Afucosylated igg targets fcγriv for enhanced tumor therapy in mice

Rens Braster, Marijn Bögels, Hreinn Benonisson, Manfred Wuhrer, Rosina Plomp, Arthur E. H. Bentlage, Rianne Korthouwer, Remco Visser, J. Sjef Verbeek, Marjolein van Egmond, Gestur Vidarsson

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (FcγR) IIIa/b, resulting in enhanced antibody dependent cell cytotox-icity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We gener-ated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine FcγRIV, the mouse orthologue of human FcγRIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in FcγRIV-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies.
Original languageEnglish
Article number2372
JournalCancers
Volume13
Issue number10
DOIs
Publication statusPublished - 2 May 2021

Keywords

  • Afucosylated IgG
  • Fc-receptors
  • Melanoma

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