Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors
Carmine Fedele1, Gennaro Riccio, Carmela Coppola
1Department of Structural and Functional Biology, Federico II University, Naples, Italy.
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 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.
Insights
Two new immunoconjugates targeting ErbB2-positive cancers show no cardiotoxicity. Erbicin-derived immunoagents (EDIA) offer a safer alternative to existing treatments like Trastuzumab, especially for patients with cardiac issues.
Area of Science:
- Oncology
- Immunology
- Cardiology
Background:
- ErbB2-positive cancers are treated with immunoconjugates like Trastuzumab.
- Trastuzumab can cause cardiotoxicity, limiting its use in some patients.
- Novel immunoconjugates targeting ErbB2 are needed to overcome these limitations.
Purpose of the Study:
- To evaluate the cardiotoxic effects of novel Erbicin-derived immunoagents (EDIA).
- To compare the cardiotoxicity of EDIA with Trastuzumab, Pertuzumab (2C4), and Lapatinib.
- To assess EDIA's safety in combination with anthracyclines and its in vivo cardiac function impact.
Main Methods:
- In vitro assessment of EDIA cardiotoxicity on human fetal cardiomyocytes.
- In vivo evaluation of cardiac function in mice using Color Doppler echocardiography.
- Comparative analysis of EDIA, Trastuzumab, Pertuzumab, and Lapatinib cardiotoxicity.
Main Results:
- EDIA demonstrated no cardiotoxicity in vitro and no additive toxicity with doxorubicin.
- In vivo, EDIA did not impair cardiac function in mice.
- Trastuzumab, Pertuzumab, and Lapatinib significantly reduced cardiac function markers (radial strain, fractional shortening).
Conclusions:
- EDIA represent a safer therapeutic option for ErbB2-positive cancers, particularly for patients at risk of cardiotoxicity.
- Radial strain (RS) emerges as a potential early marker for detecting drug-induced cardiac dysfunction.
- EDIA could expand treatment options for patients unable to tolerate current anti-ErbB2 therapies due to cardiac concerns.
