MoAb Targeting Death Receptor in Breast Cancer

SAN FRANCISCO—A new monoclonal antibody, TRA-8, produces a higher rate of regression in breast cancer when used with paclitaxel (Taxol) or doxorubicin (Adriamycin) than either of the chemotherapies alone, according to animal studies presented at the 93rd Annual Meeting of the American Association for Cancer Research (abstract 4984). When used alone, TRA-8 produced significantly more tumor growth inhibition than either paclitaxel or doxorubicin alone.

"This monoclonal antibody has striking antitumor activity against cancers that express the death receptor DR5," said Donald J. Buchsbaum, PhD, professor of radiation oncology, University of Alabama at Birmingham.

TRA-8 is a monoclonal antibody related to TRAIL—TNF (tumor necrosis factor)-related apotosis-inducing ligand. It targets only one death receptor, DR5, which is expressed by breast and other cancer cells. This selectivity may make TRA-8 more effective than TRAIL, which binds to two death receptors, DR4 and DR5, and two decoy receptors, DcR1 and DcR2, Dr. Buchsbaum said. TRA-8 was first described in the August 2001 issue of Nature Medicine (8:954-960, 2001).

The study presented at the AACR meeting involved mice with human breast cancer xenografts of the DR5-positive 2LMP line. Ten of 14 mice (71%) had a complete regression with TRA-8/doxorubicin, and 3 of 8 (38%) with TRA-8/paclitaxel, compared with 6 of 30 (20%) with TRA-8 alone. In contrast, only 1 of 46 control mice experienced a complete regression, while none of the mice injected with doxorubicin alone or paclitaxel alone achieved a complete response.

The mean time to doubling of tumor size was 71 to 81 days with the combination treatments, 47 days with TRA-8 alone, and 16 to 25 days with chemotherapy alone. The results for tumor regression were significantly greater for the combination regimens vs TRA-8 alone (P = .023), but the two combinations did not differ from each other (P = .296).

The next step will be to test TRA-8 against other tumor types and with other chemotherapy agents. Besides breast cancer, other cancers such as ovarian, colon, prostate, and pancreatic cancers express the DR5 death receptor and could be likely targets for TRA-8. Studies are planned in several models of these cancers. The researchers said they are also planning to investigate combination treatment with radiation therapy.

TRA-8 was developed through a partnership between the UAB Arthritis and Musculoskeletal Center and Sankyo Company, Limited of Tokyo.