臺灣博碩士論文加值系統

甲氧基聚乙二醇 (methoxy PEG) 被接附在許多蛋白質、肽、核酸和奈米藥物上，用以提高它們的生物相容性。然而，抗聚乙二醇的抗體已存在於許多的個體中，並且可以在施打聚乙二醇化修飾藥物後產生。與聚乙二醇“主鏈”相結合的抗聚乙二醇抗體已知會加速聚乙二醇修飾藥物的清除並對藥物活性和安全性產生不利影響，但針對聚乙二醇末端甲氧基結合的抗聚乙二醇甲氧基抗體是否影響聚乙二醇化藥物還尚無研究。在此次研究中，我們藉由經測定過會結合於聚乙二醇主鏈（抗聚乙二醇）或聚乙二醇末端甲氧基（抗聚乙二醇甲氧基）的單株克隆抗體G和M來探討這些抗體是如何影響具有單支聚乙二醇鏈、單岔分支狀聚乙二醇鏈、或多支聚乙二醇鏈的蛋白以及聚乙二醇化脂質體。我們發現抗聚乙二醇主鏈抗體可以和所有種類的聚乙二醇化物質形成大號免疫複合物，但抗聚乙二醇甲氧基抗體唯獨只和聚乙二醇化脂質體形成大型免疫複合物。抗聚乙二醇抗體G和M都會加速所有聚乙二醇化化合物的清除，但抗聚乙二醇甲氧基抗體不會影響具有單支或分支狀聚乙二醇分子的蛋白質的清除速率。另外，肝臟中的庫佛氏細胞主要吞噬聚乙二醇化脂質體，而抗聚乙二醇抗體和抗聚乙二醇甲氧基抗體的存在則是會使含有多量聚乙二醇鏈的蛋白被肝竇內皮細胞所攝取。我們的實驗結果顯示相較於抗聚乙二醇抗體，抗聚乙二醇甲氧基抗體對於聚乙二醇化物質的免疫複合物形成和清除率更取決於修飾物質上聚乙二醇的結構狀態；抗聚乙二醇甲氧基抗體不會擾動只具有單支或支鏈狀聚乙二醇分子的化合物，但會對於結構中聚乙二醇鏈數量的增加的化合物有越來越大的影響。

Proteins, peptides, nucleic acids, and nanomedicines are commonly modified with methylated polyethylene glycol (mPEG) to improve their compatibility with living systems. However, after being exposed to pegylated medications, many persons naturally generate antibodies that adhere to PEG. Despite the fact that antibodies binding to the PEG backbone may decrease drug activity and increase elimination, research about the impact of anti-mPEG antibodies, which target the terminal methoxy end of mPEG, on the effectiveness and safety of pegylated pharmaceuticals is currently lacking. Here, we investigated how pegylated proteins or liposomes with one PEG chain, a single branched PEG chain, or numerous PEG chains could be affected by anti-PEG and anti-mPEG antibodies. Although anti-PEG antibodies can create immune complexes of significant size with all pegylated compounds, anti-mPEG antibodies can combine and produce massive complexes only with pegylated liposomes. Also, both IgG and IgM antibodies binding to PEG backbone accelerated the removal of compounds that had been pegylated; however, antibodies targeting mPEG had no impact on the clearance of proteins that included one or a branched PEG component. Kupffer cells in the liver were primarily responsible for engulfing pegylated liposomes. Anti-PEG and anti-mPEG antibodies, however, made it easier for a highly pegylated protein to enter liver sinusoidal endothelial cells. According to our research, when using anti-mPEG antibodies, immune complex formation and drug clearance are based on the pegylation structure as opposed to anti-PEG antibodies. Anti-mPEG antibodies can bypass products with just one or a branching mPEG molecule, while items with more intricate PEG structures become more susceptible.

Acknowledgements ......................................................................................................I
Contents .....................................................................................................................III
List of Tables.............................................................................................................VI
List of Figures ............................................................................................................VI
List of Appendix……………..……………………………………………………VII
Chinese Abstract.......................................................................................................1
Abstract..........................................................................................................3
Chapter 1 Introduction ...................................................................................4
1.1 Biological Drug modification…………………….………………………………..4
1.2 Polyethylene glycol (PEG)…...............................................................................5
1.3 Anti-PEG antibodies........................................................................................7
1.3.1 Animal studies.............................................................................7
1.3.2 Clinical studies………………………............................................8
1.3.3 Prevalence of pre-existing anti-PEG antibodies……………………10
1.4 Methoxy PEG............................................................................................11
1.5 Mechanisms of anti-PEG antibody formation………….………………………12
1.6 Anti-PEG antibody binding to mPEG………………………………………13
1.7 Adverse effect of anti-PEG antibody…………………………………………..13
Goal and Significance...........................................................................................15
Chapter 2 Materials and methods ......................................................................16
2.1 Reagents...............................................................................................16
2.2 Cell cultures.......................................................................................................16
2.3 Antibodies......................................................................................................16
2.4 Antibody class switch by CRISPR/Cas9..............................................................17
2.5 Preparation of mPEG conjugated BSA and E. coli β-glucuronidase.................17
2.6 Preparation of fluorescent pegylated proteins....................................................18
2.7 Preparation of fluorescent liposomes................................................................19
2.8 Anti-PEG antibody assay............................................................................19
2.9 In vitro immune complex (IC) formation..............................................................20
2.10 Ex vivo immune complex binding by PBMCs or Kupffer cells……….................20
2.11 Cryo-electron Microscopy of Onivyde......................................................22
2.12 125I-protein labeling................................................................................22
2.13 Characterization of immune-complex (ICs) formation with size-exclusion chromatography................................................................................22
2.14 Immune complex uptake by RAW 264.7 cells...............................................23
2.15 Accelerated blood clearance of pegylated compounds........................................23
2.16 Biodistribution of pegylated compounds………………………………..………24
2.17 Mouse liver perfusion and liver cells isolation...............................................24
2.18 Statistical analysis..........................................................................................24
Chapter 3 Results ...........................................................................................25
3.1 Characterization of binding of anti-PEG and anti-mPEG antibodies to pegylated molecules…….……...………………………………..................................................25
3.2 Characterization of binding of anti-PEG and anti-mPEG antibodies to pegylated proteins and liposomes………………………………………………………….....26
3.3 In vitro immune complex formation.................................................................... 27
3.4 Measurement of ICs size by Dynamic light scattering (DLS).............................28
3.5 Gel filtration analysis of ICs……..………………………………………….….30
3.6 Immune complex uptake in RAW 264.7 cells……………………………..31
3.7 Accelerated blood clearance of pegylated compounds…….……………………...32
3.8 Biodistribution of pegylated products in the presence of anti-PEG or anti-mPEG antibodies…………………………………………………………………………….35
3.9 Biodistribution of multiple PEG conjugated products in non-hepatocyte cells in the presence of anti-PEG or anti-mPEG antibodies………………………………..…36
Chapter 4 Discussion………..………………………………………………………39
Conclusions………………………………………………………………………..51
Tables…………………………………………………………………………..…52
Figures………………………………………………………………………………54
References............................................................................................................80
Appendix…………………………………………………………………………94

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