Q1 · CROSS-FIELD
ArticleOA
Author: Takesue, Hiroaki ; Hayasaka, Akira ; Nakamura, Genki ; Okazaki, Makoto ; Torizawa, Takuya ; Yamada, Kenta ; Igawa, Tomoyuki ; Miura-Okuda, Momoko ; Hino, Hiroshi ; Wakabayashi, Tetsuya ; Nagaya, Nishiki ; Nemoto, Takayuki ; Nishihara, Masamichi ; Mizoroki, Akihiko ; Irie, Machiko ; Nezu, Junichi ; Ishii, Shinya ; Kuramochi, Taichi ; Ikawa-Teranishi, Yuri ; Harfuddin, Zulkarnain ; Ozono, Yui ; Sollid, Ludvig M ; Gan, Siok Wan ; Tsushima, Takashi ; Takahashi, Noriyuki ; Kitazawa, Takehisa ; Shimada, Hideaki ; Muraoka, Masaru ; Okura, Yuu ; Ito, Shunsuke
AbstractIn 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.