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首页> 外文学位 >Defining the Role of Fc-Fc Gamma Receptor Interactions in the Anti-Tumor Function of Anti-CD137 Monoclonal Antibody Therapy.
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Defining the Role of Fc-Fc Gamma Receptor Interactions in the Anti-Tumor Function of Anti-CD137 Monoclonal Antibody Therapy.

机译：定义Fc-Fcγ受体相互作用在抗CD137单克隆抗体治疗的抗肿瘤功能中的作用。

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摘要

Agonistic monoclonal antibodies (mAbs) directed against the co signaling molecule CD137 (4-1BB) elicit potent anti-tumor immunity in mice. This enhanced anti-tumor immunity has traditionally been thought to result from the ability of the Fab portion of anti-CD137 mAb to function as a CD137L analogue. Although engagement of CD137 by anti-CD137 mAbs has the potential to cross-link the Fc fragments, mediating Fc engagement of low to moderate affinity Fc gamma receptors (FcgammaR), the relative import of such Fc-FcgammaR interactions in mediating CD137 associated anti-tumor immunity is unknown. In order to address this knowledge gap, we studied the ability of rat anti-mouse CD137 mAb (2A) to mediate the anti-tumor response against the EL4E7 lymphoma in WT and FcgammaR-/- strains. We hypothesized that Fc interactions through activating FcgammaRs would enhance the anti-tumor immune response elicited by anti-CD137 mAb. 2A treated Fcgamma chain deficient mice have improved anti-tumor immunity against EL4E7 lymphoma relative to WT mice, which can be completely recapitulated in FcgammaRIII-/- mice. We tested the hypothesis using the MC38 colon carcinoma, but did not find the same enhanced anti-tumor immune response in the FcgammaRIII-/- mice as in the EL4E7 lymphoma. Kinetic experiments to analyze the immune response in the tumor bearing 2A treated FcgammaRIII-/- mice identified an increase in splenic CD8beta+ T cell and dendritic cell (DC) populations compared to WT mice and IgG controls. There was a significant increase in the number of DCs expressing CD40, CD80, and CD86 molecules in the 2A treated FcgammaRIII-/- mice suggesting the potential for more effective antigen presentation compared to WT mice. The increased numbers of splenic CD8beta+ T cell and dendritic cell (DC) populations in the 2A treated FcgammaRIII-/- mice significantly correlated with the tumor volume on Day 16. Collectively, these data suggest FcgammaRIII ligation negatively regulates anti-CD137 mAb stimulation of DCs with a secondary increase in CD8beta+ T cells involved in the anti-tumor immune response. Our results demonstrate an unexpected inhibitory role for FcgammaRIII in the anti-tumor function of anti-CD137 mAb in the EL4E7 lymphoma, and underscore the need to consider antibody isotype when engineering therapeutic mAbs.
机译：针对co信号分子CD137（4-1BB）的激动性单克隆抗体（mAb）在小鼠中引起有效的抗肿瘤免疫力。传统上认为，这种增强的抗肿瘤免疫力是由于抗CD137 mAb的Fab部分充当CD137L类似物的能力所致。尽管抗CD137单克隆抗体与CD137的结合具有交联Fc片段的潜力，介导了中低亲和力的Fcγ受体（FcgammaR）的Fc结合，但这种Fc-FcgammaR相互作用在介导CD137相关的抗-Fc方面的相对重要性。肿瘤免疫力未知。为了解决这一知识鸿沟，我们研究了大鼠抗小鼠CD137 mAb（2A）介导WT和FcgammaR-/-菌株中针对EL4E7淋巴瘤的抗肿瘤反应的能力。我们假设通过激活FcγRs的Fc相互作用将增强抗CD137 mAb引发的抗肿瘤免疫应答。相对于WT小鼠，2A处理的Fcgamma链缺陷型小鼠具有针对EL4E7淋巴瘤的增强的抗肿瘤免疫力，可以在FcgammaRIII-/-小鼠中完全概括。我们使用MC38结肠癌检验了这一假设，但在FcgammaRIII-/-小鼠中未发现与EL4E7淋巴瘤相同的增强的抗肿瘤免疫应答。动力学实验分析了荷瘤2A处理的FcgammaRIII-/-小鼠的免疫应答，与WT小鼠和IgG对照相比，脾脏CD8beta + T细胞和树突状细胞（DC）群体有所增加。在2A处理的FcgammaRIII-/-小鼠中，表达CD40，CD80和CD86分子的DC数量显着增加，这表明与WT小鼠相比，更有效的抗原呈递潜力。在第16天，接受2A处理的FcgammaRIII-/-小鼠中脾脏CD8beta + T细胞和树突状细胞（DC）数量的增加与肿瘤体积显着相关。这些数据共同表明，FcgammaRIII的连接负调节DC的抗CD137 mAb刺激作用与参与抗肿瘤免疫反应的CD8beta + T细胞的继发性增加有关。我们的结果证明FcgRmIII在EL4E7淋巴瘤中抗CD137 mAb的抗肿瘤功能中具有意想不到的抑制作用，并强调了在设计治疗性mAb时需要考虑抗体同种型的需求。

著录项

  • 作者

    Sallin, MIchelle.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Health Sciences Immunology.;Biology Cell.;Health Sciences Medicine and Surgery.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 160 p.
  • 总页数 160
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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