Glycosylation-dependent antitumor therapeutic monoclonal antibodies

The therapeutic market for monoclonal antibodies (MAbs) has grown exponentially since 2000. It is expected that the world-wide market for MAbs could reach $125 billion in 2020. For cancer treatment alone, more than 30 MAbs have been approved by the US Food and Drug Administration since 1997. Unlike structure-defined small molecule-based anti-cancer drugs, the expensive MAb is a mixture of heterogeneously glycosylated proteins. All MAbs typically have a single N-glycosylation site on each of the Fc region. The clinical efficacy of the MAbs depends on the N-glycan structures. Loss of N-glycosylation on the MAbs leads to the loss of the ability to activate complement, to bind to Fc receptors, and to induce antibody-dependent cellular cytotoxicity (ADCC). Moreover, antigen-antibody complexes produced from N-glycan-deficient MAbs are failed to be eliminated rapidly from the blood circulation. Even in certain cases, the N-glycan heterogeneity does not significantly influence pharmacokinetics or half-life of MAbs, reduced terminal galactosylation decreases complement-dependent cytotoxicity, the absence of core fucosylation enhances ADCC due to the increased affinities for the FcγRIIIа receptor, and high sialylation levels reduce ADCC activity and impact inflammatory responses. Furthermore, only mammalian cell lines that make human-like N-glycan structures can be used for MAbs production since certain mammalian cell lines can produce non-human glycan epitopes such as galactose-α-1,3-galactose and N-glycolylneuraminic acid (NGNA), which can trigger unwanted immune response. Therefore, mastering the knowledge of N-glycan structures and glycobiology is the key to produce and provide patients with reliable MAbs with consistent glycosylation profile and expected clinical efficacy.