Detection of tyrosin phosphorylation in B cell receptor by site-specific monoclonal antibodies for prediction of sensitivity to Ibrutinib

• Project/Area Number: 16K07158
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: National Institutes of Biomedical Innovation, Health and Nutrition
• Principal Investigator: ISE Tomoko 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, プロジェクト研究員 (20771900)
• Project Period (FY): 2016-10-21 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: B細胞受容体 / リン酸化酵素阻害剤 / 部位特異的抗リン酸化抗体 / 薬剤感受性 / 薬物治療 / B細胞 / シグナル伝達

Outline of Final Research Achievements

Activation of B cell Receptor (BCR), initiated by phosphorylation of the multiple tyrosin residues, plays important roles for tumorigenesis and proliferation of B cell malignancies. Many kinase inhibitor drugs involving the B cell signaling have been developed to treat B cell malignancies. In order to predict the efficacy of these kinase inhibitors and analyze the mechanisms of the therapeutic effects, we produced novel monoclonal antibodies specific to two different phosphorylated tyrosines in BCR and evaluated the site-specific phosphorylation in B cell lines. We revealed constitutive phosphorylation of CD79BY196 in the BCR in an Ibrutinib-resistant cell line by flow cytometry.

Academic Significance and Societal Importance of the Research Achievements

B細胞悪性腫瘍の治療薬としてB細胞受容体シグナル伝達に関与する多くのリン酸化酵素に対して様々な阻害剤が開発されているが、その治療効果は、標的リン酸化酵素の発現やリン酸化状態とは必ずしも相関せず、適切な治療薬選択は難しい現状である。我々の新規抗体によってもたらされた本研究成果は、薬剤の標的リン酸化酵素の上流に位置するB細胞受容体自身の特定のチロシンリン酸化の検出が、治療効果の予測に有用である可能性を示した。

Research Products

• [Journal Article] Preclinical development of anti-BCMA immunotoxins targeting multiple myeloma (2018)
  • Author(s): Shancer Zoe、Williams Matthew、Igelman Austin、Nagata Satoshi、Ise Tomoko、Pastan Ira、Bera Tapan K
  • Journal Title: Antibody Therapeutics Volume: 1 Issue: 1 Pages: 19-25
  • DOI: 10.1093/abt/tby004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical significance of MUC13 in pancreatic ductal adenocarcinoma (2018)
  • Author(s): Khan Sheema、Zafar Nadeem、Khan Shabia S.、Setua Saini、Behrman Stephen W.、Stiles Zachary E.、Yallapu Murali M.、Sahay Peeyush、Ghimire Hemendra、Ise Tomoko、Nagata Satoshi、Wang Lei、Wan Jim Y.、Pradhan Prabhakar、Jaggi Meena、Chauhan Subhash C.
  • Journal Title: HPB Volume: 20 Issue: 6 Pages: 563-572
  • DOI: 10.1016/j.hpb.2017.12.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Recombinant immunotoxins targeting B-cell maturation antigen are cytotoxic to myeloma cell lines and myeloma cells from patients (2018)
  • Author(s): Bera T K、Abe Y、Ise T、Oberle A、Gallardo D、Liu X-f、Nagata S、Binder M、Pastan I
  • Journal Title: Leukemia Volume: 32 Issue: 2 Pages: 569-572
  • DOI: 10.1038/leu.2017.315
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 標的に抗体が結合できる部位はいくつあるか？ 次世代抗体医薬の衝撃 (2018)
  • Author(s): 永田諭志，伊勢知子，鎌田春彦
  • Journal Title: 実験医学 Volume: 36 Pages: 1867-1874