8W84

HLA-DQ2.5-alpha2 gliadin peptide in complex with DQN0344AE02

Summary for 8W84

• Entry DOI: 10.2210/pdb8w84/pdb
• Descriptor: DQN0344AE02 Fab heavy chain, DQN0344AE02 Fab light chain, HLA class II histocompatibility antigen, DQ alpha 1 chain, ... (6 entities in total)
• Functional Keywords: celiac disease, antibody, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 95731.98

Authors

Irie, M.,Tsushima, T.,Teranishi-Ikawa, Y.,Takahashi, N.,Ishii, S.,Okura, Y.,Fukami, T.A.,Torizawa, T. (deposition date: 2023-08-31, release date: 2023-11-08, Last modification date: 2024-10-09)

Primary citation

Okura, Y.,Ikawa-Teranishi, Y.,Mizoroki, A.,Takahashi, N.,Tsushima, T.,Irie, M.,Harfuddin, Z.,Miura-Okuda, M.,Ito, S.,Nakamura, G.,Takesue, H.,Ozono, Y.,Nishihara, M.,Yamada, K.,Gan, S.W.,Hayasaka, A.,Ishii, S.,Wakabayashi, T.,Muraoka, M.,Nagaya, N.,Hino, H.,Nemoto, T.,Kuramochi, T.,Torizawa, T.,Shimada, H.,Kitazawa, T.,Okazaki, M.,Nezu, J.,Sollid, L.M.,Igawa, T.
Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.
Nat Commun, 14:8502-8502, 2023

PubMed Abstract: In human celiac disease (CeD) HLA-DQ2.5 presents gluten peptides to antigen-specific CD4 T cells, thereby instigating immune activation and enteropathy. Targeting HLA-DQ2.5 with neutralizing antibody for treating CeD may be plausible, yet using pan-HLA-DQ antibody risks affecting systemic immunity, while targeting selected gluten peptide:HLA-DQ2.5 complex (pHLA-DQ2.5) may be insufficient. Here we generate a TCR-like, neutralizing antibody (DONQ52) that broadly recognizes more than twenty-five distinct gluten pHLA-DQ2.5 through rabbit immunization with multi-epitope gluten pHLA-DQ2.5 and multidimensional optimization. Structural analyses show that the proline-rich and glutamine-rich motif of gluten epitopes critical for pathogenesis is flexibly recognized by multiple tyrosine residues present in the antibody paratope, implicating the mechanisms for the broad reactivity. In HLA-DQ2.5 transgenic mice, DONQ52 demonstrates favorable pharmacokinetics with high subcutaneous bioavailability, and blocks immunity to gluten while not affecting systemic immunity. Our results thus provide a rationale for clinical testing of DONQ52 in CeD.

PubMed: 38135691
DOI: 10.1038/s41467-023-44083-4

Experimental method

X-RAY DIFFRACTION (2.105 Å)