Radioimmunotherapy with an 211At-labeled anti–tissue factor antibody protected by sodium ascorbate

Hiroki Takashima, Yoshikatsu Koga, Shino Manabe, Kazunobu Ohnuki, Ryo Tsumura, Takahiro Anzai, Nozomi Iwata, Yang Wang, Takuya Yokokita, Yukiko Komori, Daiki Mori, Sachiko Usuda, Hiromitsu Haba, Hirofumi Fujii, Yasuhiro Matsumura, Masahiro Yasunaga

Research output: Contribution to journalArticlepeer-review

Abstract

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti-TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody-drug conjugates (ADCs) and molecular imaging probes. We prepared an anti-TF mAb, clone 1084, labeled with astatine-211 (211At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50-100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the 211At-conjugated clone 1084 (211At-anti-TF mAb) was disrupted by an 211At-induced radiochemical reaction, we demonstrated that astatinated anti-TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF–expressing gastric cancer xenograft model, 211At-anti-TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected 211At-anti-TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to 211At-radioimmunotherapy.

Original languageEnglish
Pages (from-to)1975-1986
Number of pages12
JournalCancer science
Volume112
Issue number5
DOIs
Publication statusPublished - 2021 May

Keywords

  • antibody denaturation
  • astatine-211
  • radioimmunotherapy
  • sodium ascorbate
  • tissue factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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