Novel Agonist Developed and Tested at UAB

People with advanced malignancies who have failed to respond to conventional therapies or whose advanced disease makes them ineligible for standard approaches may one day benefit from TRA-8, a unique monoclonal antibody developed at UAB, where it is now in clinical trials. The experimental drug targets the human death receptor 5 (DR5), which is expressed on the surface of the majority of tumor cells, but not on normal cells.

“TRA-8 is a direct agonist, unlike other monoclonal antibodies that antagonize tumor cell function. Our laboratory studies show that TRA-8 binds to DR5 and directly stimulates the pathway to programmed cancer cell death or apoptosis,” says UAB hematologist-oncologist and Comprehensive Cancer Center (CCC) Senior Scientist Andres Forero-Torres, MD. “UAB’s phase 1 trials are open to patients with solid tumors such as ovarian, breast, and pancreatic cancers, as well as those with lymphomas without leukemic phase. None of the patients who are enrolled in our studies have developed hepatocyte toxicity, including those with hepatocellular carcinoma or liver metastases.”

Unique Approach
“TRA-8 is one of the most promising antibodies our cancer investigators have observed,” says CCC scientist Tong Zhou, MD, who led the team that developed the antibody. Zhou and colleagues conducted in vitro and in vivo studies that showed the antibody’s high selectivity avoids cytotoxicity to normal cells (Cancer Gene Ther. 2006;13[2]:203-214).

“We generated TRA-8 [IgG1-k] by immunizing genetically modified mice with a fusion protein containing the extracellular domain of human DR5 and the Fc portion of human IgG1 [DR5-Ig]. Recent studies demonstrate that DR5, one of two death receptors bound by tumor necrosis factor-related, apoptosis-inducing ligand [TRAIL], shows increased expression on most malignantly transformed cells. It also appears synergistically potent when coupled with chemotherapy or ionizing radiation,” Forero-Torres says.

As principal investigator for three ongoing phase 1 trials of TRA-8, Forero-Torres hopes to study the antibody’s continuing efficacy in the fight against cancer. “We are seeking the maximum tolerated dose of TRA-8 in 12 patients by testing 1, 2, 4, and 8 mg/kg doses, which have been well-tolerated thus far,” he says. “We are encouraged to see that several patients on different doses now have stable disease.”

Future Applications
Future studies will explore combining TRA-8 with standard chemotherapy for certain pancreatic and ovarian cancers and as a neoadjuvant option for locally advanced breast cancers, Forero-Torres says.

UAB is a leader in the research, development, and approval of monoclonal anti-body immunotherapy. TRA-8 is quickly moving from bench to bedside as an effective therapeutic strategy in cancer, and the approach may eventually extend to autoimmune diseases such as rheumatoid arthritis.

“Our work will increase understanding of death receptor-mediated apoptosis and may provide biomarker clues to identify the patients most likely to benefit from treatment,” says monoclonal antibody innovator and former CCC Director Albert F. LoBuglio, MD.

For more information:
Dr. Andres Forero-Torres
Dr. Tong Zhou
Dr. Albert LoBuglio
1.800.UAB.MIST
mist@uabmc.edu