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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳宗益(Chung-Yi Wu) | |
| dc.contributor.author | Chin-Wei Lin | en |
| dc.contributor.author | 林津瑋 | zh_TW |
| dc.date.accessioned | 2021-06-16T09:36:45Z | - |
| dc.date.available | 2022-02-17 | |
| dc.date.copyright | 2017-02-17 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-02-11 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59763 | - |
| dc.description.abstract | Antibodies are crucial glycoproteins that consist of two antigen binding fragments (Fab) and one crystalizable fragment (Fc). At the Fc region, there are asparagine-linked glycosylations which function to mediate and modulate its recruitments or interactions with various effector cells or receptors. Through such modulations, one antibody can display different strength in functions, including cancer killing, pathogen defending, and anti-inflammation, etc. Pharmaceutically, many FDA-approved immunoglobulin G monoclonal antibodies have been successfully administrated to patients with leukemia, solid tumors, or autoimmune diseases. However, these antibodies are all heterogeneous in glycosylation and may contain few or none of the optimal glycan form for best efficacy of treatment. Therefore, high dosage of antibody is often indispensable and it follows high cost and high frequency of injection. In addition, the inaccessibility of pure antibody with homogeneous glycosylation further troubles researchers in defining and comparing the impact of each specific Fc glycan on activity, half life and side effects.
To overcome the aforementioned problems, various well-defined homogeneous glycosylated antibodies were prepared using one-pot enzymatic reaction to remove the whole bunch of glycans, followed by re-attaching the defined glycans back to antibodies for activity assessment. Significantly, it was found that antibodies with the 2,6-sialylated Fc glycosylation, a known potent composition of intravenous immunoglobulin for exhibiting anti-inflammatory activity, display superior binding affinity towards FcγRIIIa/FcγRI, remarkable antibody-dependent cell-mediated cytotoxicity（ADCC）against both breast cancer cells, and good anti-H1N1 influenza activity, implying multifaceted functions derived from single Fc glycan form of 2,6-sialylation. Furthermore, both the pairing and the different modifications of Fc glycans, including the core-fucose, the branch, the length, and the sialylation linkage were investigated to supply a clear picture about the interactions with the FcγRIIIa/FcγRI and the corresponding effectors functions, including the ADCC and oxidative burst. The results indicate that the 1,6’-branch is more potent to increase the affinity towards FcγRIIIa/FcγRI than that of the 1,3’-branch and such interactions intensify as the length of Fc glycans increase. Meanwhile, it was also illustrated that the 2,3-sialylation disrupts the aforementioned interaction and shows elevated dissociation rate constants whereas the 2,6-sialylation maintains the affinity compared to the non-sialylated counterpart. Among the various antibodies with different Fc glycan modifications, the adverse effect of core-fucosylation on the affinity exceeds the others in the case of anti-FcγRIIIa but lessens for FcγRI. Moreover, not only the affinity but also the threshold for activating FcγRIIIa was found to be mediated by various Fc glycans. Interestingly, the Fab/Fc interdomain interaction and the minor adjustments of Fab binding by the Fc glycans were observed as well. The affinity and threshold for FcγRs activation might relate to the the efficiency of antigen uptake whereas the fine-tuning of the Fab recognition could lead to the distinct footprint for presenting to T cells after the proteolytic processing. Based on the results in this study and previous reports, an alternative affinity maturation mediated by the Fc glycosylation was implied. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T09:36:45Z (GMT). No. of bitstreams: 1 ntu-106-D98223204-1.pdf: 13503970 bytes, checksum: fcb2d75da4c8d04f7ab71c6cc2bf8eef (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | Acknowledge i
