Under the vigorous engine of modern translational biotechnology, mAbs and derivatives are estimated to be >30% of the new licensed drugs ( 4). Currently, more than 60 mAbs and derivatives are approved in USA and Europe for human use with some of them being blockbusters in the biopharmaceutical markets ( 2, 3). Monoclonal antibody (mAb)-based therapeutics have been the fastest growing class of human pharmaceuticals with applications in various clinical indications such as oncology, inflammatory diseases, organ transplantation, and bacteria and virus infection ( 1). The advances in the understanding of Fc glycobiology and development of novel glycoengineering technologies have facilitated the generation of therapeutic mAbs with homogenous glycoforms and improved therapeutic efficacy. Furthermore, we briefly discuss two novel therapeutic mAbs formats: aglycosylated mAbs and Fc glycan specific antibody–drug conjugates (ADCs).
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We begin with the discussion of the structures of IgG N-glycans and biosynthesis followed by reviewing the impact of IgG glycoforms on antibody effector functions and the current Fc glycoengineering strategies with emphasis on Fc defucosylation. Herein, we review the current progress of IgG-Fc glycoengineering. The chemoenzymatic glycosylation remodeling also offers useful avenues for site-specific conjugations of small molecule drugs onto mAbs. A plethora of cell glycoengineering and chemoenzymatic glycoengineering strategies is emerging to produce IgGs with homogenous glycoforms especially without core fucose. Defucosylated immunoglobulin Gs (IgGs) are thus highly pursued as next-generation therapeutic mAbs with potent ADCC at reduced doses. While the terminal galactose enhances CDC activity, the fucose significantly decreases ADCC. Fc glycoforms affect mAbs effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) by modulating the Fc–FcγRs and Fc–C1q interactions.
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Different Fc glycoforms impact their effector function, pharmacokinetics, stability, aggregation, safety, and immunogenicity. They are typically IgG1 molecules with N-glycans attached to the N297 residue on crystallizable fragment (Fc). Monoclonal antibody (mAb)-based therapeutics are the fastest growing class of human pharmaceuticals. Protein Interactions Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, United States.