RT Journal Article
SR Electronic
T1 Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 840561
DO 10.1101/840561
A1 Rahel Frick
A1 Lene S. Høydahl
A1 Ina Hodnebrug
A1 Shraddha Kumari
A1 Grete Berntsen
A1 Jeliazko R. Jeliazkov
A1 Kristin S. Gunnarsen
A1 Terje Frigstad
A1 Erik S. Vik
A1 Knut E.A. Lundin
A1 Sheraz Yaqub
A1 Jørgen Jahnsen
A1 Jeffrey J. Gray
A1 Ludvig M. Sollid
A1 Inger Sandlie
A1 Geir Åge Løset
YR 2019
UL http://biorxiv.org/content/early/2019/11/15/840561.abstract
AB 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.