Novel Human Anti-ErbB2 Immunoagents

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 scFv1, termed Erbicin, with either a human RNase2 or the Fc region of a human IgG13. Both Erbicin-Derived Immunoagents immunoagents (EDIA) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo 2-4. The finding that EDIA recognize an epitope different from that of Herceptin5 led to ascertain whether they might not present the most negative properties of Herceptin: cardiotoxicity and inability to act on resistant tumors. EDIA did not show cardiotoxic effects in vitro on rat and human cardiomyocytes whereas Herceptin was strongly toxic. This difference was found to be due to their different mechanism of action: Herceptin, at difference with EDIA, induces apoptosis in cardiac cells6. Furthermore, EDIA did not impair cardiac function in vivo in a mouse model whereas Herceptin significantly reduced radial strain at 3 days of treatment and fractional shortening (% FS) at 6 days of treatment compared to the sham group in a fashion similar to Doxorubicin. Similarly, cardiac fibrosis, an index of collagen accumulation following cardiac muscle deterioration, was significantly attenuated in mice treated with EDIA as compared to those treated with Herceptin or Doxorubicin6. 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 ErbB27. Thus, EDIA could fulfil the therapeutic need of cancer patients ineligible to Herceptin treatment due to cardiac dysfunction and to primary or acquired Herceptin-resistance