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Impact of glycoengineering and immunogenicity on the anti-cancer activity of a plant-made lectin-Fc fusion protein

Matthew Dent, Katarina L. Mayer, Noel Verjan Garcia, Haixun Guo, Hiroyuki Kajiura, Kazuhito Fujiyama, View ORCID ProfileNobuyuki Matoba
doi: https://doi.org/10.1101/2022.05.31.494188
Matthew Dent
1Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
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Katarina L. Mayer
2UofL Health – Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
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Noel Verjan Garcia
2UofL Health – Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
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Haixun Guo
3Department of Radiology, University of Louisville School of Medicine, Louisville, KY, USA
4Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, KY, USA
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Hiroyuki Kajiura
5International Center for Biotechnology, Osaka University, Osaka, Japan
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Kazuhito Fujiyama
5International Center for Biotechnology, Osaka University, Osaka, Japan
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Nobuyuki Matoba
1Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
2UofL Health – Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
4Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, KY, USA
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  • ORCID record for Nobuyuki Matoba
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ABSTRACT

Plants are an efficient production platform for manufacturing glycoengineered monoclonal antibodies and antibody-like molecules. Avaren-Fc (AvFc) is a lectin-Fc fusion protein or lectibody produced in Nicotiana benthamiana, which selectively recognizes cancer-associated high-mannose glycans. In this study, we report the generation of a glycovariant of AvFc that is devoid of plant glycans, including the core α1,3-fucose and β1,2-xylose residues. The successful removal of these glycans was confirmed by glycan analysis using HPLC. This variant, AvFcΔXF, has significantly higher affinity for Fc gamma receptors and induces higher levels of luciferase expression in an antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay against B16F10 murine melanoma cells without inducing apoptosis or inhibiting proliferation. In the B16F10 flank tumor mouse model, we found that systemic administration of AvFcΔXF, but not an aglycosylated AvFc variant lacking affinity for Fc receptors, significantly delayed the growth of tumors, suggesting that Fc-mediated effector functions were integral. AvFcΔXF treatment also significantly reduced lung metastasis of B16F10 upon intravenous challenge whereas a sugar-binding-deficient mutant failed to show efficacy. Lastly, we determined the impact of anti-drug antibodies (ADAs) on drug activity in vivo by pretreating animals with AvFcΔXF before implanting tumors. Despite a significant ADA response induced by the pretreatment, we found that the activity of AvFcΔXF was unaffected by the presence of these antibodies. These results demonstrate that glycoengineering is a powerful strategy to enhance AvFc’s antitumor activity.

Competing Interest Statement

N.M. filed a patent application related to this work (PCT/US2018/017617).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 31, 2022.
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Impact of glycoengineering and immunogenicity on the anti-cancer activity of a plant-made lectin-Fc fusion protein
Matthew Dent, Katarina L. Mayer, Noel Verjan Garcia, Haixun Guo, Hiroyuki Kajiura, Kazuhito Fujiyama, Nobuyuki Matoba
bioRxiv 2022.05.31.494188; doi: https://doi.org/10.1101/2022.05.31.494188
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Impact of glycoengineering and immunogenicity on the anti-cancer activity of a plant-made lectin-Fc fusion protein
Matthew Dent, Katarina L. Mayer, Noel Verjan Garcia, Haixun Guo, Hiroyuki Kajiura, Kazuhito Fujiyama, Nobuyuki Matoba
bioRxiv 2022.05.31.494188; doi: https://doi.org/10.1101/2022.05.31.494188

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