First and Second Generation 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, is effective in the therapy of breast carcinoma, but it engenders cardiotoxicity and many breast cancer patients are resistant to Herceptin-treatment. Two human antitumor immunoconjugates were engineered in our laboratory by fusion of a human anti-ErbB2 scFv, termed Erbicin, with either human pancreatic RNase (HP-RNase) or the Fc region of a human IgG1 (Erb-hcAb). Both Erbicin-Derived Immunoagents (EDIA) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. EDIA recognize an epitope different from that of Herceptin, are active on some Herceptin-resistant cancer cells both in vitro and in vivo, and are not cardiotoxic. Indeed, EDIA, differently from Herceptin, do not show toxic effects in vitro on rat and human cardiomyocytes, and do not impair cardiac function in vivo in a mouse model. Second generation EDIA were obtained either by the fusion of Erb-hcAb with HP-RNase (Erb-hcAb-RNase) or by the conjugation of Erbicin with a dimeric variant of HP-RNase (Erb-HHP-RNase). Both the novel immunoRNases retain the RNase enzymatic activity and specifically bind to ErbB2-positive cells. Moreover, the novel EDIA are endowed with an effective and selective cytotoxic action for ErbB2-positive tumor cells more potent than that of the first generation ImmunoRNases. Thus, EDIA could fulfil the therapeutic need of cancer patients ineligible to Herceptin treatment due to cardiac dysfunction and to Herceptin-resistance.