99mTc-Labeled mapatumumab

Excerpt

Although anti-growth factor antibodies (Abs) are available for the treatment of cancers (1-3), another technique under investigation to treat this disease is the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor (TRAIL-R) agonist Abs such as mapatumumab and lexatumumab (4, 5). These antibodies (Abs) activate a complex apoptotic pathway in the tumor cell, thereby inducing cell death.The apoptotic pathway and the four TRAIL-R types in humans (designated 1 through 4) have been described in detail by Johnstone et al. (4) and Ashkenazi (5). Mapatumumab (TRM-1 or HGS-ETR1) is a TRAIL-R1 monoclonal antibody (mAb) that targets TRAIL-R1; it is under commercial development and has been approved for clinical trials by the United States Food and Drug Administration (USFDA) to treat various cancers. A similar mAb, lexatumumab (TRM-2 or HGS-ETR2), is a TRAIL-R2 mAb that acts as an agonist specifically for the TRAIL-R2 and has been approved by the USFDA for clinical trials.

Paclitaxel and docetaxel are anti-cancer drugs that inhibit the mitosis and proliferation of cells by interfering with the depolymerization of microtubules. The mechanism of action of these drugs was discussed in detail by Saloustros et al. (6). Gong et al. observed that the anti-tumor activity of HGS-ETR1 could be enhanced in mice bearing colorectal cancer cell xenograft tumors with pretreatment with paclitaxel (7). Using HGS-ETR1 labeled with radioactive technetium (^99mTc) (^99mTc-EC-HGS-ETR1), the investigators determined that the activity of HGS-ETR1 was increased because the pretreatment with paclitaxel upregulated the expression of TRAIL-R1 in Colo205 cell xenograft tumors in nude mice.