Cardiotoxic effects of the novel anti-ErbB2 agent ado trastuzumab emtansine

Background

Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate consisting of trastuzumab (TRAS) covalently linked to the highly potent microtubule inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2 positive breast cancer patients, previously treated with TRAS and taxane. Although the potential cardiotoxic effects of T-DM1 have not yet been fully elucidated, they can include all the mechanisms of TRAS-related cardiotoxicity, such as blockade of ErbB2,PI3K-Akt and MAPK pathways. Furthermore, since TDM1 is also used in combination with other anti-ErbB2 agents, the risk of cardiotoxic side effects could be further increased. Here, we aim to assess the cardiotoxic side effects of TDM1 in vitro and in vivo.

Methods

To evaluate the cardiotoxic effects of TDM1 in vitro, human fetal cardiomyocytes (HFC) and cardiomyoblasts (H9C2) were treated, for 3 days, in the absence or in the presence of increasing concentrations of TDM1 and TRAS. Moreover, to assess the cardiac function in vivo, C57/BL6 mice, 2-4 months old, were daily treated with TDM1 (44.4 mg/kg/day). At day 0 and after 7 days, fractional shortening (FS) and ejection fraction (EF) were measured, by M/B mode echocardiography, and radial and longitudinal strain (RS and LS) were evaluated using 2D speckle-stracking.

Results

TDM1 shows a higher toxicity on HFC and H9C2 cells with respect to TRAS. TDM1 clearly causes more marked changes in HFC cell morphology, cells, that indeed lost their typical features to assume distorted forms (rounded-shape). In in vivo studies: after 7 days with TDM1, FS decreased to 53.6 ± 0.9 %, versus 61.0 ± 0.8 % (sham), (p 

Conclusions

Here we show for the first time the cardiotoxic effects of TDM1, both in in vitro, and in vivo models.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

Fondi di Ricerca Corrente destinati all' Istituto Nazionale Tumori Pascale - Napoli

Disclosure

All authors have declared no conflicts of interest.