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

抗cd98单克隆抗体HBJ127在体外表现出生长抑制作用。由于CD98在肿瘤组织中表达升高，特别是在鳞状细胞癌中，因此可以通过主动免疫HBJ127识别的表位衍生的肽，在宿主体内诱导抗肿瘤免疫。本研究利用噬菌体展示随机肽库对HBJ127表位进行了鉴定，并对表位肽免疫小鼠血清进行了表征。我们在分离的hbj127反应性肽序列中鉴定出与人CD98重链（h.c .） 442-444 （AFS）相对应的肽序列。结果表明，413F是人类特有的氨基酸。我们估计这个基序是HBJ127表位，因为1)HBJ127只与人类物种发生反应，2)HBJ127表位预测在人类CD98 h. c的418-529中。接下来，我们制备了几个表位肽-锁孔帽贝血青素（KLH）偶联物，并用BALB/c小鼠免疫。免疫血清与表位肽- klh呈浓度依赖性反应。它们也与表位肽-牛血清白蛋白（BSA）反应。从这些结果来看，免疫反应不仅发生在载体蛋白上，也发生在半抗原（表位肽）上。免疫血清也与重组人CD98 h.c发生浓度依赖性反应。这些结果表明，cd98反应性抗体库可以通过免疫HBJ127的表位肽在宿主体内诱导。这可能表明肿瘤抑制抗体源性表位肽免疫对诱导抗肿瘤免疫的有效性。

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.