Monoclonal antibodies are specialized proteins used by the immune system to identify and neutralize threats. A technique known as afucosylation represents a major focus in biotechnology, offering a way to significantly improve the function of these therapeutic proteins. This modification is a subtle change to the antibody structure that alters how it interacts with the body’s immune cells. By manipulating this molecular feature, scientists can engineer drug therapies with an enhanced ability to target and eliminate diseased cells, such as those in cancer or autoimmune disorders.
Understanding Glycosylation and Fucosylation
Antibodies, like many proteins, undergo glycosylation, which involves the attachment of sugar molecules (glycans) to the protein structure. These glycans influence how the protein folds, how long it survives in the bloodstream, and how it interacts with other cells. The specific arrangement of these sugar units determines an antibody’s overall biological activity.
A common modification on the fragment crystallizable (Fc) region is fucosylation, the attachment of the simple sugar fucose. In naturally occurring human antibodies, fucose is present in high amounts, forming a core part of the N-linked glycan chain. The presence of core fucose moderates the strength of the antibody’s interaction with certain immune receptors.
The Definition and Mechanism of Afucosylation
Afucosylation is the absence of the core fucose sugar on the antibody’s Fc region. The afucosylated antibody possesses a modified glycan structure, causing a significant structural change in the antibody.
The fucose sugar, when present, introduces molecular bulk that restricts the antibody’s overall conformation. Removing this sugar unit allows the Fc region to adopt a more open and flexible conformation. This structural rearrangement optimizes the antibody’s shape for interaction with specific immune cell receptors. This engineering removes a structural element that otherwise hinders the antibody’s ability to engage the immune system effectively.
Enhanced Immune Cell Activity
The structural change from afucosylation allows the modified antibody to bind with increased affinity to Fc-gamma receptor IIIa (FcγRIIIa). This receptor is predominantly found on Natural Killer (NK) cells, which are lymphocytes specialized for recognizing and eliminating abnormal cells. The removal of the fucose residue eliminates the steric hindrance between the antibody’s glycan and the FcγRIIIa receptor.
This optimized interaction results in 10 to 100-fold stronger binding of the afucosylated antibody to the NK cell receptor compared to its fucosylated counterpart. The tight binding initiates Antibody-Dependent Cell Cytotoxicity (ADCC), where the NK cell uses the antibody as a guide to target and destroy a flagged cell. This enhanced binding boosts the NK cell’s killing power, making the immune response faster and more efficient.
Application in Therapeutic Antibodies
The enhanced immune function conferred by afucosylation has been leveraged in the development of therapeutic monoclonal antibodies for treating cancers and autoimmune disorders. Engineering antibodies to be afucosylated maximizes the ADCC mechanism, increasing the drug’s efficacy against diseased cells. This modification is achieved through advanced biotechnology techniques, such as glycoengineering, which uses genetically modified cell lines to prevent fucose attachment during production.
Obinutuzumab, used to treat chronic lymphocytic leukemia, is engineered to have reduced fucosylation and demonstrates superior tumor-killing ability compared to older, fully fucosylated antibodies. Mogamulizumab, an afucosylated antibody approved for certain lymphomas, also exhibits enhanced activity due to its high-affinity binding to FcγRIIIa.