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首页> 外文学位 >Trastuzumab-metal chelating polymer (MCP) radioimmunoconjugates for Auger electron radioimmunotherapy of breast cancer.
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Trastuzumab-metal chelating polymer (MCP) radioimmunoconjugates for Auger electron radioimmunotherapy of breast cancer.

机译：曲妥珠单抗金属螯合聚合物（MCP）放射免疫缀合物用于乳腺癌的俄歇电子放射免疫疗法。

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摘要

Objective: Trastuzumab modified with nuclear translocation sequence (NLS) peptides and diethylenetriaminepentaacetic acid (DTPA) for complexing 111In (111In-DTPA-NLS-trastuzumab) has shown promise for Auger electron radioimmunotherapy of HER2-positive breast cancer (BC), but a limitation is the low specific activity (SA) achievable for labeling with 111In. Our objective was to synthesize and characterize trastuzumab modified site-specifically with a metal chelating polymer (MCP) that presents multiple DTPA chelators for complexing 111In to increase the SA and the amount of 111In delivered to HER2-overexpressing BC cells.;Methods: The first set of MCPs was synthesized with a polyglutamide backbone with 24 or 29 DTPA units, with or without NLS peptide modification, and a terminal hydrazide group (Hy-) for reaction with aldehydes generated by sodium meta periodate (NaIO4)-oxidation of glycans on the Fc domain of trastuzumab. The maximum SA for 111 In-labeling of trastuzumab modified with a MCP [trastuzumab-Hy-MCP-(NLS)] was determined. Cytotoxicity was evaluated by clonogenic assays in HER2-positive BC cell lines. The second set of MCPs was synthesized with a polyglutamide backbone with 23 or 30 DTPA units, with or without 7 polyethylene glycol (PEG) chains [trastuzumab-Hy-(PEG)-MCP]. Tumor and normal tissue accumulation of trastuzumab-Hy-(PEG)-MCP-111In, its elimination from the blood, and its normal tissue toxicity were evaluated in mice.;Results: The maximum SA for labeling trastuzumab-Hy-MCP-111In was 90-fold greater than for trastuzumab modified with two DTPA. Clonogenic survival (CS) of HER2 overexpressed SK-BR-3 cells (1.3x106 receptor/cell), ZR-75-1 cells with intermediate HER2 density (4x105 receptor/cell) but no HER2 gene amplification, and HER2 overexpressed (5x105 receptor/cell) but trastuzumab resistant TrR1 cells were decreased to 1.8 +/- 1.3%, 20.5 +/- 4.3% and 17.1 +/- 1.6% respectively by high SA trastuzumab-Hy-MCP- 111In (20 nmol/L). Trastuzumab-Hy-PEG-MCP-111In achieved 1.6 fold higher HER2-mediated uptake than trastuzumab-Hy-MCP-111In (1.3 +/- 0.3 %ID/g vs. 0.8 +/- 0.4 %ID/g) in s.c HER2 overexpressed BT-474 xenografts in mice. In non tumor bearing mice, kidney uptake of trastuzumab-Hy-PEG-MCP- 111In was 5.5-fold lower than trastuzumab-Hy-MCP-111In (3.0 +/- 0.4 % ID/g vs. 16.6 +/- 4.3 %ID/g). There was no normal tissue toxicity of trastuzumab-Hy-PEG-MCP-111In or trastuzumab-Hy-MCP- 111In (14 MBq, 10mug).;Conclusion: These results are promising for further development of trastuzumab-Hy-PEG-MCP-111In for Auger electron radioimmunotherapy of BC.
机译：目的：用核易位序列（NLS）肽和二亚乙基三胺五乙酸（DTPA）修饰的曲妥珠单抗复合111In（111In-DTPA-NLS-曲妥珠单抗）已显示出对HER2阳性乳腺癌（BC）的俄歇电子放射免疫疗法的希望，但存在局限性是用111 In标记可实现的低比活（SA）。我们的目标是合成和表征用金属螯合聚合物（MCP）进行特异性位点修饰的曲妥珠单抗，该螯合剂提供了多种DTPA螯合剂，用于络合111In以增加SA和111In的量递送至过表达HER2的BC细胞。一组MCP的合成是使用具有24或29个DTPA单元的聚谷氨酰胺主链（带有或不带有NLS肽修饰）和一个末端酰肼基（Hy-），用于与间高碘酸钠（NaIO4）-聚糖在聚糖上的氧化反应生成的醛反应。曲妥珠单抗的Fc结构域。确定了用MCP [曲妥单抗-Hy-MCP-（NLS）]修饰的曲妥珠单抗111 In-标记的最大SA。通过克隆形成测定在HER2阳性BC细胞系中评估细胞毒性。使用具有23个或30个DTPA单元的聚谷氨酰胺主链（带有或不带有7个聚乙二醇（PEG）链[曲妥珠单抗-Hy-（PEG）-MCP））合成第二组MCP。评估了曲妥珠单抗-Hy-（PEG）-MCP-111In的肿瘤和正常组织的积累，从血液中的清除以及正常组织的毒性。结果：标记曲妥珠单抗-Hy-MCP-111In的最大SA为比用两种DTPA修饰的曲妥珠单抗高90倍。 HER2过表达的SK-BR-3细胞（1.3x106受体/细胞），具有中等HER2密度的ZR-75-1细胞（4x105受体/细胞）但无HER2基因扩增和HER2过表达（5x105受体）的克隆存活（CS） /细胞），但高曲妥珠单抗-Hy-MCP-111In（20 nmol / L）分别将抗曲妥珠单抗的TrR1细胞分别降至1.8 +/- 1.3％，20.5 +/- 4.3％和17.1 +/- 1.6％。在sc HER2中，曲妥珠单抗-Hy-PEG-MCP-111In比曲妥珠单抗-Hy-MCP-111In达到1.6倍高的HER2介导摄取（1.3 +/- 0.3％ID / g对0.8 +/- 0.4％ID / g）在小鼠中过度表达的BT-474异种移植物。在非荷瘤小鼠中，曲妥珠单抗-Hy-PEG-MCP-111In的肾脏摄取量比曲妥珠单抗-Hy-MCP-111In低5.5倍（3.0 +/- 0.4％ID / g vs. 16.6 +/- 4.3％ID /G）。曲妥珠单抗-Hy-PEG-MCP-111In或曲妥珠单抗-Hy-MCP-111In（14 MBq，10mug）没有正常的组织毒性。结论：这些结果对于曲妥珠单抗-Hy-PEG-MCP-MCP-的进一步发展很有希望111In用于BC俄歇电子放射免疫疗法。

著录项

  • 作者

    Ngo Ndjock Mbong, Ghislaine.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 257 p.
  • 总页数 257
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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