There’s a bit of sugar attached to your billion-dollar biotech product. Omitting the sugar (fucose) can help the product work better, Emory immunologists think.
Many drugs now used to treat cancer and autoimmune diseases are antibodies, originally derived from the immune system. A classic example of a “therapeutic antibody” is rituximab, a treatment for B cell malignancies that was FDA-approved in 1997. It has been responsible for billions of dollars in revenue for its maker, pharmaceutical giant Roche.
Researchers at Emory Vaccine Center previously observed that in a mouse model of chronic viral infection, a traffic jam inside the body limits how effective therapeutic antibodies can be. One of the ways these antibodies work is to grab onto malignant or inflammatory cells. One end of the antibody is supposed to bind the target cell, while another is a flag for other cells to eliminate the target cell. During a chronic viral infection, a mouse’s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from depleting their target cells.
In a recent Science Immunology paper, postdoc Andreas Wieland, Vaccine Center director Rafi Ahmed and colleagues showed that antibodies that lack fucosylation have an enhanced ability to get rid of their intended targets. Fucosylation is a type of sugar modification of the antibody. (It is the red triangle in the diagram, provided by Wieland.) When it is not present, then the “flag for removal” region of the antibody can interact more avidly with the Fc gamma receptor on immune cells. Thus, the introduced antibodies can compete more effectively with the antibodies being produced by the body already.
Wieland and colleagues also showed that alternative strategies can work. Basically, scientists need to choose a different molecule on their target cells that is abundant enough to avoid being covered up by immune complexes. However, when designing antibodies for use in translational or clinical studies, sometimes it will not make sense to shift gears in this way.
It is possible to engineer antibodies’ production in culture so that they lack fucosylation. Wieland says that the biotechnology field is moving toward therapeutic antibodies that lack fucosylation or are otherwise modified to interact better with Fc gamma receptors, because these newer antibodies are more effective, milligram per milligram. Here is a recent review on the topic. Rituximab, for example, is fucosylated but a second-generation version lacking fucosylation (obinutuzumab) was FDA-approved in 2013.
Beyond rituximab, the Emory team’s findings have implications for treating other forms of cancer and autoimmune diseases in the context of chronic infections, or other situations, such as systemic lupus erythematosus, when immune complexes might interfere with therapeutic antibodies.