Cutting back on the carbs.

Glycans are essential components in maintaining many important biological processes within the body, and can be found in forms ranging from simple monomers to complex polymeric assemblies. On the cell surface, oligosaccharides are presented and recognized by an array of carbohydrate-binding proteins (lectins), such as sialic acid-binding Ig-like lectins (Siglecs), selectins, and galectins. The interactions play critical roles in cellular adhesion, migration, inflammation, and immunological responses through cellular recognition and signaling activities (1). Dysregulation of glycan–lectin interactions has been implicated in both autoimmune diseases and cancer (2, 3). Consequently, the glycome and its interacting partners have attracted a great deal of attention as targets for therapeutics, ranging from small molecules (4) to antibodies (5, 6). In PNAS, Xiao et al. (7) describe a new method to cut back on the carbohydrate structures of cancer cells in a manner that leads to the activation of the immune system. The work represents a new glycoengineering strategy that may have therapeutic applications. Drugs leading to the inhibition of glycan–lectin interactions have had considerable success in the treatment of pathogenic infections and several other glycanbased diseases (4, 8). These agents function by disrupting interactions between binding partners or by inhibiting enzymes within the glycome machinery, such as glycosidases or glycosyltransferases (9). Heparin is the most widely used glycan-derived drug, acting as an anticoagulant by binding to antithrombin, leading to the inactivation of enzymes within the coagulation system (10). Oseltamivir (Tamiflu) and zanamivir (Relenza) (11) are two successful carbohydrate-inspired antiviral agents that inhibit the influenza viral neuroamidase, which is responsible for virus release from the host cell and propagation (12). Antidiabetic agents, miglitol (Glyset), voglibose (Glustat), and acarbose (Precose), target glucosidases and amylases in the gut to inhibit the digestion of carbohydrates (13). These examples are but a few instances where modification of glycan structures can have pronounced biological and medical impacts. Glycoengineering represents an alternative approach toward altering glycan–lectin interactions. With antibodies, alteration of these interactions has been effectively achieved through modification of glycan structures residing on the heavy chains, not only having an impact on inherent glycan heterogeneity and immunogenicity but also leading to more optimized antibody pharmacokinetics and efficacy (5). These glycan alterations have been accomplished through new expression host systems or through enzymatic or chemical methods postexpression. In one powerful example of engineered cell lines, Chinese hamster ovary cells were designed to express β-1-4-N-acetylglucosaminyl transferase III, which adds a bisecting N-acetylglucosamine (GlcNAc) onto the antibody N-glycan core. The addition of GlcNAc results in glycoengineered antibodies with increased antibody-dependent cellular cytotoxicity (ADCC) activities (14, 15). Further studies have shown that incorporation of GlcNAc blocked the fucosylation of the antibody Fc, which increased ADCC through improved binding to FCγRIII (16). There are many advanced programs to produce afucosylated (16–20) antibodies, and one such agent, obinutuzumab, has been approved for the treatment of various CD20positive lymphomas (6). In PNAS, Xiao et al. (7) present an interesting glycoengineering twist. Instead of changing the glycan profile of the therapeutic as has beendonewith antibodybased drugs, the new approach involves the development of an antibody–enzyme conjugate designed to alter the cell-surface glycans of antigen-positive cancer cells catalytically, allowing for increased ADCC downstream effects. The investigators note that cancer cells are often able to circumvent the immune system through the overexpression of “self-ligands” that inhibit the onset of immune cell signaling. Clinically approved drugs, such as nivolumab and ipilimumuab, enhance the immune system by targeting PD-1 and CTLA-4, respectively (21, 22). In PNAS, Xiao et al. (7) highlight a method to combat cancers that thwart the immune system by capping their cell-surface glycans with sialic acid to generate a “self” signature (23). Sialylated cell-surface glycans on cancer cells evade the immune system in several ways. They can serve as ligands for Siglecs found on natural killer (NK) cells