Novel Human Anti-ErbB2 Immunoagents

Background: Overexpression of ErbB2 receptor is a sign of malignancy and poor prognosis of breast cancer. Herceptin, a humanized anti-ErbB2 antibody, has proved to be effective in the therapy of breast carcinoma, but it can engender cardiotoxicity and many breast cancer patients are resistant to Herceptin-treatment. Two novel human antitumor immunoconjugates were engineered in our laboratory by fusion of a human anti-ErbB2 scFv, termed Erbicin, with either a human RNase or the Fc region of a human IgG1. Both Erbicin-Derived Immunoagents immunoagents (EDIA) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo. Methods: The finding that EDIA recognize an epitope different from that of Herceptin led to ascertain whether they might not present the most negative properties of Herceptin: cardiotoxicity and inability to act on resistant tumors. Results: EDIA did not show cardiotoxic effects both in vitro on rat and human cardiomyocytes and in vivo on a mouse model, whereas Herceptin was strongly toxic. This difference was found to be due to their different mechanism of action: Herceptin, at difference with Erb-hcAb, induces apoptosis in cardiac cells. More interestingly, EDIA were active on some Herceptin-resistant cancer cells both in vitro and in vivo. The sensitivity of these cells to treatment with EDIA is likely due to their different epitope, since EDIA, at difference with Herceptin, was able to inhibit the signalling pathway downstream ErbB2. Conclusions: EDIA could fulfil the therapeutic need of cancer patients ineligible to Herceptin treatment due to cardiac dysfunction and to primary or acquired Herceptin-resistance.