Several anti-tumor antibody-maytansinoid conjugates, commonly called TAPs (tumor-activated prodrugs) are currently under clinical evaluation. In particular, cantuzumab mertansine (huC242-DM1), has been evaluated in three Phase I clinical trials (A.W. Tolcher et al., J Clin Oncol 2003, 21:211-22; P.R. Helft et al., Clin Cancer Res 2004, 10:4363-4368) using different dosing schedules to treat patients with tumors expressing the CanAg target antigen. The immunoconjugate could be safely administered at pharmacologically meaningful doses and evidence of anti-tumor activity was seen in several patients, which led to a recommendation for broad clinical development of the agent (A.W. Tolcher et al., J Clin Oncol 2003, 21:211-22). During the clinical evaluation, further advancement in the TAP technology led to the development of TAPs with disulfide-containing linkers with increased stability under physiological conditions. One of these new TAPs that demonstrated improved pharmacokinetic behavior and superior anti-tumor activity in murine test models is huC242-DM4, which contains the same antibody as cantuzumab mertansine and targets therefore the same CanAg-expressing tumors. HuC242-DM4 caused complete regressions in several tumor xenograft models even with single i.v. administration at doses far below its maximal tolerated dose (MTD). For example, treatment of SCID mice bearing measurable N87 human gastric tumor xenografts with a single dose of 3.4 mg/kg caused complete regression of the tumors, with significant tumor regression observed at a dose below 2 mg/kg. With a MTD in SCID mice of greater than 40 mg/kg when given as a single i.v. bolus injection, a therapeutic index of over 20 was achieved. HuC42-DM 4 was also curative in mice bearing human colon tumor xenografts of HT29 and COLO 205 cells, at doses that were non-toxic. The disulfide linkage of huC242-DM4 was approximately 2-fold more stable during circulation in mice than that of cantuzumab mertansine. While the huC242-DM4 conjugate demonstrated increased stability and efficacy in vivo compared to cantuzumab mertansine, preliminary acute toxicity studies suggest that the two conjugates have similar tolerability in normal mice. The resulting increased therapeutic window for huC242-DM4 provides a preclinical rationale for its clinical evaluation in patients with CanAg-positive tumors, such as colorectal, pancreatic, gastric, and esophageal carcinomas.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]