Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action

The availability of glucose to CHO cells affects the intracellular lipid-linked oligosaccharide distribution, site occupancy and the N-glycosylation profile of a monoclonal antibody

“…The position of conserved glycan in the restricted interstitial space between the Fc domains of the heavy chains of an antibody typically restrains glycosyltransferase access, such as galactosyltransferase and sialyltransferase, which disrupts galactosylation and sialylation of an antibody (Jefferis, 2009). In the EG2 antibody, the lack of light chain pairings, in addition to its smaller size, may contribute to a more relaxed and open structural environment around the glycan site.…”

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…Engineering of antibodies with enhanced affinity for Fcγ receptors has resulted in greater effector activation and killing of antibody-coated target cells (94). Additionally, modification of the n-glycans attached to the antibody constant region has been employed for enhancing antibody ADCC-mediated activity (95)(96)(97). As nonfucosylated IgGs show stronger affinity for FcγRIIIa binding, superior in vivo efficacy has been demonstrated with nonfucosylated therapeutic antibodies in both animal studies and human clinical trials (98)(99)(100).…”

Aglycosylated IgG variants expressed in bacteria that selectively bind FcγRI potentiate tumor cell killing by monocyte-dendritic cells

“…In contrast, FcRn, which binds to the interface of CH2 and CH3 (5), is not significantly affected by the glycosylation status of the antibody constant region. The glycosylation state of IgG determines its affinity for effector FcγRs and thus, modulates the activation of cytotoxic immune cells and their ability to participate in antibody-dependent cellmediated cytotoxicity (ADCC) (6,7). ADCC is important for the clinical efficacy and outcomes of many important antibody therapeutics (8).…”

“…Glycan composition and glycoform heterogeneity, which is intrinsic to the expression of antibodies in mammalian cells, has a well-documented effect on the response to widely used therapeutics such as Rituxan (rituximab, anti-CD20) and Herceptin (trastuzumab, anti-Her2) (8,9). This has led to intense efforts to generate improved antibodies via glycoengineering (7). Wild-type aglycosylated antibodies can be expressed at a high yield in bacterial cells and exhibit normal serum persistence and binding to FcRn (10).…”