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首页> 外文期刊>Molecular cancer therapeutics >A Bispecific HER2-Targeting FynomAb with Superior Antitumor Activity and Novel Mode of Action
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A Bispecific HER2-Targeting FynomAb with Superior Antitumor Activity and Novel Mode of Action

机译：具有卓越的抗肿瘤活性和新型作用方式的双特异性HER2靶向FynomAb。

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Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. On the basis of the approved antibody pertuzumab, we have created a panel of bispecific FynomAbs, which target two epitopes on HER2. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. One bispecific FynomAb, COVA208, was characterized in detail and showed a remarkable ability to induce rapid HER2 internalization and apoptosis in vitro. Moreover, it elicited a strong inhibition of downstream HER2 signaling by reducing HER2, HER3, and EGFR levels in vitro and in vivo. Importantly, COVA208 demonstrated superior activity in four different xenograft models as compared with the approved antibodies trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. (C) 2014 AACR.
机译：HER2的上调是浸润性乳腺癌的20％至30％的标志，使该受体成为癌症治疗的诱人靶标。尽管HER2靶向剂已作为癌症治疗剂提供了可观的临床益处，但仍需要开发旨在规避抗HER2耐药性的新药物。在批准的抗体帕妥珠单抗的基础上，我们创建了一组针对HER2上两个表位的双特异性FynomAb。 FynomAb是抗体和Fyn SH3衍生的结合蛋白的融合蛋白。详细描述了一种双特异性FynomAb COVA208，它具有在体外快速诱导HER​​2内在化和凋亡的显着能力。此外，它通过降低体外和体内的HER2，HER3和EGFR水平，强烈抑制了下游HER2信号传导。重要的是，与批准的曲妥珠单抗和帕妥珠单抗相比，COVA208在四种不同的异种移植模型中均显示出优异的活性。双特异性FynomAb COVA208具有增强临床疗效和扩大HER2指导疗法范围的潜力，并勾画出一种设计用于其他受体靶标的新型基于抗体的疗法的范例。 （C）2014 AACR。

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