The Role of Antibody Glycosylation for Antigen Recognition and Immunogenicity

Wolf, Babette. The Role of Antibody Glycosylation for Antigen Recognition and Immunogenicity. 2021, Doctoral Thesis, University of Basel, Associated Institution, Faculty of Science.


Official URL: https://edoc.unibas.ch/83805/

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Background: Most biotherapeutics are glycoproteins and glycosylation is important for their function. 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. Some of this human-like glycosylation may constitute signatures that allows entry into and activation of immune cells via recognition by receptors with carbohydrate ligand specificity (lectin receptors). The goal of my work is to investigate whether and how glycosylation affects immune recognition of therapeutic antibodies.
Approach: Using the tool antibody rituximab (RTX) with a high incidence in clinical immunogenicity (i.e., anti-drug antibodies), I investigated glycosylation-mediated effects covering the three main aspects: 1. antigen recognition and uptake by dendritic cells (DCs), 2. antigen presentation to T cells and 3. humoral immune responses.
Results: I 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. In addition, I can show that DC-uptake is increased or decreased if glycosylation is selectively modified to recognize activating or inhibitory lectin receptors. Furthermore, glycosylation seems to influence antigen presentation by DCs because specific glycovariants tend to induce either stronger or weaker T cell activation. Finally, I could demonstrate that antibody glycosylation impacts humoral immune responses.
Conclusion: I could show that glycosylation is relevant for immune recognition of the therapeutic antibody RTX. Defined glycan structures can modulate immune recognition subsequently leading to increased or decreased responses. Thus, glyco-engineering may be used to reduce clinical immunogenicity.
Advisors:Kammüller, Michael
Committee Members:De Libero, Gennaro and von Gunten, Stephan
Faculties and Departments:05 Faculty of Science
UniBasel Contributors:De Libero, Gennaro
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14250
Thesis status:Complete
Number of Pages:172
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss142504
edoc DOI:
Last Modified:04 May 2023 01:30
Deposited On:09 Sep 2021 08:05

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