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Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation

View ORCID ProfileRahel Frick, View ORCID ProfileLene S. Høydahl, Ina Hodnebrug, Shraddha Kumari, Grete Berntsen, View ORCID ProfileJeliazko R. Jeliazkov, Kristin S. Gunnarsen, Terje Frigstad, Erik S. Vik, View ORCID ProfileKnut E.A. Lundin, Sheraz Yaqub, Jørgen Jahnsen, View ORCID ProfileJeffrey J. Gray, View ORCID ProfileLudvig M. Sollid, Inger Sandlie, View ORCID ProfileGeir Åge Løset
doi: https://doi.org/10.1101/840561
Rahel Frick
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
2Centre for Immune Regulation and Department of Biosciences, University of Oslo, Norway
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Lene S. Høydahl
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
2Centre for Immune Regulation and Department of Biosciences, University of Oslo, Norway
3KG Jebsen Coeliac Disease Research Centre, University of Oslo, Norway
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  • ORCID record for Lene S. Høydahl
Ina Hodnebrug
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
2Centre for Immune Regulation and Department of Biosciences, University of Oslo, Norway
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Shraddha Kumari
4Nextera AS, Oslo, Norway
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Grete Berntsen
4Nextera AS, Oslo, Norway
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Jeliazko R. Jeliazkov
5Program in Molecular Biophysics, Johns Hopkins University, Baltimore, Maryland, USA
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  • ORCID record for Jeliazko R. Jeliazkov
Kristin S. Gunnarsen
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
2Centre for Immune Regulation and Department of Biosciences, University of Oslo, Norway
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Terje Frigstad
4Nextera AS, Oslo, Norway
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Erik S. Vik
4Nextera AS, Oslo, Norway
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Knut E.A. Lundin
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
3KG Jebsen Coeliac Disease Research Centre, University of Oslo, Norway
6Department of Gastroenterology, Oslo University Hospital-Rikshospitalet Oslo, Norway
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Sheraz Yaqub
7Department of Gastrointestinal Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
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Jørgen Jahnsen
8Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
9Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Jeffrey J. Gray
5Program in Molecular Biophysics, Johns Hopkins University, Baltimore, Maryland, USA
10Department of Chemical and Biomolecular Engineering and Institute of NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
11Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Ludvig M. Sollid
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
3KG Jebsen Coeliac Disease Research Centre, University of Oslo, Norway
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Inger Sandlie
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
2Centre for Immune Regulation and Department of Biosciences, University of Oslo, Norway
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Geir Åge Løset
1Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Norway
2Centre for Immune Regulation and Department of Biosciences, University of Oslo, Norway
4Nextera AS, Oslo, Norway
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  • For correspondence: g.a.loset@ibv.uio.no
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Abstract

Antibodies specific for antigenic peptides bound to major histocompatibility complex (MHC) molecules are valuable tools for studies of antigen presentation. Such T-cell receptor (TCR)-like antibodies may also have therapeutic potential in human disease due to their ability to target disease-associated antigens with high specificity. We previously generated celiac disease (CeD) relevant TCR-like antibodies that recognize the prevalent gluten epitope DQ2.5-glia-α1a in complex with HLA-DQ2.5. Here, we report on second-generation high-affinity antibodies towards this epitope as well as a panel of novel TCR-like antibodies to another immunodominant gliadin epitope, DQ2.5-glia-α2. The strategy for affinity engineering was based on Rosetta modeling combined with pIX phage display and is applicable to similar protein engineering efforts. We isolated picomolar affinity binders and validated them in Fab and IgG format. Flow cytometry experiments with CeD biopsy material confirm the unique disease specificity of these TCR-like antibodies and reinforce the notion that B cells and plasma cells have a dominant role in gluten antigen presentation in the inflamed CeD gut. Further, the lead candidate 3.C11 potently inhibited CD4+ T-cell activation and proliferation in vitro in an HLA and epitope specific manner, pointing to a potential for targeted disease interception without compromising systemic immunity.

Significance Statement Consumption of gluten-containing food drives celiac disease in genetically predisposed individuals. The underlying disease mechanism is not fully understood, but it is strictly dependent on activation of pathogenic T cells. We have engineered high-affinity human antibodies recognizing the T-cell target HLA-DQ2.5 in complex with gluten epitopes and studied cell-specific antigen presentation in patients, which shows that plasma cells and not dendritic cells dominate the inflamed tissue. The only available treatment is lifelong adherence to a gluten-free diet, which is difficult and not effective in all cases. We show that at least one of our antibodies can specifically inhibit activation of pathogenic T-cells in vitro and therefore shows promise for therapy.

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-NC-ND 4.0 International license.
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Posted November 15, 2019.
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Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation
Rahel Frick, Lene S. Høydahl, Ina Hodnebrug, Shraddha Kumari, Grete Berntsen, Jeliazko R. Jeliazkov, Kristin S. Gunnarsen, Terje Frigstad, Erik S. Vik, Knut E.A. Lundin, Sheraz Yaqub, Jørgen Jahnsen, Jeffrey J. Gray, Ludvig M. Sollid, Inger Sandlie, Geir Åge Løset
bioRxiv 840561; doi: https://doi.org/10.1101/840561
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Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation
Rahel Frick, Lene S. Høydahl, Ina Hodnebrug, Shraddha Kumari, Grete Berntsen, Jeliazko R. Jeliazkov, Kristin S. Gunnarsen, Terje Frigstad, Erik S. Vik, Knut E.A. Lundin, Sheraz Yaqub, Jørgen Jahnsen, Jeffrey J. Gray, Ludvig M. Sollid, Inger Sandlie, Geir Åge Løset
bioRxiv 840561; doi: https://doi.org/10.1101/840561

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