中文摘要 ii ABSTRACT iii I. Introduction 1.1 Immunoglobulin G antibodies 1 1.2 Therapeutic antibodies 3 1.3 Fc glycosylation 4 1.4 Interactions towards FcγRs and relevant diseases 6 1.5 Modulations and allosteric interactions inside antibodies 7 1.6 Fc glycosylation engineering and pertinent glycosynthases 8 II. Results and Discussion 2.1 Glycoengineering of IgG1 antibody 11 2.1.1 Fucosidase screening and the preparation of antibodies with mono-GlcNAc 16 2.1.2 Transglycosylation of oxazoline glycans to antibodies 21 2.2 FcγRIIIa binding affinity of various glycoengineered Herceptins in SPR 27 2.2.1 The relevance of glycan length to the affinity of anti-FcγRIIIa 31 2.2.2 The relevance of glycan branch to the affinity of anti-FcγRIIIa 32 2.2.3 The relevance of sialylation linkage to the affinity of anti-FcγRIIIa. 33 2.2.4 The relevance of bisecting GlcNAc to the affinity of anti-FcγRIIIa 33 2.2.5 The relevance of fucosylation to the affinity of anti-FcγRIIIa 34 2.2.6 The binding mode of FcγRIIIa to Herceptins with various glycan forms 37 2.3 The V158-FcγRIIIa mediated ADCC reporter bioassay of glycoengineered Herceptins 42 2.4 FcγRI binding affinity of various glycoengineered Herceptins in SPR 45 2.5 The multifaceted functions of 2,6-NSCT glyco-remodeling in antibodies 51 2.5.1 Theprotection of 2,6-NSCT glycan modification in anti-viral antibodies 52 2.5.2 The unknown influence of the 2,6-NSCT anti-PD1 antibody on the immune modulation 56 2.6 The Fab/Fc interdomain interaction and Fc glycosylations 57 2.6.1 The effect of Fab/Fc interdomain interaction and Fc glycans on the binding towards FcγRIIIa 58 2.6.2 The fine tuning of antigen recognition mediated by Fc glycosylations 68 2.7 Glycoengineering of IgG with hemi-Fc glycosylation 78 III. Conclusion 95 IV. Materials and Methods 97 4.1 Glycan preparation and activation for transglycosylation 98 4.1.1 Preparation of 2,6-sialyl complex type glycan (2,6-SCT)from hen eggs 98 4.1.2 Synthesis of oxazoline-sugars 99 4.2 Engineering of antibodies: Herceptin®, Rituximab, FI6, Humira®, ant-Ebola Ab (4G7, KZ52, c13C6, 2G4), anti-PD1 IgG4 101 4.2.1 Identification of N-linked glycosylation on Ab 101 4.2.2 Engineering of antibodies 101 4.3 Bindings and assays 106 4.3.1 Anti-FcγRI and IIIa binding 106 4.3.2 Anti-HER2 binding assay 107 4.3.3 ADCC reporter assay 107 4.3.4 Flow cytometry-based binding assay 108 4.3.5 Superoxide burst assay 108 V. References 110 Appendices 118 Appendix 1. Denotations for glycan donors 119 Appendix 2. Xtract (deconvoluted) LTQFT UltraMS spectra of trypsinized glycopeptides for glycoengineered Herceptins 120 Appendix 3. Major glycan form detected from deconvoluted MS analysis of glycoengineered Herceptins 126 Appendix 4. SDS-PAGE of glycoengineering antibodies 127 Appendix 5. The comparison of NS2S3 and 2,6-NSCT Herceptins in binding towards FcγRIIIa and FcγRI 131 Appendix 6. Supplementary data respecting glycan preparation and activation for transglycosylation 132 Appendix 7. ESI/MS analysis of intact antibodies with Fc glycans of mono-GlcNAc, hemi- or fully-2,6-NSCT 146 | |
| dc.language.iso | en | |
| dc.subject | 抗體依賴細胞介導的細胞毒殺作用 | zh_TW |
| dc.subject | 唾液酸醣化 | zh_TW |
| dc.subject | 噁唑咻醣 | zh_TW |
| dc.subject | 噁唑咻醣 | zh_TW |
| dc.subject | 唾液酸醣化 | zh_TW |
| dc.subject | 抗體依賴細胞介導的細胞毒殺作用 | zh_TW |
| dc.subject | 抗體醣化修飾 | zh_TW |
| dc.subject | 醣均質化 | zh_TW |
| dc.subject | 抗體醣化修飾 | zh_TW |
| dc.subject | 醣均質化 | zh_TW |
| dc.subject | Fc glycosylation | en |
| dc.subject | glycoengineered antibodies | en |
| dc.subject | homogeneous antibodies | en |
| dc.subject | endoglycosidase | en |
| dc.subject | sugar oxazoline | en |
| dc.subject | antibody-dependent cell-mediated cytotoxicity | en |
| dc.subject | Fc glycosylation | en |
| dc.subject | glycoengineered antibodies | en |
| dc.subject | homogeneous antibodies | en |
| dc.subject | endoglycosidase | en |
| dc.subject | sugar oxazoline | en |
| dc.subject | antibody-dependent cell-mediated cytotoxicity | en |
| dc.title | 免疫球蛋白G的Fc醣體改造與其相關活性研究 | zh_TW |
| dc.title | Engineering of IgG Fc Glycosylation and the Relevant Activity Studies | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 方俊民(Jim-Min Fang) | |
| dc.contributor.oralexamcommittee | 翁啟惠(Chi-Huey Wong),張子文(Tse-Wen Chang),謝世良(Shie-Liang Hsieh),馬徹(Che Alex Ma) | |
| dc.subject.keyword | 抗體醣化修飾,醣均質化,抗體依賴細胞介導的細胞毒殺作用,唾液酸醣化,噁唑咻醣, | zh_TW |
| dc.subject.keyword | Fc glycosylation,glycoengineered antibodies,homogeneous antibodies,endoglycosidase,sugar oxazoline,antibody-dependent cell-mediated cytotoxicity, | en |
| dc.relation.page | 147 | |
| dc.identifier.doi | 10.6342/NTU201700515 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-02-12 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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