TRA-8 Takes Aim at Cancer
By Troy Goodman
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Tong Zhou discovered a monoclonal antibody that pinpoints “death receptors” on tumor cells while sparing healthy cells.
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Herceptin. Erbitux. Avastin. Time and again the UAB Comprehensive Cancer Center has played a pivotal role in the basic-science research, development, and regulatory approval of blockbuster anticancer monoclonal antibodies. Now it may have a promising new addition to that list.
The antibody TRA-8 was discovered by Tong Zhou, M.D., a Cancer Center scientist and professor of immunology and rheumatology. “It started nearly a decade ago with a newly discovered ligand (type of molecule) that induced tumor-cell death, or apoptosis. It was a very exciting time because people were looking for something that could selectively kill tumor cells without harming healthy cells,” Zhou recalls. Hope for the new ligand as a cancer fighter fizzled when later tests found it unsafe for healthy cells, but the discovery inspired Zhou and colleagues in his laboratory.
They focused on the one receptor located on the surface of tumor cells that seemed to lock arms with the ligand. Zhou theorized that targeting the one receptor, now called the “death receptor,” while leaving the other receptors alone could spare healthy cells. It worked so well in practice that Zhou’s TRA-8 findings were published in the journal Nature Medicine in August 2001.
The UAB study laid out the tumor-killing potential of TRA-8 in an animal model. But the one-receptor concept was so new that it drew skeptics. “Immediately there were arguments against our discovery,” Zhou recalls. “Nobody believed that the antibody was sufficiently powerful to induce apoptosis. Luckily we proved them wrong.” Today TRA-8 is garnering plenty of interest from other scientists and drug developers.
Engineering a Breakthrough
At their most basic level, monoclonal antibodies are genetically engineered copies of the immune system’s frontline defenses, explains Andres Forero, M.D., a hematologist-oncologist and Cancer Center senior scientist responsible for the clinical testing for TRA-8 and many other antibodies.
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Zhou’s illustration shows how TRA-8 kills cancer cells.
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Forero remembers the early years when these molecules were complicated and time-consuming to make. Scientists had to appropriate mouse proteins to build the experimental antibodies, which often involved taking murine antibodies to places they had rarely been in biology. Sometimes the murine signature would trigger a human immunological reaction that canceled out any anticancer benefit.
Today scientists avoid this setback by using genetic engineering to “humanize” antibodies or by making fully human antibodies and then filtering out the ones that seem clinically significant. “Now monoclonal antibody development can be very quick because we can predict the toxicity and efficacy in animal models,” Forero explains.
The aim of this research is to develop an agent that breaks new ground in cancer care—and one that works well with other therapies. Novel oncology treatment regimens usually involve not just one, but two or more therapies; monoclonal antibodies in particular work best when combined with treatments such as standard chemotherapy.
A phase 1 clinical trial of TRA-8’s humanized version (CS-1008), now complete, showed that it is well tolerated by the body. A phase 2 trial for treating pancreatic cancer is currently under way at UAB, Forero says. After years of laboratory work, the Cancer Center may be on the verge of writing oncology history once more. But Forero keeps his eye on the antibody’s practical potential. “We want to target the tumor cell and do it effectively. TRA-8, like so many others that came before it, gives us another arrow to hit our target.”