Scientists have discovered a new role for many of the changes that occur to antibodies as they mature to fight disease. The discovery could change the thinking about how the human immune system protects against foreign substances and might eventually lead to the development of better antibody-based drugs.
The researchers found that the immune system not only makes changes to antibodies that enhance their ability to bind to foreign substances like viruses, but also optimizes them to be more stable.
Humans naturally produce a collection of antibodies, called the germ-line repertoire, that is activated when foreign substances are detected. That detection causes immune cells to modify antibodies to a mature form that is more effective in fighting a particular invader.
Scientists have known for some time that many of the mutations that occur in this maturation process do not actually help the antibodies bind more effectively to the foreign substances.
Research groups at Ohio State University and The Scripps Research Institute (TSRI) in La Jolla, Calif., showed in this new work that many mutations occur so that the antibody remains stable. They also showed that many of the mutations that improve the binding actually destabilize the molecule, suggesting that additional peripheral mutations might be required to ensure that antibodies function properly.
“We mainly have thought of antibodies as being very stable molecules that are tolerant of the mutations needed to make them into better binders,” said Thomas Magliery, assistant professor in the Department of Chemistry and Biochemistry at Ohio State and a lead author of the study. “But what we know now is that many of the binding mutations lead to instability, and that many of the peripheral mutations that looked unimportant really compensate for the destabilizing ones.”
The research is reported in the online early edition of Proceedings of the National Academy of Sciences.
With the use of a technique called X-ray crystallography, the team was able to show that an antibody with only the destabilizing mutations in the binding site disturbed networks of nearby atoms that are likely to be important for stability. But exactly how the more distant peripheral mutations stabilize the mature antibodies is not yet clear.
The discovery may suggest that the immune system actively works to keep antibodies stable, but offered only a hint about how it might do that.
Besides shedding new light on how the immune system functions, the discovery could also lead to more effective drugs.
“So-called biologics, which are mostly antibody-based drugs at this point, often suffer from problems with aggregation or storage because of instability,” said Magliery. “Studying these peripheral mutations might help solve that problem.”