Development of cancer immunotherapy using antibody specific for tumor antigens recognized by tumor-infiltration B cells

使用肿瘤浸润 B 细胞识别的肿瘤抗原特异性抗体开发癌症免疫疗法

• 批准号: 17591495
• 负责人: TAKENOYAMA Mitsuhiro
• 金额: $ 1.92万
• 依托单位: University of Occupational and Environmental Health, Japan
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591495/
• 关键词: SEREX; tumor-infiltrating B cell; tumor antigen; antibody; immunotherapy; lung cancer; マウス

Recent progress of immunotherapy by antibody have provided us hope of identification of target antigen as a novel immunotherapy. We previously demonstrated that tumor-infiltrating B cells recognized tumor antigens and produced antibodies against them by a using modified SEREX method. In the present study, we have identified tumor-associated antigens in two lung cancer patients and analyzed the usefulness of antigens for tumor marker and immunotherapy. In patient 1 (G603), one of identified antigens was revealed to be MAGE-B2. In the immuno-monitoring of the patient's sera, high antibody titer against MAGE-B2 was observed before operation and the titer decreased after resection of the primary tumor. It was elevated again at the time of adrenal metastasis, but then decreased after resection, indicating that anti-MAGE-B2 antibody could be used as tumor markers for the patient. In patient2, 22 distinct antigens were isolated. Of these antigens, Protein X was highly expressed in 5 out of 9 lung cancer cell lines by RT-PCR. Moreover, Protein X was overexpressed in 9 out of 15 lung cancer tissues compared with corresponding normal lung tissues. Polyclonal antibody against Protein X was generated and was analyzed for localization of antigens and for anti-tumor activity. Flow cytometory showed that Protein X expressed in the cell surface of tumor cells with high expression of this antigen. Immunohistochemical analysis revealed that Protein X was expressed in cell membrane of tumor cells in 7 out of 28 tumor tissues. Tumor implanted in SCID mouse regressed by the inoculation of anti-Protein X antibody. In vitro analysis, anti-tumor acticity was mediated by CDC mechanism. These result indicated that these antigens recognized by TIB could be usefull for clinical diagnosis as a tumor marker and for clinical application of antibody-mediated immunotherapy.

抗体免疫治疗的最新进展为我们提供了鉴定靶抗原作为一种新的免疫治疗方法的希望。我们以前证明肿瘤浸润B细胞识别肿瘤抗原，并使用改进的SEREX方法产生针对它们的抗体。在本研究中，我们鉴定了两例肺癌患者的肿瘤相关抗原，并分析了抗原在肿瘤标志物和免疫治疗中的作用。在患者1 （G603）中，鉴定出的抗原之一显示为MAGE-B2。患者血清免疫监测显示术前MAGE-B2抗体滴度高，原发肿瘤切除后滴度下降。肾上腺转移时再次升高，切除后下降，提示抗mage - b2抗体可作为患者的肿瘤标志物。在患者2中，分离出22种不同的抗原。通过RT-PCR检测，9株肺癌细胞系中有5株高表达蛋白X。此外，与相应的正常肺组织相比，15例肺癌组织中有9例蛋白X过表达。制备针对蛋白X的多克隆抗体，分析其抗原定位和抗肿瘤活性。流式细胞术显示，蛋白X在肿瘤细胞表面表达，该抗原高表达。免疫组化分析显示，28个肿瘤组织中有7个肿瘤细胞的细胞膜表达了蛋白X。接种抗X蛋白抗体后，SCID小鼠体内肿瘤消退。体外分析表明其抗肿瘤活性是通过CDC机制介导的。这些结果表明，TIB识别的这些抗原可作为肿瘤标志物用于临床诊断和抗体介导免疫治疗的临床应用。

项目成果

Identification of a new cancer/germline gene, KK-LC-1, encoding an antigen recognized by autologous CTL induced on human lung adenocarcinoma

• DOI: 10.1158/0008-5472.can-05-3840
• 发表时间: 2006-05-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Fukuyama, Takashi;Hanagiri, Takeshi;Yasumoto, Kosei
• 通讯作者: Yasumoto, Kosei

Haplotype loss of HLA class I antigen as an escape mechanism from immune attack in lung cancer

• DOI: 10.1158/0008-5472.can-04-3787
• 发表时间: 2005-07-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: So, T;Takenoyama, M;Yasumoto, K
• 通讯作者: Yasumoto, K

Identification of HLA-A24 restricted shared antigen recognized by autologous cytotoxic T lymphocytes from a patient with large cell carcinoma of the lung.

鉴定来自大细胞肺癌患者的自体细胞毒性 T 淋巴细胞识别的 HLA-A24 限制性共享抗原。

• 发表时间: 2007
• 期刊: Int J Cancer 120(5)
• 作者: Sugaya;M.
• 通讯作者: M.

Tumor specific expression of survivin-2B in lung cancer as a novel target of immunotherapy

• DOI: 10.1016/j.lungcan.2004.10.017
• 发表时间: 2005-05-01
• 期刊: LUNG CANCER
• 影响因子: 5.3
• 作者: Ichiki, Y;Hanagiri, T;Yasumoto, K
• 通讯作者: Yasumoto, K

Antigens recognized by IgG derived from tumor-infiltrating B lymphocytes in human lung cancer.

• 发表时间: 2006-09
• 期刊: Anticancer research
• 影响因子: 2
• 作者: M. Yasuda;Makiko Mizukami;T. Hanagiri;Y. Shigematsu;Takashi Fukuyama;Y. Nagata;T. So;Y. Ichiki;M. Sugaya;M. Takenoyama;K. Sugio;K. Yasumoto