Rxivist logo

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

By 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

Posted 15 Nov 2019
bioRxiv DOI: 10.1101/840561

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.

Download data

  • Downloaded 406 times
  • Download rankings, all-time:
    • Site-wide: 42,511 out of 94,912
    • In immunology: 1,141 out of 2,857
  • Year to date:
    • Site-wide: 20,615 out of 94,912
  • Since beginning of last month:
    • Site-wide: 34,351 out of 94,912

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News