Trastuzumab, a humanized anti-HER2 monoclonal antibody, for the treatment of breast cancer

The HER2/neu gene encodes a 185 kDa transmembrane receptor (HER2) that belo ngs to the epidermal growth factor receptor family and has intrinsic tyrosi ne kinase activity. HER2 is overexpressed in 25-30% of breast cancers and i s suggested to have a direct role in the pathogenesis and clinical aggressi veness of HER2 overexpressing tumors. A murine monoclonal antibody, 4D5, di rected against the extracellular domain of HER2, is a potent inhibitor of g rowth of human breast cancer cells overexpressing HER2 in vitro and in xeno graft models. To facilitate clinical investigation, 4D5 was humanized by in serting the complementary determining regions of 4D5 into the framework of a consensus human IgG1. The resulting recombinant humanized anti-HER2 MAb, trastuzumab, was found to inhibit the growth of human cancer cells and tumo r xenografts overexpressing HER2. Data from phase II trials in women with b reast cancer whose tumors overexpress HER2 have shown that trastuzumab has a favorable toxicity profile, is active as a single agent and induces long- lasting objective tumor responses. In combination studies, there was no evi dence that trastuzumab enhanced the toxicity of cisplatin and the pharmacok inetic parameters of trastuzumab were unaltered by coadministration of cisp latin. Furthermore, clinical response rates were higher than those reported with either agent alone in a similar patient population. Results of a mult icenter, phase III clinical trial of chemotherapy (doxorubicin- or paclitax el-based) plus trastuzumab as compared to chemotherapy alone in patients wi th advanced breast cancers overexpressing HER2 showed a significant enhance ment in the effects of chemotherapy on time to disease progression, respons e rates and survival with coadministration of trastuzumab, without increase s in overall severe adverse events. Myocardial dysfunction syndrome, simila r to that observed with anthracyclines, was reported more commonly with che motherapy plus trastuzumab. Positive results from clinical studies led to t he approval of trastuzumab in the U.S in October 1998 for the treatment of metastatic breast cancer in patients with tumors overexpressing HER2. Since then, the MAb has also been marketed in Switzerland and Canada. (C) 1999 P rous Science. All rights reserved.