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Development and clinical application of new anti-cancer drugs for oncoprotein CD98 as a molecular target.

以癌蛋白CD98为分子靶点的新型抗癌药物的开发及临床应用。

基本信息

批准号：
17590467
负责人：
ITOH Kunihiko
金额：
$ 1.92万
依托单位：
University of Shizuoka
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-17590467/
关键词：
CD98 Monoclonal antibody Phage display Epitope peptide Molecular targeting drugs 分子標的治療

项目摘要

Anti-CD98 monoclonal antibody, HBJ127 shows growth inhibition in vitro. Since elevated expression of CD98 is detected in tumor tissues, especially in squamous cell carcinomas, anti-tumor immunity may be inducible in the host by active immunization of peptides derived from epitope recognized by HBJ127. In this study, we identified HBJ127 epitope using phage display random peptide library and characterized the serum from epitope peptide-immunized mice. We identified the peptide sequence corresponding to the 442-444 (AFS) of human CD98 heavy chain (h. c. ) among isolated HBJ127-reactive peptide sequences. It was found that 413F is human specific amino acid. We estimated that this motif is HBJ127 epitope, since 1) HBJ127 reacts only with human species, and 2) HBJ127 epitope position is predicted in 418-529 of human CD98 h. c. Next, we prepared several epitope peptide-keyhole limpet hemocyanine (KLH) conjugates and immunized with BALB/c mice. The immune serum reacted with epitope peptide-KLH in a concentration dependent manner. They also reacted with epitope peptide-bovine serum albumin (BSA). From these results, the immune response occurred not only against the carrier protein but also against hapten (epitope peptide). The immune serum also reacted with recombinant human CD98 h. c. in a concentration dependent manner. These results suggest that CD98-reactive antibody repertoire can be inducible in the hosts by immunization of epitope peptide derived from HBJ127. This may indicate the usefulness of tumor suppressive antibody-derived epitope peptide immunization for induction of anti-tumor immunity.

抗CD 98单克隆抗体HBJ 127在体外显示生长抑制作用。由于在肿瘤组织中，特别是在鳞状细胞癌中检测到CD 98的表达升高，因此通过主动免疫源自HBJ 127识别的表位的肽，可以在宿主中诱导抗肿瘤免疫。本研究利用噬菌体随机肽库技术对HBJ 127抗原表位进行了鉴定，并对抗原表位免疫小鼠的血清进行了鉴定。我们鉴定了对应于人CD 98重链442-444（AFS）的肽序列（h. C.）。发现413 F是人特异性氨基酸。我们估计该基序是HBJ 127表位，因为1）HBJ 127仅与人类物种反应，并且2）HBJ 127表位预测位于人CD 98 h的418-529。C.其次，我们制备了几种表位肽-钥孔血吸虫（KLH）偶联物并免疫BALB/c小鼠。免疫血清与表位肽KLH呈浓度依赖性反应。它们还与表位肽-牛血清白蛋白（BSA）反应。根据这些结果，不仅针对载体蛋白，而且针对半抗原（表位肽）发生免疫应答。免疫血清与重组人CD 98 h也呈阳性反应。C.以浓度依赖的方式。这些结果表明，CD 98-反应性抗体库可以通过源自HBJ 127的表位肽的免疫在宿主中诱导。这可能表明肿瘤抑制抗体衍生的表位肽免疫用于诱导抗肿瘤免疫的有用性。