Analysis of antigen to renal cell carcinoma and establishment of cancer specific antibody teratment

肾细胞癌抗原分析及癌症特异性抗体方法的建立

基本信息

批准号：
18591777
负责人：
SHIROKI Ryoichi
金额：
$ 2.57万
依托单位：
Fujita Health University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591777/
关键词：
Renal cell Cancer Antibody therapy Cancer-specific antigen Phage library

项目摘要

Renal cell cancer (RCC) has a heterogeneous clinical presentation with up to 30% metastatic cases at initial diagnosis and 30% of initially organ-confined cases developing metastases during follow-up at variable intervals. Recently antibodies against specific molecules have been applied for clinical treatment to malignant diseases. Although several murine monoclonal antibodies (mAbs) which have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers due to our lack of knowledge which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of RCC cells. They were individually screened by immunostaining and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by mass spectrometry. We isolated 357 mAbs with unique sequences and identified 7 distinct. Ags highly expressed on several carcinomas. After preparing complete IgGi Abs the in vitro assay for antibody-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine anti tumor activity. The mAbs converted to IgG1 revealed effective ADCC as well as and tumor activity in vivo. Thus, the procedure adopted in our study enabled us to succeed in comprehensive identification of tumor-associated antigens (TAAs) and simultaneous isolation of mAbs against RCC. Therefore, we believe that some Ags detected will be useful targets for cancer therapy and several mAbs will become useful therapeutic agents to RCC in the foreseeable future.

肾细胞癌（RCC）具有异质性临床表现，在初始诊断时，转移性病例高达30％，最初的器官夹具病例的30％在随访期间以可变的间隔开发转移。最近，针对特定分子的抗体已应用于恶性疾病的临床治疗。尽管已经被人性化的几种鼠单克隆抗体（mAb）成为了针对一些恶性肿瘤的有用治疗剂，但由于我们缺乏抗原（AGS）可以成为有用的靶标，因此大多数人类癌症的治疗性ABS尚未可用于人类癌症。在本研究中，我们通过广泛隔离可能成为治疗性的人物MAB，建立了一种全面识别此类AG的程序。我们使用噬菌体 - 播放AB库，我们分离了大量与RCC细胞表面结合的人物mAB。选择了它们通过免疫染色和优先染色和强烈染色的恶性细胞的免疫染色和克隆进行筛选。这些克隆识别的AG通过免疫沉淀分离，并通过质谱鉴定。我们隔离了具有独特序列的357个mAb，并鉴定出7个不同的mab。 AGS在几个癌上高度表达。在制备完整的IgGI ABS后，进行了抗体依赖性细胞介导的细胞毒性（ADCC）的体外测定，并在耐癌症的胸膜小鼠中进行体内测定法以检查抗肿瘤活性。转换为IgG1的mAB显示有效的ADCC以及体内的肿瘤活性。因此，我们的研究中采用的程序使我们能够成功地全面鉴定与肿瘤相关的抗原（TAA）和同时分离对RCC的mAb。因此，我们认为检测到的某些AG将是癌症治疗的有用靶标，在可预见的将来，几个mAB将成为RCC的有用治疗剂。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Zoledronic acid for bone metastases due to advanced renal cell carcinoma under chronic hemodialysis.

唑来膦酸用于治疗慢性血液透析下晚期肾细胞癌引起的骨转移。

DOI：
发表时间：
期刊：
Japanese J Urol. (in press)
影响因子：
0
作者：
Arima A;K;Shiroki R;Kusaka M;Hoshinagaet al.
通讯作者：
Hoshinagaet al.

Comprehensive screening for antigens overexpressed on carcinomas via isolation of human monoclonal antibodies that may be therapeutic

通过分离可能具有治疗作用的人单克隆抗体，全面筛查癌症上过度表达的抗原

DOI：
发表时间：
期刊：
Proceedings of the National Academy of Sciences (In press)
影响因子：
0
作者：
Gene Kurosawa;Yasushi Akahoril;Ryoichi Shiroki;Kiyotaka Hoshinaga;Yoshikazu Kurosawa
通讯作者：
Yoshikazu Kurosawa

Comprehensive isolation of complete human antibodies bound to renal cell carcinoma.

全面分离与肾细胞癌结合的完整人抗体。