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A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease.
- Source :
-
Clinical immunology (Orlando, Fla.) [Clin Immunol] 2024 Jul; Vol. 264, pp. 110259. Date of Electronic Publication: 2024 May 18. - Publication Year :
- 2024
-
Abstract
- 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).<br />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.<br />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).<br />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.<br />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.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Female
Epitopes, T-Lymphocyte immunology
Adult
Male
CD4-Positive T-Lymphocytes immunology
Peptides immunology
Middle Aged
T-Lymphocytes immunology
Interferon-gamma immunology
Interferon-gamma metabolism
Immunodominant Epitopes immunology
Diet, Gluten-Free
Celiac Disease immunology
Glutens immunology
HLA-DQ Antigens immunology
Antibodies, Bispecific immunology
Antibodies, Bispecific pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-7035
- Volume :
- 264
- Database :
- MEDLINE
- Journal :
- Clinical immunology (Orlando, Fla.)
- Publication Type :
- Academic Journal
- Accession number :
- 38768856
- Full Text :
- https://doi.org/10.1016/j.clim.2024.110259