Team Develops More Effective Therapeutic Antibodies
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Antibodies with identical protein structures (Y-shaped center structures) often have naturally occurring differences in their attached sugar groups (left, inside green ovals). These differences result in enhanced or suppressed abilities to activate the immune response. A process designed at the University of Maryland and tested with help from The Rockefeller University allows the engineering of antibodies with identical sugar groups (right, inside pink ovals), which can standardize the activity of the antibodies. [Tiezheng Li and Lai-Xi Wang/UMD]
Researchers from the University of Maryland (UMD) and The Rockefeller University, who 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, report that they have 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 ("Modulating IgG Effector Function by Fc Glycan Engineering"), published online in 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, according to the investigators.
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% 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, Ph.D., 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."
Most therapeutic antibodies on the market are designed to treat cancer and autoimmune diseases. For example, rituximab is an antibody-based drug used to treat lymphoma, leukemia, and rheumatoid arthritis. Rituximab and other similar antibody drugs are usually produced in cultured cell lines.
"These processes are not optimized at all. There is no easy way to control glycosylation," noted Dr. Wang. Glycosylation is the process by which sugar groups are added to a protein such as an antibody. "Our method could be used to improve antibodies already on the market because it modifies the antibodies directly instead of working at the genetic level."
Dr. Wang's group, which specializes in the biochemistry of protein glycosylation, developed the methodology to modify the antibody sugar groups. They partnered with Jeffrey Ravetch, M.D., Ph.D., and his group at The Rockefeller University, which specializes in immunology and animal models, to test the effects of various glycoforms on the immune response. The new findings will help guide the development of future antibody-based therapeutics.
"Our method would be generally applicable because it can be used on a wide variety of antibodies," explained Dr. Wang. "It's an important step forward in the effort to engineer therapeutic antibodies that can target specific cancers, inflammation, and other diseases. Soon we will be able to build customized antibodies."