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Nucleic acid–triggered tumoral immunity propagates pH ‐selective therapeutic antibodies through tumor‐driven epitope spreading

2022; Wiley; Volume: 114; Issue: 1 Linguagem: Inglês

10.1111/cas.15596

1349-7006

Genta Furuya, Hiroto Katoh, Shinichiro Atsumi, ITARU HASHIMOTO, Daisuke Komura, Ryo Hatanaka, Shogo Senga, Shuto Hayashi, Shoji Akita, Hirofumi Matsumura, Akihiro Miura, Hideaki Mita, Makoto Nakakido, Satoru Nagatoishi, Akira Sugiyama, Ryôhei Suzuki, Hiroki Konishi, Asami Yamamoto, Hiroyuki Abé, Nobuyoshi Hiraoka, Kazunori Aoki, Yukio Kato, Yasuyuki Seto, Chihoko Yoshimura, Kazutaka Miyadera, Kouhei Tsumoto, Tetsuo Ushiku, Shumpei Ishikawa,

Glycosylation and Glycoproteins Research

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.