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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3171-3178
Number of pages8
JournalFASEB Journal
Volume23
Issue number9
DOIs
Publication statusPublished - Sep 2009

    Fingerprint

Keywords

  • Heart failure
  • Her2
  • Herceptin
  • ImmunoRNase
  • Immunotherapy
  • Trastuzumab

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Riccio, G., Esposito, G., Leoncini, E., Contu, R., Condorelli, G., Chiariello, M., Laccetti, P., Hrelia, S., D'Alessio, G., & De Lorenzo, C. (2009). Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents. FASEB Journal, 23(9), 3171-3178. https://doi.org/10.1096/fj.09-131383