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 pairsthe "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 m
Contact: Jim Stallard