| 著者 |
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 SW, 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 LM, Igawa T.
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| 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.
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