Abstract

TCR-like antibodies tackle celiac disease Ingestion of gluten-containing food triggers the gastrointestinal symptoms of celiac disease in patients with CD4+ T cells specific for deamidated gluten peptides presented by disease-associated HLA-DQ class II MHC molecules. Frick et al. used phage display technology to screen for TCR-like antibodies specific for an immunodominant gluten peptide bound by HLA-DQ2.5. Antibody engineering optimized affinity and binding stability, yielding an improved TCR-like antibody that structurally mimicked the TCR interface with gluten peptide–MHC complexes. These TCR-like antibodies blocked activation and proliferation of gluten-responsive human CD4+ T cells both in vitro and in DQ2.5 transgenic mice. TCR-like antibodies that block immunodominant epitope recognition have potential as personalized medicine treatments for blunting gluten-activated T cell responses without compromising effector functions provided by other T cells. Antibodies specific for peptides bound to human leukocyte antigen (HLA) molecules are valuable tools for studies of antigen presentation and may have therapeutic potential. Here, we generated human T cell receptor (TCR)–like antibodies toward the immunodominant signature gluten epitope DQ2.5-glia-α2 in celiac disease (CeD). Phage display selection combined with secondary targeted engineering was used to obtain highly specific antibodies with picomolar affinity. The crystal structure of a Fab fragment of the lead antibody 3.C11 in complex with HLA-DQ2.5:DQ2.5-glia-α2 revealed a binding geometry and interaction mode highly similar to prototypic TCRs specific for the same complex. Assessment of CeD biopsy material confirmed disease specificity and reinforced the notion that abundant plasma cells present antigen in the inflamed CeD gut. Furthermore, 3.C11 specifically inhibited activation and proliferation of gluten-specific CD4+ T cells in vitro and in HLA-DQ2.5 humanized mice, suggesting a potential for targeted intervention without compromising systemic immunity. A human TCR-like antibody blocks gluten-dependent activation of celiac disease T cells in vitro and in HLA-DQ2.5 humanized mice. A human TCR-like antibody blocks gluten-dependent activation of celiac disease T cells in vitro and in HLA-DQ2.5 humanized mice.