臺灣博碩士論文加值系統

肝癌為全球性致死性疾病，於晚期肝癌的治療中，蕾莎瓦 (Sorafenib) 為目前唯一的常規用藥。然而，藥物反應不佳、抗藥性、嚴重副作用已被廣泛報導。因此，發展新的肝癌治療策略成為至關重要的議題。肝癌衍生生長因子 (HDGF) 為一種在多種癌症皆廣泛發現之致癌因子，亦與肝癌的發展高度相關。為發展HDGF之中和性抗體，噬菌體顯現法 (phage display) 提供了全人類化抗體之離體 (in vitro) 篩選策略。本研究使用獨特的 Fc融合蛋白/protein G磁珠篩選平台進行生物掏洗 (biopanning)，成功的由噬菌體顯現人類單鏈抗體庫 (phage displayed human naïve scFv library) 篩選出十三株HDGF 親和性噬菌體。將這些HDGF 親和性噬菌體序列重新構築為全人類IgG進行抗體生產，並以酵素免疫分析法 (ELISA)、免疫螢光染色 (immunofluorescence) 及shHDGF 之Huh7 細胞株對抗體進行功能驗證。其中，hmAb-7抗體展現良好的癌症抑制效果，於Huh7, HepG2, SK-Hep1三株細胞中抑制了包含細胞生長、群落生成、侵犯行為及球體生成等癌化現象。而hmAb-7抗體的癌症抑制現象與抑制PI3K/AKT/mTOR訊息傳遞途徑有關。此外，hmAb-7 抗體抑制癌症侵犯能力主要藉由抑制MMP-2蛋白質活性造成；hmAb-7 抑制球體生成則主要由抑制癌症幹細胞相關基因之表現。將Huh7及HepG2細胞株進行連續球體培養，這些細胞呈現較強之群落生成及球體生成特性，然而這些癌化行為依然有效的被hmAb-7抗體所抑制。此外，於Huh7細胞異種移植之NOD/SCID免疫缺陷小鼠模式中，hmAb-7抗體略為抑制腫瘤生成 (p = 0.1091) 並延長整體存活率 (Overall survival; OS) 達8天。雖然HDGF中和性抗體於體內 (in vivo) 實驗對肝癌之抑制未達顯著差異，基於細胞離體 (in vitro) 實驗對肝癌細胞有效抑制，與其他藥物進行合併治療 (combination therapy) 及輔助治療 (adjuvant therapy) 將可提供新的治療途徑以加強療效。此外，於本研究已建立HDGF 檢測之三明治酵素連結免疫吸附法 (sandwich ELISA)；此sandwich ELISA 於10-0.15625 ng/ml濃度中呈現良好的線性範圍，且已可應用於人類及大鼠的血清檢測。本研究所建立的HDGF抗體亦被使用於其他延伸應用上，包含止痛應用、抑制癌症幹細胞及對於蕾莎瓦 (Sorafenib) 具有抗藥性之Huh7-SR細胞株。於實驗中發現，hmAb-7抗體於慢性收縮性損傷 (chronic constrictive injury; CCI) 合併腺病毒 (adenovirus) 傳送HDGF基因 (AdHDGF) 之大鼠實驗模式具有良好的止痛效果。此外，hmAb-7抗體不只對於連續性球體細胞培養之Huh7及HepG2細胞具有良好的抑制效果；對於蕾莎瓦抗藥性之Huh7-SR細胞株中，hmAb-7抗體依然展現了良好的群落及球體抑制能力。最後，以腺病毒攜帶對抗HDGF單鏈抗體 (scFv) 之基因傳送亦能有效於Huh7及Huh7-SR細胞中抑制群落及球體生成。以腺病毒攜帶單鏈抗體之基因傳送方式將能提供新的治療途徑，並應用於對抗HDGF療法及相關基礎研究。

Hepatocellular carcinoma (HCC), a deadly disease worldwide. For advanced HCC therapy, Sorafenib is the only conventional drug, however, low response rate, drug resistance, and strong side effects had been reported in Sorafenib therapy. Therefore, investigation of novel therapeutic strategy is a critical issue. HDGF is a cancerous factor in various cancer types including HCC. To develop anti-HDGF neutralizing antibody, phage display technology provides an effective in vitro selection strategy to identify fully human antibody. In the biopanning, thirteen HDGF affinity phage clones had been identified from phage display human naïve scFv library using unique Fc fusion protein/protein G dynabeads method. After fully human IgG construction