A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific t cells induced by gluten ingestion in patients with celiac disease
- Author(s)
- Hardy, MY; Henneken, LM; Russell, AK; Yuu, O; Akihiko, M; Yui, O; Shinta, K; Yosuke, M; Tye-Din, JA;
- Journal Title
- Clinical Immunology
- Abstract
- The gluten-free diet for coeliac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52). OBJECTIVE: To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides encompassing immunodominant T cell epitopes. METHODS: We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-gamma enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody). RESULTS: In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87.3% (IQR 72.4-92.4). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens. CONCLUSION: DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.
- Publisher
- Elsevier
- Keywords
- Celiac disease; Gluten-specific T cell; T cell receptor (TCR); TCR-like antibody
- Research Division(s)
- Immunology
- PubMed ID
- 38768856
- Publisher's Version
- https://doi.org/10.1016/j.clim.2024.110259
- Open Access at Publisher's Site
https://doi.org/10.1016/j.clim.2024.110259- Terms of Use/Rights Notice
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Creation Date: 2024-06-24 11:25:20
Last Modified: 2024-06-28 03:14:34