘要 iii Abstract iv Abbreviation vi Table of Contents viii CHAPTER 1 1 Introduction to Glycobiology 1 1.1 Definition of carbohydrate, glycan, saccharide, or sugar 1 1.2 Major classes of glycoconjugates and glycans 2 1.2.1 N-Linked glycosylation 4 1.2.2 O-Linked glycosylation 5 1.2.3 Proteoglycan, glycosaminoglycans (GAGs) 6 1.2.4 Glycolipid 7 1.3 Glycosyltransferases and glycan-processing Enzymes 9 1.4 Biological roles of glycans 10 1.5 Diseases of glycosylation 13 1.6 Glycolipids as targets for tumor immunotherapy 17 1.6.1 Stage-specific embryonic antigen 4 (SSEA 4) 18 1.6.2 Globo H 22 1.6.3 Stage-specific embryonic antigen-3 (SSEA-3) 25 1.7 Mechanisms of tumour cell killing by antibodies 28 1.8 Purpose in this thesis 31 CHAPTER 2 33 Developing antibodies for SSEA-4: . 33 2.1 Specific Aim 33 2.2 Results and discussion 33 2.2.1 Flow cytometric analysis of globo-series glycan on pancreatic cancer cell lines 34 2.2.2 Generation and characterization of SSEA-4 antibodies 36 2.2.3 Determination of the surface dissociation constant of SSEA-4 mAbs 41 2.2.4 SSEA-4 antibodies mediates complement-dependent cytotoxicity against pancreatic cancer cell Lines 42 2.2.5 mAb MC48 specifically recognizes pancreatic cancer cells and tissues 43 2.2.6 Growth inhibition of pancreatic cancer in nude mice by anti-SSEA-4 antibody 45 2.2.7 Isolation, construction, expression of chimeric antibody (chi48) from hybridoma 47 2.2.8 Chimeric antibody (chi48) mediates complement-dependent cytotoxicity against BxPC3 pancreatic cancer cell Lines 48 2.3 Conclusion 49 2.4 Materials and methods 51 CHAPTER 3 57 Investigation the binding protein for Globo H: 57 3.1 Specific Aim 57 3.2 Results and discussion 33 3.2.1 Synthesis of Globo H conjugated biotin 62 3.2.2 The affinity capture of Globo H‐binding proteins using protein array 62 3.2.3 Binding analysis of Globo H binding protein in ELISA plate and glycan array 64 3.2.4 Determination of the surface dissociation constant of Artemin for GH 66 3.2.5 Expression Profiles of GH-Related Structures in Breast Cancer Cells 67 3.2.6 Effect of forced expression of Artemin on mammary carcinoma cell MCF-7 and MDA-MB-231 68 3.3 Conclusion 70 3.4 Materials and methods 72 References 75 Content of Figures Figure 1.1. Definition of carbohydrate, glycan, saccharide, or sugar 1 Figure 1.2. Nine common monosaccharides found in vertebrate. 3 Figure 1.3. Major classes of glycoconjugates in vertebrate 3 Figure 1.4. The three major types of glycans 5 Figure 1.5. The major structure of glycosaminoglycans(GAGs) 7 Figure 1.6. Mammalian glycan linkages produced by glycosylation 10 Figure 1.7. Biological roles of glycans 12 Figure 1.8. Summary of tumor-associated carbohydrates in human. 16 Figure 1.9. Structure of SSEA-4, SSEA-3 and Globo H 18 Figure 1.10. Expression of globo-series GSLs in cancer cell lines 20 Figure 1.11. The glycan binding profile from SSEA-4 immunized mice 21 Figure 1.12. FKBP4 were mediated SSEA-4 trafficking in breast cancer cell 22 Figure 1.13. The glycan binding profile from Globo H immunized mice 24 Figure 1.14. Monoclonal antibodies currently FDA approved in oncology 29 Figure 1.15. Mechanisms of tumor cell killing by antibodies 30 Figure 2.1. Expression profiles of globo-series GSL epitopes in pancreatic cancer cell lines 35 Figure 2.2. The induced antibodies (IgG) collected from SSEA-4 immunized mice 36 Figure 2.3. The binding of mAb MC45, MC48 to SSEA-4 and its analogue on glycan array 38 Figure 2.4. The binding of mAb MC46 to SSEA-4 and its analogue on glycan array…………………………………………………………………………….…...36 Figure 2.5. Representative glycan structures on the printed array 39 Figure 2.6. The binding of mAb MC45, MC46 and MC48 to SSEA-4 on toal glycan array 40 Figure 2.7. Surface dissociation constants (KD,surf) of antibodies MC45, MC48 to SSEA-4. on microarray 41 Figure 2.8. SSEA-4 antibodies mediated Complement-Dependent Cytotoxicity of pancreatic cancer cells 42 Figure 2.9. Validation of SSEA-4 expression on cancer cell lines by MC48 Ab 44 Figure 2.10. Growth inhibition of pancreatic cancer in nude mice by anti SSEA-4 antibodies 46 Figure 2.11. Construction of human IgG1 expression 47 Figure 2.12. CDC assay using chimeric Ab (chi48) on pancreatic cancer cell BxPC3 48 Figure 3.1. Protein list of human protein microarray 60 Figure 3.2. Detection of protein-protein or protein-small molecular interaction using protein microarray 61 Figure 3.3. Synthesis of Globo H conjugated biotin. 62 Figure 3.4. The affinity capture of Globo H‐binding proteins on protein array………………………………………………………………………………....63 Figure 3.5. Globo H‐binding proteins detected on ELISA platform 64 Figure 3.6. Binding profiling of Artemin (ART) for Globo H analogues on glycan microarray 66 Figure 3.7. Determination of the surface dissociation constant of ART toward Globo H analogues on glycan array 67 Figure 3.8. Expression Profiles of GH-Related Structures in Breast Cancer Cells 68 Figure 3.9. Constriction of pCMV-Taq 4a-ARTN 67 Figure 3.10. Expression profiles of GH-related structures in breast cancer MCF-7 (a) Cells MDA-231(b) which transient expressed Artemin 69 | |
| dc.language.iso | en | |
| dc.title | SSEA-4抗體的開發與應用於胰臟癌之研究 | zh_TW |
| dc.title | Development of anti SSEA-4 antibodies for
targeting pancreatic cancer cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 吳宗益,沈家寧,蕭宏昇,吳漢忠,林劭品 | |
| dc.subject.keyword | SSEA-4,Globo H,SSEA-3,單株抗體,胰臟癌,醣類結合蛋白,蛋白質晶片,醣晶片,Artemin, | zh_TW |
| dc.subject.keyword | glycolipid,SSEA-4,Globo H,SSEA-3,monoclonal antibody,pancreatic cancer,immunotherapy,glycan-binding protein,protein microarray,Artemin, | en |
| dc.relation.page | 79 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-09-29 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 生物科技研究所 | zh_TW |
| 顯示於系所單位： | 生物科技研究所 | |
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