Afucosylated is a scientific term describing a specific modification to biological molecules. It refers to the absence of a fucose sugar unit, a type of monosaccharide, from a larger molecule, typically a protein.
The Role of Sugars on Proteins
Cells naturally attach sugar chains, known as glycans, to proteins after they are produced in a process called glycosylation. These glycans serve various roles, including influencing protein stability, proper folding, and interactions with other cells.
Fucose is a common sugar molecule frequently added during glycosylation, specifically to N-linked glycans attached to proteins. The act of adding this fucose is called fucosylation, and it is catalyzed by enzymes such as fucosyltransferase 8 (FUT8). Fucosylation is important for maintaining the correct structure and function of many glycoproteins and plays a role in cell-cell interactions and immune responses. This natural attachment helps proteins perform their various biological tasks within the body.
Afucosylation and Antibody Function
Antibodies are specialized proteins that serve as a main component of the immune system. These Y-shaped proteins naturally undergo glycosylation. A specific sugar modification, or its absence, significantly impacts their activity.
When an antibody is “afucosylated,” it means the fucose sugar is missing from a particular glycan structure located in its Fc region, specifically at the N297 position of the heavy chain. This structural change in the Fc region alters how the antibody interacts with immune cells. The absence of fucose allows the antibody to bind much more strongly to a specific receptor called FcγRIIIa, which is found on immune cells like Natural Killer (NK) cells. This enhanced binding affinity, which can be improved by approximately 50-fold compared to fucosylated antibodies, leads to a tighter and more effective connection.
Enhancing Immune Response Through Afucosylation
The enhanced binding of afucosylated antibodies to FcγRIIIa on NK cells has a direct and powerful consequence for the immune system. This stronger interaction significantly boosts Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). ADCC is a mechanism where antibodies flag target cells for destruction by immune cells.
In the ADCC process, NK cells recognize and attach to the antibody-coated target cells via their FcγRIIIa receptors. Because afucosylated antibodies bind more tightly to these receptors, they trigger a more potent activation of the NK cells. This intensified activation leads to a more efficient release of cytotoxic agents from NK cells, resulting in increased destruction of the target cells. Afucosylation makes the body’s natural killer cells more effective at eliminating harmful cells. This enhancement can lead to more rapid killing of target cells and enable NK cells to engage in serial killing.
Therapeutic Applications in Medicine
Scientists use biotechnology to intentionally produce afucosylated monoclonal antibodies (mAbs) for therapeutic purposes. This process, often referred to as “glycoengineering,” involves modifying the antibody’s sugar components to remove or reduce fucose residues in the Fc region. The goal is to create more powerful biologic therapies with enhanced immune system engagement.
A primary application of these engineered antibodies is in cancer therapy. For example, obinutuzumab, a glycoengineered anti-CD20 antibody, has been developed to treat certain leukemias and lymphomas. This antibody is designed with an afucosylated Fc region, enhancing its affinity for FcγRIIIa receptors on NK cells and boosting ADCC activity against tumor cells. By leveraging afucosylation, these engineered antibodies can more effectively guide the patient’s own immune system to attack and destroy malignant cells. This approach represents a significant strategy in modern drug development to create more potent and targeted treatments.