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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張崇毅(Chung-I Chang) | |
| dc.contributor.author | Jiun-Shyang Leou | en |
| dc.contributor.author | 柳鈞翔 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:16:41Z | - |
| dc.date.copyright | 2020-08-11 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-05 | |
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P., Tran, T., Lynn, J., Chen, J. Y., Volkmer, J. P., Agoram, B., Huang, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Chao, M. P., and Smith, S. M. (2018) CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma. N Engl J Med 379, 1711-1721 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17498 | - |
| dc.description.abstract | 先前的研究發現癌症細胞表面蛋白CD47與巨噬細胞表面上的SIRP-α蛋白結合會使得癌症細胞抑制巨噬細胞的吞噬作用進而逃脫免疫細胞的攻擊，而這個結合作用被視為髓細胞特有的免疫檢查點 (myeloid specific immune checkpoint)，目前有研究發現利用抗體去阻斷CD47與SIRP-α蛋白結合能夠促進巨噬細胞對癌症細胞的吞噬作用，然而此抗體會造成紅血球凝集而造成安全上的危害。因此抗體若能同時具有功效及安全性的話則會是個具有癌症治療潛力的抗體，為此，在本研究中，先開發了癌症病人噬菌體Fab抗體庫 (cancer specific phage-displayed Fab library)，且以此找尋到具有高親和力及專一性的抗體，之後將CwP1A1, CwP2F12及BrP1F11抗體可結晶區域片段(Fragment crystallizable region)改成IgG4的型式，進一步分析此三個IgG4 format抗體具有抑制CD47與SIRP-α的結合的能力，也能夠誘導巨噬細胞利用吞噬作用對白血病細胞株 (Leukemia cell line) Jurkat及 HL-60進行毒殺作用，並且不會造成抗體依賴型細胞介導的細胞毒性作用(antibody-dependent cell-mediated cytotoxicity, ADCC) 及細胞凋亡(apoptosis)。之後，紅血球凝集實驗結果發現我們所開發之抗體CwP1A1及BrP1F11不同於目前其他開發的抗體，並不會造成紅血球不正常的凝集，因此，之後若進行臨床試驗時則可以大大的降低其副作用風險。最後，在異體移植白血病及三陰性乳癌細胞株個別於重症聯合免疫缺陷小鼠 (SCID mice) 及裸鼠模式上，CwP1A1抗體具有非常好的抑制腫瘤效果，也因此，我們期許在之後能以此基礎去研發、改良出具有更好抑制腫瘤且具有更低副作用的免疫療法藥物。 | zh_TW |
| dc.description.abstract | The CD47/signal regulatory protein alpha (SIRP-) axis is a key molecular interaction that inhibits antitumor activation by macrophages and myeloid cells, thereby acting as a myeloid-specific immune checkpoint. Blocking CD47/ SIRP- interaction promotes phagocytosis of tumor cells. Currently, CD47 antibody in clinical trial showed RBC agglutination and this effect may cause safety risk issue. In this thesis new human CD47 blocking antibodies were identified from a cancer patient antibody Fab library. The anti-CD47 antibodies exhibited high affinity and specificity against recombinant and cell surface CD47, which are able to inhibit the CD47-SIRP- interaction comparable to Hu5F9-G4, which is a humanized CD47 blocking antibody currently under clinical investigations. The human IgG4-reformatted CD47 antibodies, CwP1A1, CwP2F12, and BrP1F11, were generated dependent on the result of affinity screening. The IgG4-reformatted CD47 blocking antibody were confirmed to be effective in treatment of a cancer since it is found that the IgG4-reformatted CD47 blocking antibody treated cancer cells, such as Jurkat-1 or HL-60 cells, and induced robust phagocytosis activity explicated by polarized THP-1 macrophages as well as peripheral blood mononuclear cell (PBMC), but not antibody-dependent cell-mediated cytotoxicity (ADCC) and apoptosis of tested cancer cells, in vitro. Furthermore, CwP1A1 and BrP1F11 did not induce hemagglutination of human RBCs compared to Hu5F9-G4. Finally, CwP1A1 showed the good anti-tumor activities in both hematologic and solid tumor cell lines mouse xenograft model. In the future, we will further confirm the safety of these antibodies and further study these antibodies in clinical trials. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:16:41Z (GMT). No. of bitstreams: 1 U0001-0508202010310200.pdf: 3339890 bytes, checksum: 9646e667e38b0f2da37ef9d618171b95 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 國立台灣大學博士學位論文口試委員會審定書 I
謝誌 II 中文摘要 III Abstract IV Abbreviation V Contents VIII List of Figures XI List of Tables XIII Chapter 1. Introduction and Research Background 1 1.1 Antibody structure and function 1 1.2 Innate and adaptive immunity 3 1.3 Immune checkpoint 4 1.4 Phagocytosis 6 1.5 CD47 7 1.6 CD47-SIRPα interaction 9 1.7 CD47 antibody progress 10 1.8 Phage display 11 1.9 Aims of study 14 Chapter 2. Materials and Methods 16 2.1 Construction of a human phage antibody library 16 2.2 Human antibody Fab library bio-panning against recombinant CD47 17 2.3 Enrichment test by phage ELISA 18 2.4 CD47 binder screening, sequencing analysis and reformatting 18 2.5 Cell culture, Antibody expression and purification 19 2.6 CD47 binding study 20 2.7 Cell Surface antigen-binding assay 21 2.8 Competition assay of CD47 binding using flow cytometry 21 2.9 The CD47-SIRP-α interaction blocking assay 22 2.10 In vitro antibody-mediated phagocytosis assay 22 2.11 Antibody-dependent cell-mediated cytotoxicity (ADCC) assay 23 2.12 Apoptosis assay 24 2.13 RBC surface antigen-binding assay and RBC aggregation assay 24 2.14 In vitro anti-CD47 antibody efficacy evaluation using mouse xenograft model 25 Chapter 3. Results 27 3.1 Human Fab library construction 27 3.2 Selection of a Fab phage antibody library specific for CD47 proteins 27 3.3 Human anti-CD47 antibodies binding affinity and specificity analysis 28 3.4 Human CD47 antibodies on CD47-SIRPα interaction blocking activities 30 3.5 Human CD47 antibodies promotes phagocytosis of cancer cells 30 3.6 Human CD47 antibodies did not induce ADCC and apoptosis 31 3.7 Human CD47 antibodies did not induce RBC aggregation 32 3.8 In vivo studies of CD47 antibodies confirm anti-tumor activity 33 Chapter 4. Conclusion 36 Chapter 5. Disccusion 37 References 74 | |
| dc.language.iso | en | |
| dc.title | 新型人類CD47抗體開發及其癌症免疫治療應用 | zh_TW |
| dc.title | The Development of Novel Human CD47 Antibodies for Cancer Immunotherapy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 吳漢忠(Han-Chung Wu),郭呈欽(Cheng-Chin Kuo),李雨青(Yu-Ching Lee),莊國祥(Kuo-Hsiang Chuang) | |
| dc.subject.keyword | CD47,SIRP-α,吞噬作用,紅血球凝集, | zh_TW |
| dc.subject.keyword | CD47,SIRP-α,phagocytosis,RBC hemagglutination, | en |
| dc.relation.page | 84 | |
| dc.identifier.doi | 10.6342/NTU202002435 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-08-06 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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