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

• DOI: 10.1111/cas.15596
• Publication Date: 2022-09-22T15:50:29Z
• Authors: 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; Ryohei Suzuki; Hiroki Konishi; Asami Yamamoto; Hiroyuki Abe; Nobuyoshi Hiraoka; Kazunori Aoki; Yasumasa Kato; Yasuyuki Seto; Chihoko Yoshimura; Kazutaka Miyadera; Kouhei Tsumoto; Tetsuo Ushiku; Shumpei Ishikawa
• Keywords: 0301 basic medicine; Epitopes; 03 medical and health sciences; Nucleic Acids; Neoplasms; Antigens, Surface; Humans; Original Articles; Antigens; Hydrogen-Ion Concentration; Antibodies; 3. Good health

AbstractImportant 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.