and production, these antibodies were further confirmed binding affinity using ELISA, immunofluorescence, and HDGF conditional knockdown Huh7 cell line. Among them, hmAb-7 exhibited multiple anti-cancer activity, including cell growth, colony formation, invasion and sphere formation in Huh7, HepG2, and SK-Hep1 cells. The anti-cancer effects of hmAb-7 might participated with downregulation of PI3K/AKT/mTOR signaling pathway. The hmAb-7 inhibits of invasion through MMP-2 down-regulation; sphere formation was eliminated through downregulation of cancer stemness genes. In continuously cultured Huh7 and HepG2 cells, these cells present higher colony and spheroid forming features, however, the cancerous behavior able to abolish through hmAb-7 treatment. In sorafenib resistant Huh7 cells, hmAb-7 presents colony and sphere inhibition ability. Furthermore, the Huh7 xenograft model in NOD/SCID mice was performed and the data indicated that hmAb-7 slightly inhibited tumor growth (p = 0.1091) and prolong the overall survival for 14 days. Although anti-HDGF hmAb-7 single treatments not significantly inhibit tumor growth in vivo, but based on the cancerous inhibition effects in vitro, combination therapy might provide an approach to enhance therapeutic effect. Furthermore, a HDGF sandwich ELISA platform with well linear range between 10-0.15625 ng/ml has been established and able to detect the HDGF level in human and rat serum. Anti-HDGF antibody was also used for extended applications, included in analgesic application and allow to treat cancer stemness and Sorafenib drug resistant Huh7 cells (Huh7-SR). Our finding indicated anti-HDGF hmAb-7 exhibited analgesic effect in rat chronic constrictive injury (CCI) model plus with Adenoviral HDGF gene delivery. Besides, hmAb-7 not only shown sphere and colony inhibitory effects in continuous spheroid cell cultured Huh7 and HepG2 cells, but also inhibited cancerous behaviors in Huh7-SR cells. Finally, adenovirus mediated anti-HDGF-scFv gene delivery suppressed the colony and sphere formation in both Huh7 and Huh7-SR cells. The adenovirus mediated scFv gene delivery provided a novel approach for anti-HDGF therapy and allowed for further basic studies.

