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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張世宗 | zh_TW |
| dc.contributor.advisor | Shih-Chung Chang | en |
| dc.contributor.author | 游博皓 | zh_TW |
| dc.contributor.author | Po-Hao Yu | en |
| dc.date.accessioned | 2023-10-03T16:49:45Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-10-03 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-09 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90605 | - |
| dc.description.abstract | 新型冠狀病毒 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) 已隨著全球大流行，迅速演化出不同的變異株。其中，Omicron (B.1.1.529) 變異株在S蛋白 (Spike) 受體結合區 (receptor-binding domain, RBD) 的大量突變，導致其能逃脫既有的疫苗與抗體保護力。Omicron的高傳播力也使帶有不同突變的Omicron亞型持續出現，因此，開發出廣效性中和抗體是對抗COVID-19疫情的長久之計。本研究以BA.2-RBD-hFc作為免疫小鼠之抗原，成功篩選出四株針對BA.2-RBD的單株抗體D1H5、D2G8、D1A4和D1B6。透過抗原決定位之分析以及RBD結合實驗，可知D1H5與D2G8的抗原決定位在RBD的高度保守區域，因而能廣泛地結合不同變異株的RBD。D1A4和D1B6則會因為來自BA.5與BQ.1變異株的L452R突變，喪失對RBD的結合能力。此外，除了D1H5具有對BA.5變異株的微弱中和力，其餘三株抗體皆無法中和SARS-CoV-2病毒。為了提升抗體的中和能力，將中和性抗體改造成雙專一性抗體 (bispecific antibodies, bsAbs) 是一種解方。本研究透過還原抗體鉸鏈區 (hinge region) 之雙硫鍵，再進行氧化，將中和性抗體S2-8D或S2-4A與無中和力的HR2單株抗體S2-8A重新組裝，成功製造出能結合兩種抗原決定位的雙專一性抗體bs8D8A與bs4A8A。此成果揭示了化學性改造對於開發雙專一性抗體之可行性。 | zh_TW |
| dc.description.abstract | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the global pandemic, has rapidly evolved into different variants. Among these variants, Omicron has garnered significant attention due to its extensive mutations on the receptor-binding domain (RBD) of Spike (S) protein, enabling it to evade vaccine and antibody therapies. The increased transmissibility of Omicron has led to the continuous emergence of subvariants with distinct mutations. Therefore, the development of broadly neutralizing antibodies (NAbs) is a long-term strategy to combat the COVID-19 pandemic. In this study, BA.2-RBD-hFc was employed as the antigen for mouse immunization, and four monoclonal antibodies (mAbs), D1H5, D2G8, D1A4, and D1B6, were successfully isolated and characterized. D1H5 and D2G8 were found to recognize highly conserved epitopes on RBDs of various SARS-CoV-2 variants. However, D1A4 and D1B6 lost their RBD-binding capabilities due to the L452R mutation found in BA.5 and BQ.1 subvariants. Furthermore, D1H5 showed weak neutralizing activity against BA.5 subvariant, but D2G8, D1A4, and D1B6 failed to neutralize SARS-CoV-2 authentic viruses. To enhance the neutralizing