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Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

Yuu OkuraYuri Ikawa-TeranishiAkihiko MizorokiNoriyuki TakahashiTakashi TsushimaMachiko IrieZulkarnain HarfuddinMomoko Miura-OkudaShunsuke ItoGenki NakamuraHiroaki TakesueYui OzonoMasamichi NishiharaKenta YamadaSiok Wan GanAkira HayasakaShinya IshiiTetsuya WakabayashiMasaru MuraokaNishiki NagayaHiroshi HinoTakayuki NemotoTaichi KuramochiTakuya TorizawaHideaki ShimadaTakehisa KitazawaMakoto OkazakiJunichi NezuLudvig M SollidTomoyuki Igawa
Published in: Nature communications (2023)
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.
Keyphrases
  • celiac disease
  • clinical trial
  • cancer therapy
  • immune response
  • climate change
  • pluripotent stem cells