Studies of antibody therapy for treatment of adult T-cell leukemia targeting surface carbohydrate molecules

靶向表面碳水化合物分子的抗体疗法治疗成人 T 细胞白血病的研究

• 批准号: 19390153
• 负责人: BABA Masanori
• 金额: $ 12.06万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19390153/
• 关键词: HTLV-1; ATL; 表面分子; 糖鎖; 抗体分子; 抗体療法

Comprehensive analysis for the gene expression of human T-cell leukemia virus type 1 (HTLV-1)-infected and uninfected T cell lines by DNA microarray revealed that CD70 was a molecule highly and specifically expressed on the surface of adult T-cell leukemia (ATL) cells. Further analysis for the gene expression of glycosyltransferases by real-time PCR and high-throughput analysis of cell surface sugar chains by mass spectrometry demonstrated the existence of several ATL cell-specific sugar chains. In addition, with a newly developed fluorescent linker compound, the surface sugar chains of ATL cells were successfully immobilized on a chip. Using a human single chain Fv (scFv) phage library, a scFv specific to an ATL cell line was successfully isolated. The antigen recognized by the scFv was HLA-DR1β, which was also highly expressed on the surface of ATL cells. The scFv could induce the apoptosis of the ATL cell line at low concentrations in its dimer form. To obtain the scFv that binds to ATL cell-specific surface sugar antigens, a novel synthetic scFv library was constructed by introducing random mutations on the complementary determining regions (CDR) of a single frame antibody.

利用DNA芯片技术综合分析人T细胞白血病病毒1型（HTLV-1）感染和未感染T细胞株的基因表达，发现CD70是一个在成人T细胞白血病（ATL）细胞表面高特异性表达的分子。通过实时荧光定量PCR对糖基转移酶基因表达的进一步分析和质谱对细胞表面糖链的高通量分析证实了ATL细胞特异性糖链的存在。此外，利用新开发的荧光连接化合物，成功地将ATL细胞表面糖链固定在芯片上。利用人单链病毒（scFv）噬菌体文库，成功分离出ATL细胞系特异性的单链病毒。scFv识别的抗原是HLA-DR1β，该抗原在ATL细胞表面也高表达。scFv以低浓度二聚体形式诱导ATL细胞株凋亡。为了获得与ATL细胞特异性表面糖抗原结合的scFv，通过在单框架抗体的互补决定区（CDR）上引入随机突变，构建了一个新的合成scFv文库。

项目成果

成人t細胞白血病細胞表層に特異的に発現する糖鎖解析

成人T细胞白血病细胞表层特异表达的糖链分析

• 发表时间: 2008
• 作者: 佐藤昌紀;時任麻衣子;濱崎隆之;馬場昌範;有馬直道;伊東祐二;伊藤浩美;澤木弘道;成松久;若尾雅広;隅田泰生
• 通讯作者: 隅田泰生

ATL細胞特異的に抗腫瘍効果を有する薬剤の探索

寻找针对ATL细胞具有抗肿瘤作用的药物

• 发表时间: 2008
• 作者: 時任真衣子;濱崎隆之;馬場昌範
• 通讯作者: 馬場昌範

Discovery of hydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hyposhesis.

在基于多模板假设构建的小型化学库中发现氢四甲基萘类似物作为成人 T 细胞白血病细胞选择性增殖抑制剂。

• 发表时间: 2009
• 期刊: Bioorg. Med. Chem 17
• 作者: Nakamura M;Hamasaki T;Tokitou M;Baba M;Hashimoto Y;Aoyama H
• 通讯作者: Aoyama H

Discovery of tetrahydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hyposhesis

在基于多模板假设构建的小型化学库中发现四氢四甲基萘类似物作为成人 T 细胞白血病细胞选择性增殖抑制剂

• 发表时间: 2009
• 期刊: Bioorganic Medicinal Chemistry 17
• 作者: Nakamura M;Hamasaki T;Tokitou M;Baba M;Hashimoto Y;Aoyama H.
• 通讯作者: Aoyama H.

Effective induction of cell death on adult T-cell leukemia cells by HLA-DRβ-specific small antibody fragment isolated from human antibody phage library

从人抗体噬菌体库中分离的 HLA-DRβ 特异性小抗体片段有效诱导成人 T 细胞白血病细胞死亡

• 发表时间: 2009
• 期刊: Journal of Biochemistry (印刷中)
• 作者: Muraoka S;Ito Y;Kamimura M;Baba M;Arima N;Suda Y;Hashiguchi S;Torikai M;Nakashima T;Sugimura K
• 通讯作者: Sugimura K