Mutated SEA-D227A-conjugated antibodies greatly enhance antitumor activity against MUC1-expressing bile duct carcinoma

Hideaki Kodama, Masanori Suzuki, Yu Katayose, Masao Shinoda, Naoki Sakurai, Shin Ichi Takemura, Hiroshi Yoshida, Hisaaki Saeki, Masahiko Ichiyama, Kohei Tsumoto, Ryutaro Asano, Izumi Kumagai, Kohzoh Imai, Yuji Hinoda, Seiki Matsuno, Toshio Kudo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we have directed our attention to superantigens (SAgs), the most potent known activators of T lymphocytes. In our previous study, staphylococcal enterotoxin A (SEA) was conjugated chemically with MUSE11 mAb, which recognizes the MUC1 cancer-associated antigen, and shown to enhance the specific cytotoxic activity of T-LAK cells against MUC1-expressing BDC cells (TFK-1) in vitro and in vivo. However, it is probable that SEA might cause side-effects because of nonspecific binding to class II positive cells. In order to overcome these, we generated mutated SEA (mSEA) by changing Asp at position 227 of native SEA to Ala, which has reduced affinity to MHC class II molecules, but retains the potential for T cell activation. When mSEA-D227A was administered to rabbits to examine effects on blood pressure, 500 times more mSEA-D227A was tolerated than native SEA. This prompted us to construct a mSEA-D227A-conjugated mAb, reactive with MUC1. It augmented the antitumor activity of T-LAK cells significantly, and furthermore, mSEA-D227A could be conjugated to two bispecific antibodies, BsAb (anti-MUC1×anti-CD3) and BsAb (anti-MUC1×anti-CD28), which in combination had greater enhancing effects than mSEA-D227A-conjugated anti-MUC1 mAb, and combination of unconjugated BsAbs. These findings indicate a utility of mSEA-D227A-conjugated antibodies for targeted cancer immunotherapy.

Original languageEnglish
Pages (from-to)539-548
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume50
Issue number10
DOIs
Publication statusPublished - 2001 Dec 1

Keywords

  • Immunotherapy
  • MUC1
  • Mutated SEA
  • Superantigen
  • Xenografted SCID mice

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Mutated SEA-D227A-conjugated antibodies greatly enhance antitumor activity against MUC1-expressing bile duct carcinoma'. Together they form a unique fingerprint.

  • Cite this

    Kodama, H., Suzuki, M., Katayose, Y., Shinoda, M., Sakurai, N., Takemura, S. I., Yoshida, H., Saeki, H., Ichiyama, M., Tsumoto, K., Asano, R., Kumagai, I., Imai, K., Hinoda, Y., Matsuno, S., & Kudo, T. (2001). Mutated SEA-D227A-conjugated antibodies greatly enhance antitumor activity against MUC1-expressing bile duct carcinoma. Cancer Immunology, Immunotherapy, 50(10), 539-548. https://doi.org/10.1007/s002620100219