William G. Kaelin, Jr., Editor

1987 to FDA approval of trastuzumab in 1998 was a relatively short period. This rapid progress reflects an understanding of the underlying science, as well as the fact that trastuzumab is a biological agent. In general, biological agents may be developed more quickly than are chemical entities.

Therapeutic antibodies have also been developed against the EGF receptor. C225, a human/mouse chimeric antibody (10), and E7. 6.3, a fully human antibody (11), bind to the EGF receptor extracellular domain and block EGF ligand binding. These antibodies block the ligand-dependent proliferation of breast cancer cell lines in cell culture, and can induce tumor regression in mouse xenograft tumor assays. Like trastuzumab, C225 appears to be especially effective in combination with doxorubicin or paclitaxel (10). C225 is currently undergoing clinical evaluation. In preliminary trial results, complete responses were noted in head and neck cancers when C225 was combined with radiotherapy. The EGF receptor is also the target for the development of inhibitors of the intracellular tyrosine kinase domain. ZD-1839 and CP-358,774, competitive inhibitors of ATP binding to the receptor’s active site, are currently in clinical trials (12, 13). Their mechanism of action has led to some concern about safety, given the variety and physiological significance of protein kinases and other enzymes that bind ATP. However, these compounds appear to have good anti-cancer activity in preclinical models, with an acceptable therapeutic index, particularly in patients with non–small cell lung cancer. The dermatological toxicity observed for these drugs is most likely mechanism based, arising as a consequence of their intended biochemical activities. More recently, highly potent and selective irreversible inhibitors of the EGF receptor kinase have been reported, such as PD-168,393 (14). This compound appears to bind specifically to an active-site cysteine