Download MendeleyCharacterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.
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.(2023) Nat Commun 14: 8502-8502
- PubMed: 38135691
- DOI: https://doi.org/10.1038/s41467-023-44083-4
- Primary Citation of Related Structures:
8W83, 8W84, 8W85, 8W86 - 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.
Organizational Affiliation:
Translational Research Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
