Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 4 No. 4 July 04, 2017 p.167-171
Predicting clinical cardiotoxicity caused by trastuzumab and E-8010 using human cardiomyocytes
  • Nobuo Aikawa (Translational Research Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd. /
Nobuo Aikawa
Translational Research Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd.
Keywords: Trastuzumab, E-8010, Cardiotoxicity, Human cardiomyocytes, Herceptin

In addition to low molecular weight drugs, many antibody drugs have been developed in recent years. The safety of these drugs is mainly evaluated in animal toxicity experiments and it is difficult to detect all the toxicities that may occur in humans. Although trastuzumab (Herceptin®), an antibody drug that is used for the treatment of breast cancer, as well as E-8010, a low molecular inhibitor of phosphodiesterase-5, did not cause cardiotoxicity (e.g. dysfunction, QT prolongation, and arrhythmias) in monkeys, they caused cardiotoxicity in humans. The present study examined, whether or not the human cardiotoxicity of these drugs could be predicted using cardiomyocytes derived from human-induced pluripotent stem cells (hiPS-CMs) using an MED64-multielectrode array and assessed the usefulness of hiPS-CMs in antibody drug testing. At 1 and 3 mg/mL, trastuzumab prolonged the field potential duration (QT interval on electrocardiography) by ≥ 10% and induced arrest, respectively. At 0.1 and 1 μmol/L, E-8010 prolonged the field potential duration by ≥ 10% and induced early after-depolarization (proarrhythmia), respectively. The human cardiotoxicity induced by trastuzumab and E-8010 could be predicted using hiPS-CMs. It was thought that a multielectrode array using hiPS-CMs would be a useful tool for predicting the clinical cardiotoxicity of antibody drug candidates in addition to small molecular drug candidates in the preclinical setting.