Fc glycan sialylation of biotherapeutic monoclonal antibodies has limited impact on antibody‐dependent cellular cytotoxicity. Issue 11 (19th October 2021)

• Record Type: Journal Article
• Authors: Branstetter, Elaine; Duff, Robert J.; Kuhns, Scott; Padaki, Rupa
• Is Part Of: FEBS open bio. Volume 11:Issue 11(2021)
• Page Start: 2943
• Page End: 2949
• Publication Date: 2021-10-19
• Subjects: glycan profiling -- antibody‐dependent cellular cytotoxicity -- sialylation -- IgG glycosylation -- monoclonal antibody -- mAb; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.13267
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : It has been well documented that the terminal sugars of Fc glycans can play a critical role in the safety and efficacy of therapeutic mAbs. However, many of the effects of highly heterogeneous Fc glycan structures have yet to be fully characterized. Different glycosylation patterns can affect Fc‐dependent activities, such as the ability of mAbs to bind Fcγ receptors on the effector cell surface, which is critical to immune effector functions, such as antibody‐dependent cellular cytotoxicity (ADCC). Previous studies on the impact of sialic acid in the Fc glycan on ADCC have not resulted in consistent conclusions. In our study, we tested sialic acid‐enriched species from a chimeric murine/human kappa light chain IgG1 (mAb1) with known Fcγ receptor IIIa binding and ADCC activities. These enriched species contained up to a fourfold increase in sialic acid‐containing glycans relative to the typical levels present in therapeutic mAbs, along with other attributes such as oxidized and deamidated species. The ADCC analysis of sialylated and asialo mAb1 provided herein shows evidence that sialic acids have little or no impact on ADCC activity. Altogether, our results highlight the value of novel glycan engineering strategies in designing therapeutic mAbs with high‐quality attributes and in improving production process controls. Abstract : In this study, it was hypothesized that ADCC activity for mAb1 has little or no dependence on the sialylation level of the Fc glycan. Experiments using the acidic fractions of mAb1 from cation exchange chromatography and sialyltransferase treatments, both enriching for sialic acid‐containing species, indicate no impact of sialic acid content on ADCC activity.