Novel human anti-ErbB2 immunoagents

Overexpression of ErbB2 receptor is associated with progression of malignancy of breast cancer, and is a sign of a poor prognosis. Herceptin, a humanized anti-ErbB2 antibody, has proved to be effective in the immunotherapy of breast carcinoma. However, it can engender cardiotoxicity and a high fraction of 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, called Erb-hRNase and Erb-hcAb (human anti-ErbB2-compact Antibody), respectively. Both immunoagents are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo. The Erbicin-Derived Immunoagents (EDIA) target on breast cancer cells an ErbB2 epitope different from that of Herceptin. As the cardiotoxic side effects of Herceptin have no obvious basis in its interactions with the low levels of ErbB2 in cardiomyocytes, we tested whether these two novel anti-ErbB2 immunoagents might not present this effect. We report that Erb-hRNase and Erb-hcAb 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, which can explain their different effects: Herceptin, at difference with Erb-hcAb, induces apoptosis in cardiac cells. More interestingly, we found that EDIA are active on Herceptin-resistant cells both in vitro and in vivo. The sensitivity of these cells to treatment with EDIA is likely due the different epitope recognized by Erbicin derived immunoagents, since Erb-hcAb, at difference with Herceptin, was found able to inhibit the signalling pathway downstream ErbB2. These results suggest that EDIA are immunoagents which could fulfil the therapeutic need of patients ineligible to Herceptin treatment due to cardiac dysfunction and could prove to be effective for treatment of some breast cancer patients which cannot be cured with Herceptin