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.