Therapeutic antibody glycosylation impacts antigen recognition and immunogenicity

Babette Wolf; Mateusz Piksa; Isabelle Beley; Agnes Patoux; Thierry Besson; Valerie Cordier; Bernd Voedisch; Patrick Schindler; Daniela Stöllner; Ludovic Perrot; Stephan von Gunten; Dominique Brees; Michael Kammüller

doi:10.1111/imm.13481

journal article May 04, 2022

Therapeutic antibody glycosylation impacts antigen recognition and immunogenicity

Babette Wolf

Mateusz Piksa Isabelle Beley Agnes Patoux Thierry Besson

Valerie Cordier Bernd Voedisch Patrick Schindler

Daniela Stöllner Ludovic Perrot Stephan von Gunten Dominique Brees Michael Kammüller

Immunology Vol. 166 No. 3 pp. 380-407 · Wiley

View at Publisher Save 10.1111/imm.13481

Abstract

AbstractIn this study we show that glycosylation is relevant for immune recognition of therapeutic antibodies, and that defined glycan structures can modulate immunogenicity. Concerns regarding immunogenicity arise from the high heterogeneity in glycosylation that is difficult to control and can deviate from human glycosylation if produced in non‐human cell lines. While non‐human glycosylation is thought to cause hypersensitivity reactions and immunogenicity, less is known about effects of Fc‐associated glycan structures on immune cell responses. We postulated that glycosylation influences antigen recognition and subsequently humoral responses to therapeutic antibodies by modulating 1) recognition and uptake by dendritic cells (DCs), and 2) antigen routing, processing and presentation. Here, we compared different glycosylation variants of the antibody rituximab (RTX) in in vitro assays using human DCs and T cells as well as in in vivo studies. We found that human DCs bind and internalize unmodified RTX stronger compared to its aglycosylated form suggesting that glycosylation mediates uptake after recognition by glycan‐specific receptors. Furthermore, we show that DC‐uptake of RTX increases or decreases if glycosylation is selectively modified to recognize activating (by mannosylation) or inhibitory lectin receptors (by sialylation). Moreover, glycosylation seems to influence antigen presentation by DCs because specific glycovariants tend to induce either stronger or weaker T cell activation. Finally, we demonstrate that antibody glycosylation impacts anti‐drug antibody (ADA) responses to RTX in vivo. Hence, defined glycan structures can modulate immune recognition and alter ADA responses. Glyco‐engineering may help to decrease clinical immunogenicity and ADA‐associated adverse events such as hypersensitivity reactions.

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References

Details

Published: May 04, 2022
Vol/Issue: 166(3)
Pages: 380-407
License: View

Authors

B

Babette Wolf