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Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents

Gennaro Riccio^*,1, Giovanni Esposito^,1, Emanuela Leoncini, Riccardo Contu, Gianluigi Condorelli, Massimo Chiariello, Paolo Laccetti^*, Silvana Hrelia, Giuseppe D'Alessio^* and Claudia De Lorenzo^*,2

^* Dipartimento di Biologia Strutturale e Funzionale and

Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università di Napoli Federico II, Naples, Italy,

Dipartimento di Biochimica "G.Moruzzi," Università di Bologna, Bologna, Italy, and

Istituto Ricovero e Cura a Carattere Scientifico, Multimedica, Milan, Italy

² Correspondence: Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, via Cinthia, 80126 Napoli, Italy. E-mail: cladelor{at}unina.it

This study investigated potential cardiotoxicity as exerted by Erbicin-derived-immunoagents (EDIAs), novel human anti-ErbB2 immunoagents engineered by fusion of a human anti-ErbB2 scFv, Erbicin, with either a human RNase or the Fc region of a human IgG1. EDIAs are strongly cytotoxic on ErbB2-positive cells in vitro and in vivo and bind to an epitope different from that of Herceptin, a humanized anti-ErbB2 mAb effective in the therapy of breast carcinoma, but cardiotoxic in a high percentage of cases. Toxicity and apoptosis were tested in vitro by 3-(4,5-dimethyl-2-thizolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), DNA fragmentation, and immunoblotting analyses. Echocardiography was measured in mice after treatment with each immunoagent. Cardiac fibrosis and detection of apoptosis were examined by Sirius red staining of collagen and TUNEL assay, respectively. EDIAs were found in vitro to have no adverse effects on cardiac cells for which Herceptin is severely toxic. In vivo studies on a mouse model showed that the EDIAs did not alter cardiac function, whereas Herceptin and doxorubicin, used as positive controls, significantly reduced the fractional shortening parameter. Cardiac fibrosis and apoptosis were not significantly affected in mice treated with EDIAs. Thus, EDIAs could fulfill the therapeutic need of patients ineligible for Herceptin treatment due to cardiac dysfunction.—Riccio, G., Esposito, G., Leoncini, E., Contu, R., Condorelli, G., Chiariello, M., Laccetti, P., Hrelia, S., D'Alessio, G., De Lorenzo, C. Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents.

Key Words: immunotherapy • immunoRNase • Herceptin • trastuzumab • Her2 • heart failure

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