capacity of antibodies, engineering two mAbs into bispecific antibodies (bsAbs) is an effective approach. In this study, the SARS-CoV-2 NAbs S2-8D or S2-4A was re-assembled with the HR2-specific non-neutralizing mAb S2-8A by using a method which involves the reducing and re-oxidizing the disulfide bonds of antibody hinge regions to generate two bsAbs, bs8D8A and bs4A8A. This achievement highlights the feasibility of chemical modification in the development of bispecific antibodies. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-10-03T16:49:45Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-10-03T16:49:45Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 摘要 vii
Abstract viii 縮寫表 ix 第一章 緒論 1 1.1新型冠狀病毒 (SARS-CoV-2) 簡介 1 1.2 SARS-CoV-2表面S蛋白 2 1.3 SARS-CoV-2變異株 3 1.4 SARS-CoV-2 Omicron變異株 3 1.4.1 BA.1亞型 4 1.4.2 BA.2亞型 5 1.4.3 BA.5亞型 5 1.4.4 BA.2.75亞型 5 1.4.5 BQ.1亞型 6 1.4.6 XBB亞型 6 1.5 開發RBD中和性抗體 6 1.6 開發SARS-CoV-2雙專一性抗體 7 1.7 研究動機 8 第二章 材料與方法 9 2.1 實驗材料 9 2.1.1 大腸桿菌 (Escherichia coli, E. coli) 9 2.1.2 人類細胞 (Expi293FTM) 9 2.1.3 小鼠細胞 (Sp2/0-Ag14) 9 2.1.4 實驗小鼠 (BALB/cAnNCrl) 10 2.2 建構表現質體 10 2.2.1 聚合酶連鎖反應 (polymerase chain reaction, PCR) 10 2.2.2 限制酶截切反應 11 2.2.3 瓊脂糖凝膠電泳 (agarose gel electrophoresis) 與核酸純化 12 2.2.4 DNA連接反應 (DNA ligation) 12 2.2.5 質體轉型 (plasmid transformation) 與表現質體之篩選 12 2.2.6 SARS-CoV-2 Omicron Spike RBD表現質體之建構 13 2.2.7 RBD丙胺酸掃描點突變 (alanine scanning mutagenesis, ASM) 14 2.2.8 SARS-CoV-2 S2片段表現質體之建構 14 2.3 表現重組蛋白質 15 2.3.1 真核表現系統 (Expi293F™) 15 2.3.2 原核表現系統 (E. coli BL21(DE3)) 15 2.4 蛋白質純化方法 16 2.4.1 蛋白質純化儀器 16 2.4.2 Protein A管柱親和層析法 16 2.4.3 Protein G管柱親和層析法 17 2.4.4 Ni-NTA親和層析法 17 2.4.5 蛋白質脫鹽 18 2.5 蛋白質分析方法 18 2.5.1 Bradford蛋白質定量法 18 2.5.2 十二烷基硫酸鈉聚丙烯醯胺凝膠電泳 (SDS-PAGE) 18 2.5.3 CBR染色法 19 2.5.4 西方墨點法 (Western blotting) 19 2.5.5 酵素結合免疫吸附分析法 (ELISA) 19 2.6 SARS-CoV-2 Omicron-RBD抗體之製備 20 2.6.1 小鼠免疫 20 2.6.2 抗血清採樣 20 2.6.3 製備融合瘤細胞 (Hybridoma Cell) 21 2.6.4 融合瘤細胞單株化 22 2.7 Omicron-RBD抗體結合位之分析 22 2.7.1 Omicron-RBD抗體對RBM之結合力 22 2.7.2 分析Omicron-RBD抗體於RBM之結合區 22 2.7.3 透過RBD丙胺酸掃描點突變分析抗體之抗原決定位 23 2.8 分析抗體對不同Omicron變異株的結合能力 23 2.9 分析抗體對SARS-CoV-2病毒之中和能力 24 2.9.1 分析抗體抑制RBD-hACE2交互作用之能力 24 2.9.2 SARS-CoV-2病毒溶斑抑制試驗 (Plague Reduction Assay) 25 2.10 開發S2雙專一性抗體之融合融合瘤細胞 25 2.10.1 S2抗體融合瘤細胞培養 25 2.10.2 製備S2抗體融合融合瘤 (Hybrid Hybridoma) 細胞 26 2.11 透過改造S2抗體製備S2雙專一性抗體 26 2.11.1 製備抗原親和管柱 26 2.11.2 測試抗原親和管柱的專一性 27 2.11.3 選擇性還原S2抗體雙硫鍵之方法 27 2.11.4 抗體雙硫鍵之再氧化 (Re-oxidation) 28 2.11.5 以抗原親和管柱純化S2雙專一性抗體 28 第三章 結果 29 3.1 Omicron RBD、RBM重組蛋白質表現與純化 29 3.2 免疫小鼠血清分析 29 3.3 單株抗體製備與純化 29 3.4 分析BA.2-RBD抗體之抗原結合位 30 3.4.1 分析抗體對RBM之結合力 30 3.4.2 分析抗體於RBM之結合區 30 3.4.3 分析抗體之抗原決定位 30 3.5 分析抗體對不同Omicron變異株之結合力 31 3.5.1 抗體對BA.5-RBD之結合力 31 3.5.2 抗體對新型Omicron變異株之結合力 32 3.6 分析抗體抑制RBD-hACE2交互作用之能力 33 3.6.1 製備hACE2重組蛋白質 33 3.6.2 競爭型ELISA分析抗體抑制RBD-hACE2交互作用之能力 33 3.7 透過病毒溶斑抑制試驗分析抗體之中和能力 33 3.8 開發S2雙專一性抗體 34 3.8.1 製備S2螢光抗原 34 3.8.2 S2單株抗體之純化與專一性測試 35 3.8.3 開發S2雙專一性抗體之融合融合瘤細胞 35 3.8.4 製備與測試抗原親和管柱 35 3.8.5 選擇性還原S2抗體雙硫鍵 36 3.8.6 抗體雙硫鍵之再氧化以形成雙價抗體 37 3.8.7 以抗原親和管柱純化S2雙專一性抗體 37 第四章 討論 39 4.1 開發Omicron BA.2-RBD單株抗體 39 4.2 開發SARS-CoV-2 S2雙專一性抗體 40 參考文獻 43 圖與表 51 圖1、Omicron RBD、RBM重組蛋白質純化 52 圖2、免疫小鼠血清分析 53 圖3、單株抗體純化與型別鑑定 54 圖4、抗體對RBM之結合力 55 圖5、抗體於RBM之結合區 56 圖6、分析抗體之抗原決定位 58 圖7、抗體對BA.5-RBD之結合力 60 圖8、抗體對新型Omicron變異株之結合力 61 圖9、競爭型ELISA分析抗體對RBD-hACE2 interaction的抑制能力 62 圖10、透過病毒溶斑抑制試驗分析抗體之中和能力 64 圖11、S2螢光抗原純化 65 圖12、S2單株抗體之純化與專一性測試 66 圖13、開發S2融合融合瘤細胞 67 圖14、測試抗原親合管柱對抗體之專一性 68 圖15、以2-MEA選擇性還原S2抗體雙硫鍵及雙硫鍵之再氧化 69 圖16、以抗原親和管柱純化S2雙專一性抗體 70 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 雙專一性抗體 | zh_TW |
| dc.subject | SARS-CoV-2 | zh_TW |
| dc.subject | Omicron變異株 | zh_TW |
| dc.subject | S蛋白 | zh_TW |
| dc.subject | 受體結合區 | zh_TW |
| dc.subject | 廣效性中和抗體 | zh_TW |
| dc.subject | Spike protein | en |
| dc.subject | SARS-CoV-2 | en |
| dc.subject | Bispecific antibodies | en |
| dc.subject | Broadly neutralizing antibodies | en |
| dc.subject | RBD | en |
| dc.subject | Omicron variant | en |
| dc.title | 抗新型冠狀病毒Omicron變異株之單株抗體與雙專一性抗體研究 | zh_TW |
| dc.title | Study of Monoclonal and Bispecific Antibodies against SARS-CoV-2 Omicron Variants | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 楊建志;林翰佑 | zh_TW |
| dc.contributor.oralexamcommittee | Chien-Chih Yang;Han-You Lin | en |
| dc.subject.keyword | SARS-CoV-2,Omicron變異株,S蛋白,受體結合區,廣效性中和抗體,雙專一性抗體, | zh_TW |
| dc.subject.keyword | SARS-CoV-2,Omicron variant,Spike protein,RBD,Broadly neutralizing antibodies,Bispecific antibodies, | en |
| dc.relation.page | 70 | - |
| dc.identifier.doi | 10.6342/NTU202303873 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2023-08-11 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | 2026-08-09 | - |
| 顯示於系所單位： | 生化科技學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-111-2.pdf 此日期後於網路公開 2026-08-09 | 5.54 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。