Researchers at The Rockefeller University, in collaboration with Genentech, Inc., have made a surprising discovery about the mechanism by which two currently used clinical antibodies fight tumors. The finding, reported in the April issue of Nature Medicine, has immediate implications for increasing the potency of an entire class of cancer drugs now on the market and for developing more effective drugs in the future.
"This should have a significant impact on immunotherapy for cancer," says senior author Jeffrey V. Ravetch, M.D., Ph.D., Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at Rockefeller. "There are more than 20 other antibodies now being developed that are in various stages of clinical trials, and this finding shows a way to make them much more effective."
The scientists discovered that two anti-tumor antibodies, Herceptin and Rituxan, operate by harnessing the immune system and directing it to kill tumor cells. The antibodies connect to the immune system by engaging receptor pairs on the surface of certain immune cells. One of these receptors acts as an "on" switch to initiate an immune response, while the other acts as an "off" switch to hold the immune system in check and prevent it from attacking the body.
As effective as Herceptin and Rituxan are, the researchers found that removing or disabling the "off" switch could make an antibody many times more potent than before. Ravetch says the technology to do so is within reach.
"It's startling to learn that these antibodies do not work the way everyone has assumed," Ravetch says. "Now that we recognize this in vivo mechanism, we should be able to manipulate it to great effectiveness."
Antibodies are nature¹s own defense against foreign intruders. Antibody molecules comprise two main segments: a variable region, which is highly specific in order to recognize any foreign shape‹or pathogen‹it may encounter; and the Fc domain, which couples the antibody to certain white blood cells, called effector cells, and initiates an immune response.
The conventional method for developing antibodies to fight tumors has involved focusing on contact between the variable region and the tumor cell. For years, scientists hoped that bioengineered molecules called monoclonal antibodies could be used as therapeutic drugs to provide specific anti-tumor action within the human body. In 1997, Genentech's Rituxan, a lymphoma-fighting drug, became the first monoclonal antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. In 1998, the FDA approved Genentech's Herceptin as the first monoclonal antibody to treat breast cancer.
Scientists had thought monoclonal antibodies' key to success was attaching to the tumor cell and disrupting essential functions that allow the tumor to grow and divide. Researchers based this theory on studies in cell culture, and it has guided their approach to developing new therapies. For example, the Herceptin antibodies were designed to inhibit breast tumor growth by blocking molecules called HER2 receptors that stud the surface of cancer cells. About 20 to 30 percent of breast cancer cases are associated with a mutation in the HER2 gene, which is thought to stimulate cancer cell growth.
However, the Rockefeller researchers found that the antibodies used in Herceptin and Rituxan work differently in mice and, most likely, in humans. The antibodies' effectiveness is determined not so much by their interaction with tumor cells, but by their engagement of Fc receptors on the surface of immune cells that are provoked into action. If the antibodies do not engage these Fc receptors, the immune response will not be triggered.
"This finding changes how we'll approach antibody development," Ravetch says. "The assumption guiding antitumor therapy has been that there are specific molecules needed for tumor-cell growth, and if you want to stop the tumor you definitely have to target those molecules. Now we're learning that how the antibody binds to the tumor cell may be far less important than its interaction with the Fc receptors. It shifts our focus to the other end of the antibody."
These receptors react to the antibody in pairs, much like a switch that turns the immune response on or off: one receptor activates an immune response and another inhibits it. When an antibody encounters a tumor cell and engages an effector cell through its Fc portion, it's really interacting with these receptor pairs. Ravetch and his colleagues found that the Fc receptor system operates by maintaining a delicate balance between these pairs‹the "on" and "off" switches of the immune response. The balance may be skewed, but the conflicting forces largely check one another so that overall response is minimal.
In the Nature Medicine study, the researchers found that blocking the "off" switch in mice unleashes the immune system's full power, suddenly making the antibody many times more potent than it was before. The scientists demonstrated this effect dramatically with studies on genetically modified mice. They gave an experimental antibody to mice with lung tumors and reduced the tumors by a factor of three to five. In mice that were altered to lack the "on"-switch receptors in their effector cells, the antibody had no effect on the tumors at all. But when they removed the "off" switch from the mouse, the same antibody was actually 100 times more potent. Although the effect with most antibodies may not be of such magnitude, the same principle applies.
The researchers believe this will hold true with human tumors and human antibodies. "We think there will be some exceptions to the rule, but the majority of antibodies we've looked at so far actually work this way," Ravetch says. "They all seem to converge on a common mechanism of action, which is this harnessing of the immune system. The crucial target for drugs may be simpler than we believed."
The applications, while powerful, should also be safe because of the specificity of the drugs for their tumor targets. Modifying the drug or the effector cell to make it more potent should not cause the immune system to rage out of control because the enhanced response is specifically targeted to tumor cells and not to innocent cells in the patient¹s body.
Ravetch points out that benefits from the discovery should come quickly because there is no mystery about where they first should be applied. It is possible to tailor the clinical antibodies by modifying certain amino acids in the Fc domain which minimize engagement to the inhibitory Fc receptors on effector cells. "Rather than starting from scratch and having to wait as long as 10 years before therapies are available, pharmaceutical researchers can modify drugs already well along in the development pipeline," he says. "This may represent the next wave of truly effective drugs for cancer."
Ravetch's co-authors are Raphael A. Clynes, M.D., Ph.D., and Terri L. Towers, Ph.D., of Rockefeller and Leonard G. Presta, Ph.D., of Genentech. The research was funded in part by grants from the National Institutes of Health and the Cancer Research Institute and by Genentech.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. The university has ties to 20 Nobel laureates, including Günter Blobel, winner of the 1999 Nobel Prize for Physiology or Medicine. Scientists at Rockefeller have made significant findings in the fields of cancer and immunology, including the discovery that a virus can cause cancer, the elucidation of the first complete chemical structure of antibodies and the finding that humans have a natural immunity to tumors. University President Arnold J. Levine, Ph.D., discovered the p53 gene, the most common mutation in human cancers.
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