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Linear epitopes that generate anti-HER-2 antibody responses with trastuzuab- (herceptin) like biological activity.

机译：线性表位，产生具有曲妥珠单抗（herceptin）之类的生物活性的抗HER-2抗体反应。

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摘要

The therapeutic monoclonal antibody trastuzumab, which recognizes a conformation-dependent epitope on the extracellular domain of HER-2, has revolutionized the treatment of HER-2pos breast cancers. However, high costs and short half-life of the antibody spurs the search for other ways to induce therapeutic anti-HER-2 antibodies. Linear T cell epitopes have already been discovered for HER-2, and these have shown promise in vaccine studies where strong cell-mediated responses have been generated. Identifying conformation-independent B cell epitopes would allow the construction of linear T-B vaccine constructs that would generate both cellular and humoral anti-HER-2 responses with potential anti-cancer activity. We therefore produced a synthetic peptide library consisting of 62 overlapping 20-mers spanning the HER-2 extracellular domain. These were used to vaccinate Balb/c (H-2d) mice. Resulting antisera were characterized and screened for reactivity against peptide and recombinant extracellular domain protein via ELISA, and whole native protein by immuno-fluorescent microscopy and FACS analysis. Sera reactive by all these criteria were tested against trastuzumab for their ability to disrupt HER-2 and HER-2/HER-3 dimer signaling in the presence and absence of heregulin. We identified a linear peptide capable of downregulating the phosphorylation of upstream HER-2 and HER-3, and downstream Akt and ERK 1/2 in a manner similar to trastuzumab. This suggests that a linear epitope/vaccination approach may be feasible for generating effective anti-HER-2 antibody responses.
机译：治疗性单克隆抗体曲妥珠单抗（Trastuzumab）识别HER-2细胞外结构域上的构象依赖性表位，彻底改变了HER-2pos乳腺癌的治疗方法。然而，抗体的高成本和短半衰期促使人们寻找其他诱导治疗性抗HER-2抗体的方法。线性T细胞抗原决定簇已经被发现用于HER-2，并且在疫苗研究中显示出了希望，其中已经产生了强烈的细胞介导的应答。鉴定不依赖于构象的B细胞表位将允许构建线性T-B疫苗构建体，该构建体将产生具有潜在抗癌活性的细胞和体液抗HER-2应答。因此，我们产生了由62个重叠的20-聚体组成的合成肽文库，跨越了HER-2细胞外域。这些被用来给Balb / c（H-2d）小鼠接种疫苗。表征所得抗血清，并通过ELISA筛选针对肽和重组胞外域蛋白的反应性，并通过免疫荧光显微镜和FACS分析筛选完整天然蛋白。在存在和不存在调蛋白的情况下，针对曲妥珠单抗测试了通过所有这些标准具有反应性的血清的抗曲妥珠单抗的能力。我们鉴定了一种线性肽，能够以类似于曲妥珠单抗的方式下调上游HER-2和HER-3，下游Akt和ERK 1/2的磷酸化。这表明线性表位/疫苗接种方法对于产生有效的抗HER-2抗体应答可能是可行的。

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  • 作者

    Showalter, Loral E.;

  • 作者单位

    Kent State University.;

  • 授予单位 Kent State University.;
  • 学科 Biomedical engineering.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 141 p.
  • 总页数 141
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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