論文審定書 i
中文摘要 ii
Abstract iv
Contents vi
Abbreviations ix
Chapter 1 Background 1
1. General Introduction 1
1.1 Hepatocellular Carcinoma 1
1.2 Screening and Current Therapeutic Strategy for HCC 3
1.3 Hepatoma-derived growth factor (HDGF) 4
1.4 Therapeutic Antibody and Market Review 7
2. Specific Aims 12
Chapter 2 Identification of Anti-HDGF Fully Human Antibodies from Phage-Displayed Human Naïve Library 13
2.1 Introduction 13
2.2 Materials and Methods 15
2.2.1 Cloning, construction, and production of secreted HDGF-Fc fusion protein in 293T cells 15
2.2.2 Biopanning from phage displayed human naïve scFv library using protein G dynabeads method 16
2.2.3 Fully human IgG production in Expi293TM expression system 17
2.2.4 Fully human IgG purification 18
2.2.5 Enzyme-linked immunosorbent assay (ELISA) 18
2.2.6 Western blot analysis 19
2.2.7 Preparation of HDGF conditional knockdown Huh7 cells 20
2.2.8 Immunofluorescent staining 20
2.2.9 Cell invasion assay 21
2.2.10 Colony formation 22
2.2.11 Sphere formation assay 22
2.2.12 ROS generation assay 23
2.2.13 Statistical analysis 23
2.3 Results 24
2.3.1 Construction, production, and confirmation of HDGF-Fc fusion protein 24
2.3.2 Biopanning from phage displayed human naïve scFv library 24
2.3.3 Evaluation of HDGF affinity phages 26
2.3.4 Fully human IgG production and functional test 26
2.3.5 Inhibitory effects of fully human anti-HDGF antibodies in HCC cells 27
2.4 Discussion 29
2.5 Figures and Legends 35
Chapter 3 Human Anti-HDGF HmAb-7 Antibody Inhibit Multiple Cancerous Behavior in HCC Cell Lines 52
3.1 Introduction 52
3.2 Materials and Methods 54
3.2.1 Cell culture 54
3.2.2 Binding assay using flow cytometry 54
3.2.3 Western blot analysis 55
3.2.4 Realtime quantitative PCR 55
3.2.5 Determination of dissociation constant (Kd) using ELISA method 56
3.2.6 Immunofluorescence staining 56
3.2.7 Cell invasion assay 57
3.2.8 Western blot analysis 57
3.2.9 Zymography analysis 58
3.2.10 Colony formation assay 58
3.2.11 Sphere formation assay 59
3.2.12 Huh7 xenograft NOD/SCID model 59
3.2.13 Statistical analysis 60
3.3 Results 61
3.3.1 Characterization of anti-HDGF hmAb-7 61
3.3.2 Anti-HDGF hmAb-7 inhibits invasive behavior in liver cancer cells 62
3.3.3 Anti-HDGF hmAb-7 inhibits colony formation and PI3K/AKT/mTOR signaling 63
3.3.4 Anti-HDGF hmAb-7 inhibits sphere formation and cancer stemness related gene expression profile 64
3.3.5 Anti-HDGF hmAb-7 briefly reduces of tumor growth in Huh7 xenograft NOD/SCID model 65
3.4 Discussion 67
3.5 Figures and Legends 75
Chapter 4 Establish of HDGF Sandwich ELISA Platform and Extended Applications Using Anti-HDGF Antibodies 90
4.1 Introduction 90
4.2 Materials and Methods 94
4.2.1 Cell culture 94
4.2.2 Generation of mouse anti-HDGF CmA9#8 antibody from hybridoma derived Ascites 95
4.2.3 Screening of capture antibody for HDGF sandwich ELISA 95
4.2.4 Optimized protocol for HDGF sandwich ELISA 96
4.2.5 Immunofluorescence staining in parafilm embedded tissue 97
4.2.6 Chronic constrictive injury (CCI) model in rats 97
4.2.7 Western blotting 98
4.2.8 The cDNA microarray in HDGF treated Huh7 cells 98
4.2.9 Sphere formation assay 99
4.2.10 Colony formation assay 99
4.2.11 Invasion assay 100
4.2.12 Adenovirus mediated anti-HDGF scFv-4-40 gene delivery 101
4.2.13 Statistical analysis 101
4.3 Results 102
4.3.1 Establish of HDGF sandwich ELISA platform 102
4.3.2 Anti-HDGF antibody inhibited neuropathic pain in rat CCI model 104
4.3.3 Anti-HDGF hmAb-7 antibody presents sphere and colony inhibition in continuously spheroid cultured HCC cells and Sorafenib resistant Huh7 (Huh7-SR) cell line 107
4.3.4 Adenovirus mediated anti-HDGF scFv-4-40 gene delivery effectively inhibit cancerous behaviors in Huh7 and Huh7-SR cells 108
4.4 Discussion 110
4.5 Figures and Legends 122
References 141
Appendix 162

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