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首页> 外文学位 >Targeted delivery of immunoliposomal doxorubicin to B-lymphoid cells via an anti-CD19 whole monoclonal antibody or fragments of antibody.
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Targeted delivery of immunoliposomal doxorubicin to B-lymphoid cells via an anti-CD19 whole monoclonal antibody or fragments of antibody.

机译：通过抗CD19完整单克隆抗体或抗体片段将免疫脂质体阿霉素靶向递送至B淋巴样细胞。

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摘要

Anticancer drug therapy can have significant adverse effects, resulting from nonselective toxicities. Treatment with antibody-targeted liposomes such as StealthRTM immunoliposomes (SIL) results in improved selectivity of chemotherapeutics for cancer cells that can be easily accessed from the vasculature, e.g., haematological malignancies. This thesis examined, in an animal model of a B-cell malignancy, the activity of doxorubicin (DXR) encapsulated in SIL and targeted via an anti-CD 19 whole monoclonal antibody (mAb), its Fab' fragment (Fab') or a single chain Fv fragment (scFv), all directed against the same epitope of CD 19. The therapeutic effect of DXR-loaded SIL (SIL-DXR) was hypothesized to be influenced by the differences in the pharmacokinetics (PK) properties of the targeted liposomes.;SIL-DXR targeted via mAb, Fab' or scFv had improved cytotoxicity to B cells, over untargeted liposomal DXR, via CD19-mediated mechanisms. PK studies demonstrated that Fab'-targeted SIL-DXR had long circulation times, similar to untargeted liposomes, while mAb-targeted SIL-DXR was rapidly cleared by the liver and spleen. The presence of poly-histidine and c-myc tags on the scFv increased their uptake into liver, compared to tagless scFv. However, the differences in PK between the various formulations of SIL-DXR did not result in differences in their therapeutic effects. These results suggested that, in the treatment of haematological malignancies, the choice between mAb, Fab' or scFv as targeting agents for SIL may be dependent on other factors, such as immunogenicity, toxicity, or production cost, rather than the PK properties of the individual construct.;Various anti-CD19 scFv constructs were compared for their stability, production yield, and affinity. Production yield and activity of native scFv from the periplasmic space of E. coli were compared with those of refolded scFv from denatured inclusion bodies. The ability to refold the scFv and the stability of the resulting construct were the major factors in determining its success as a targeting agent. Of the several scFv constructs tested, only one demonstrated suitable properties for targeting SIL. The coupling of scFv to polyethylene glycol-lipid micelles was found to increase their storage stability, making it possible to generate the amounts of scFv required for the in vivo experiments.
机译：由于非选择性毒性，抗癌药物治疗可能会产生严重的不良反应。用靶向抗体的脂质体（例如StealthRTM免疫脂质体（SIL））进行处理，可提高对癌细胞的化学治疗的选择性，这种化学治疗可轻松从脉管系统（例如血液系统恶性肿瘤）中获得。本论文在B细胞恶性动物模型中检查了封装在SIL中并通过抗CD 19完整单克隆抗体（mAb），其Fab'片段（Fab'）或抗体的阿霉素（DXR）的活性。单链Fv片段（scFv），都针对CD 19的相同表位。假设负载DXR的SIL（SIL-DXR）的治疗效果受靶向脂质体药代动力学（PK）特性的影响通过CD19介导的机制，通过mAb，Fab'或scFv靶向的SIL-DXR与未靶向的脂质体DXR相比，对B细胞的细胞毒性有所改善。 PK研究表明，靶向Fab'的SIL-DXR具有较长的循环时间，类似于未靶向的脂质体，而针对mAb的SIL-DXR则可被肝脏和脾脏迅速清除。与无标签scFv相比，scFv上多聚组氨酸和c-myc标签的存在增加了它们对肝脏的摄取。但是，各种SIL-DXR制剂之间的PK差异并未导致其治疗效果的差异。这些结果表明，在血液系统恶性肿瘤的治疗中，选择mAb，Fab'或scFv作为SIL的靶向剂可能取决于其他因素，例如免疫原性，毒性或生产成本，而不是其PK特性。比较了各种抗CD19 scFv构建体的稳定性，产量和亲和力。将大肠杆菌周质空间的天然scFv的产量和活性与变性包涵体重折叠的scFv的产量和活性进行了比较。重新折叠scFv的能力和所得构建体的稳定性是确定其作为靶向剂成功的主要因素。在测试的几种scFv构建体中，只有一种显示出靶向SIL的合适特性。发现scFv与聚乙二醇-脂质微团的偶联增加了它们的储存稳定性，使得有可能产生体内实验所需的scFv的量。

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  • 作者

    Cheng, Wilson Wan Kin.;

  • 作者单位

    University of Alberta (Canada).;

  • 授予单位 University of Alberta (Canada).;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 186 p.
  • 总页数 186
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 老年病学;
  • 关键词

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