Department of Structural and Functional Biology, Federico II University, Naples, Italy.
Breast Cancer Res Treat. 2012 Jun;133(2):511-21. doi: 10.1007/s10549-011-1783-9. Epub 2011 Sep 27.
Two novel human antitumor immunoconjugates, made up of a human anti-ErbB2 scFv, Erbicin, fused with either a human RNase or the Fc region of a human IgG1, are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. The Erbicin-derived immunoagents (EDIA) target an epitope different from that of trastuzumab, the only humanized antibody currently prescribed for treatment of ErbB2-positive breast cancer (BC). As Trastuzumab has shown cardiotoxic effects, in this study, we evaluated if any side effects were exerted also by EDIA, used as single agents or in combination with anthracyclines. Furthermore, we compared the in vitro and in vivo cardiotoxic effects of EDIA with those of the other available anti-ErbB2 drugs: Trastuzumab, 2C4 (Pertuzumab), and Lapatinib. In this article, we show that EDIA, in contrast with Trastuzumab, 2C4, and Lapatinib, have no toxic effects on human fetal cardiomyocytes in vitro, and do not induce additive toxicity when combined with doxorubicin. Furthermore, EDIA do not impair cardiac function in vivo in mice, as evaluated by Color Doppler echocardiography, whereas Trastuzumab significantly reduces radial strain (RS) at day 2 and fractional shortening (FS) at day 7 of treatment in a fashion similar to doxorubicin. Also 2C4 and Lapatinib significantly reduce RS after only 2 days of treatment, even though they showed cardiotoxic effects less pronounced than those of Trastuzumab. These results strongly indicate that RS could become a reliable marker to detect early cardiac dysfunction and that EDIA could fulfill the therapeutic need of patients ineligible to Trastuzumab treatment because of cardiac dysfunction.
两种新型的人源抗肿瘤免疫偶联物，由与人 ErbB2 scFv 结合的 Erbicin、人 RNase 或人 IgG1 的 Fc 区组成，在体外和体内对 ErbB2 阳性癌细胞具有选择性细胞毒性。与目前唯一用于治疗 ErbB2 阳性乳腺癌（BC）的人源化抗体曲妥珠单抗不同，Erbicin 衍生免疫制剂（EDIA）靶向不同的表位。由于曲妥珠单抗已显示出心脏毒性作用，因此在这项研究中，我们评估了 EDIA 是否会产生任何副作用，EDIA 被用作单一药物或与蒽环类药物联合使用。此外，我们比较了 EDIA 与其他可用的抗 ErbB2 药物（曲妥珠单抗、2C4（帕妥珠单抗）和拉帕替尼）的体外和体内心脏毒性作用。在本文中，我们表明 EDIA 与曲妥珠单抗、2C4 和拉帕替尼不同，在体外对人胎心肌细胞没有毒性作用，并且与多柔比星联合使用时不会产生附加毒性。此外，EDIA 不会在体内损害小鼠的心脏功能，如通过彩色多普勒超声心动图评估，而曲妥珠单抗在治疗第 2 天显著降低径向应变（RS），在治疗第 7 天显著降低分数缩短（FS），与多柔比星的作用方式相似。2C4 和拉帕替尼在治疗仅 2 天后也显著降低 RS，尽管它们的心脏毒性作用不如曲妥珠单抗明显。这些结果强烈表明 RS 可能成为检测早期心脏功能障碍的可靠标志物，并且 EDIA 可能满足因心脏功能障碍而不能接受曲妥珠单抗治疗的患者的治疗需求。
