A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease

Bibliographische Detailangaben
Veröffentlicht in:	Clinical immunology (Orlando, Fla.). - 1999. - 264(2024) vom: 15. Juli, Seite 110259
1. Verfasser:	Hardy, M Y (VerfasserIn)
Weitere Verfasser:	Henneken, L M, Russell, A K, Okura, Y, Mizoroki, A, Ozono, Y, Kobayashi, S, Murakami, Y, Tye-Din, J A
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2024
Zugriff auf das übergeordnete Werk:	Clinical immunology (Orlando, Fla.)
Schlagworte:	Journal Article Celiac disease Gluten-specific T cell T cell receptor (TCR) TCR-like antibody Glutens 8002-80-0 HLA-DQ Antigens HLA-DQ2 antigen Antibodies, Bispecific mehr... Epitopes, T-Lymphocyte Peptides Interferon-gamma 82115-62-6 Immunodominant Epitopes

Beschreibung
Zusammenfassung:	Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. The gluten-free diet for celiac 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 that encompass 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)-γ 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% (IQR 72-92). 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
Beschreibung:	Date Completed 14.06.2024 Date Revised 14.06.2024 published: Print-Electronic Citation Status MEDLINE
ISSN:	1521-7035
DOI:	10.1016/j.clim.2024.110259