Antibodies are the foot soldiers of our immune system. These specialized, Y-shaped proteins attach to bacteria and viruses, where they either block the pathogen’s activity directly, or signal the immune system’s cells to destroy the invader. The second function–the ability to target invaders for destruction–makes antibodies a tempting target for cancer and disease therapies.
But not all antibodies are created equal. Due to subtle but important differences in the structure of their sugar groups, two otherwise identical antibodies that attack the same invader might not be equally good at recruiting immune cells to finish the job. Researchers from the University of Maryland and Rockefeller University have previously developed a method to modify an antibody’s sugar group structure, which opened the door for biochemists to create antibodies with consistent sugar groups.
The researchers have now taken their method a step further, by determining which specific sugar combinations enhance–or suppress–an antibody’s ability to signal the immune system to attack an invader. The results, published in the March 13, 2017 early online edition of the Proceedings of the National Academy of Sciences, are an important step toward the development of highly effective antibodies to fight cancer and other diseases.
An antibody’s ability to send killer signals depends on the configuration of sugar chains attached to the protein. In naturally occurring antibodies, these sugar chains have a lot of variability. Even in antibodies currently used for disease therapy, a given dose might contain a wide variety of antibody variants, also known as “glycoforms,” distinguished by their sugar groups.
Although prior methods tried to sort out these glycoforms and collect the most effective ones, these methods are time-consuming, expensive and not 100 percent effective. The method used in the current study enables the researchers to create a given antibody with identical glycoforms using biochemical techniques. Each glycoform can then be tested independently to see whether it enhances or suppresses the immune response.
“Our first major step forward was to develop a method to produce homogeneous glycoforms,” said Lai-Xi Wang, a professor of chemistry and biochemistry at UMD. “With this, we can now look at how individual different sugars affect the properties of antibodies. Until this study, we didn’t have an efficient way to know how individual sugars in various glycoforms affect suppression or activation of the immune response.”