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Details

Autor(en) / Beteiligte
Titel
Significant Impact of Single N-Glycan Residues on the Biological Activity of Fc-based Antibody-like Fragments
Ist Teil von
  • The Journal of biological chemistry, 2012-07, Vol.287 (29), p.24313-24319
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2012
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
  • Recent studies have demonstrated that IgG-Fc fragments (Fcabs) can be engineered to form antigen-binding sites with antibody properties. Thus they may serve as an attractive alternative to conventional antibodies in therapeutic applications. The critical influence of Fc glycosylation on effector functions of IgGs is well documented; however, whether this applies to Fcabs is not known. Here we used human cells, wild type, and glycoengineered plants to generate four different glycoforms of H10-03-6, an Fcab with engineered HER2/neu-binding sites. Plant-derived H10-03-6 differed in the presence/absence of single oligosaccharide residues, i.e., core fucose and xylose, and terminal galactose. All of the glycoforms had similar binding to HER2/neu expressed on human tumor cells. By contrast, glycoforms that lacked core oligosaccharide modifications (i.e., core α1,3-fucose and β1,2-xylose) showed significantly enhanced binding to the Fcγ receptor IIIa, irrespective of whether plant or human expression systems were used. Consistent with this finding, plant-derived H10-03-6 glycoforms lacking core N-glycan residues mediated higher antibody-dependent cellular cytotoxicity against human tumor cells. No alteration in γ-receptor binding and antibody-dependent cellular cytotoxicity activity was observed upon decoration of N-glycans by terminal galactose. The results point to a significant impact of distinct N-glycan residues on effector functions of Fcabs. Moreover, the outcomes imply that the effector functions mediated by H10-03-6 can be optimized by altering the N-glycosylation profile. Biasing vaccine-induced immune responses toward optimal Fc glycosylation patterns could result in improved vaccine efficacy. Background: Fcabs are small antibody-like molecules that medicate effector functions. Results: Single N-glycan residues on Fcabs significantly contribute to therapeutically relevant effector functions. Conclusion: Therapeutic proteins with optimized efficacy can be generated by glycoengineering. Significance: Enhanced understanding of N-glycan impacts on the biological activity of a protein.

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