Molecular-based study for the development of monoclonal antibody therapy in chemokine receptors, CCR4 and CXCR3

基于分子的研究开发趋化因子受体、CCR4 和 CXCR3 的单克隆抗体疗法

• 批准号: 16390280
• 负责人: UEDA Ryuzo
• 金额: $ 7.36万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390280/
• 关键词: Chemokine receptors; T-cell Malignancies; Monoclonal antibody therapy; ADCC; Regulartory T-cell; CCR4; CXCR3; regulatory T cell; FOXP3; ケモカインレセプター; CXCR3; FoxP3; 低フコース化抗体

CCR4 was shown to be expressed in many types of T-cell malignancies, especially in adult T-cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma-unspecified (PTCL-U) and anaplastic large cell lymphoma (ALK negative) and be a significant and independent prognostic marker in ATLL and PTCL-U. Monoclonal antibody for CCR4 presented a strong anti-tumor effect for several types of T-cell malignancies via ADCC activity in vivo as well as in vitro assay, including CCR4-espressing Hodgkin lymphoma and cutaneous T-cell lymphoma. CCR4 was also expressed in the surface of cells with the character of regulatory T-cells (FOXP3 positive), strongly suggesting that the origin of ATLL tumor cells can be regulatory T-cells. Reactive T-cells surrounding Hodgkin cells (Reed-Sternberg cells) were shown to manifest both CCR4 and FOXP3 expressions on their surfaces, which suggest that CCR4 can be target molecule for the elimination of the anergy for tumor immunity. Phase I clinical study of the humanized monoclonal antibody therapy of CCR4 for T-cell malignancies was conducted and was shown to be well-tolerable with clinical resoponse.

CCR4被证明在许多类型的t细胞恶性肿瘤中表达，特别是在成人t细胞白血病/淋巴瘤（ATLL），外周t细胞淋巴瘤-未指明（PTCL-U）和间变性大细胞淋巴瘤（ALK阴性）中，并且是ATLL和PTCL-U的重要且独立的预后标志物。CCR4单克隆抗体对多种t细胞恶性肿瘤（包括表达CCR4的霍奇金淋巴瘤和皮肤t细胞淋巴瘤）的体内和体外活性检测显示出较强的抗肿瘤作用。CCR4也在具有调节性t细胞特征的细胞表面表达（FOXP3阳性），强烈提示ATLL肿瘤细胞的起源可能是调节性t细胞。霍奇金细胞周围的反应性t细胞（Reed-Sternberg细胞）表面同时表达CCR4和FOXP3，这表明CCR4可能是消除肿瘤免疫能量的靶分子。对CCR4人源化单克隆抗体治疗t细胞恶性肿瘤进行了I期临床研究，并显示出良好的耐受性和临床反应。

项目成果

The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma

• DOI: 10.1038/sj.leu.2404415
• 发表时间: 2006-12-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Ishida, T.;Ishii, T.;Ueda, R.
• 通讯作者: Ueda, R.

Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege

• DOI: 10.1158/0008-5472.can-06-0261
• 发表时间: 2006-06-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Ishida, Takashi;Ishii, Toshihiko;Ueda, Ryuzo
• 通讯作者: Ueda, Ryuzo

Introduction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor.

通过新型 IkappaB 激酶抑制剂在成人 T 细胞白血病细胞中引入细胞死亡。

• 发表时间: 2006
• 期刊: Leukemia 20
• 作者: Sanda T;Asamitsu K;Ogura H;Iida S;Utsunomiya A;Ueda R.;Okamoto;T
• 通讯作者: T

Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma : blood eosinophilia is a significant unfavorable prognostic factor

成人T细胞白血病/淋巴瘤中血液嗜酸性粒细胞增多的临床意义：血液嗜酸性粒细胞增多是一个显着的不利预后因素

• 发表时间: 2006
• 期刊: Leuk Res. (in press)
• 作者: Utsunomiya;A.
• 通讯作者: A.

pl6/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis.

p16/INK4a基因甲基化是肺MALT淋巴瘤诊断时常见的发现。

• 发表时间: 2005
• 期刊: Mod Pathol 18(9)
• 作者: Takino;H.;Okabe;M.;Li;C;Ohshima;K.;Yoshino;T.;Nakamura;S.;Ueda;R.;Eimoto;T.;Inagaki;H.
• 通讯作者: H.