Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors.

Abstract 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 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. As Trastuzumab has shown cardiotoxic effects, 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. Here 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 at day 2 and fractional shortening at day 7 of treatment in a fashion similar to doxorubicin. Also 2C4 and Lapatinib significantly reduce radial strain after only two days of treatment, even though they showed cardiotoxic effects less pronounced than those of Trastuzumab. These results strongly indicate that radial strain could become a reliable marker to detect early cardiac dysfunction and that EDIA could fulfil the therapeutic need of patients ineligible to Trastuzumab treatment due to cardiac dysfunction.