A Basic Study for Cancer-Specific Immunotherapy using a Human Natural Antibody and its Anti-idiotypic Antibodies.

SK-1是由细胞融合法产生的人-人杂交瘤分泌的人源性单抗(HuMAb)。在1999年4月至2001年3月的两年时间里，我们进行了以下几个方面的研究。1.另外制备了4株可识别肿瘤相关抗原的人源单抗。对这些抗体的进一步研究目前正在进行中。2.我们评价了提纯SK-1递增剂量治疗晚期结肠癌的安全性、毒性和初步疗效。对3组复发性结肠癌患者分别给予SK-1 2 mg、4 mg、10 mg静脉滴注，共3次。有1例患者在没有药物治疗的情况下轻微发热消退。未发现其他严重副作用。治疗后8周内血清CEA平均升高率明显下降(参考文献1，4)。3.制备了抗SK1的鼠抗独特型单抗(Ab2)和兔抗独特型抗血清(Ab3)。使用这些抗体，我们发现，在4名患者中，SK-1(AB2)抗独特型抗体的血清效价在治疗后继续增加。提示SK-1天然抗体可能诱导了肿瘤相关的抗独特型抗体反应(参考文献1，4)。4.克隆了编码SK1抗原肽的基因。在λgt22A中利用结肠癌细胞系的基因构建了表达文库(参考文献3)。5.采用体外激活的CD8+细胞毒性T淋巴细胞进行过继免疫治疗。我们发现，尽管困难，但可以用自体肿瘤细胞作为抗原在体外诱导CTL。一旦成功诱导，这种细胞群体的过继转移就能看到良好的临床效果(参考文献6，7)。

SK-1 is a human monoclonal antibody (HuMAb) secreted by a human-human hybridoma generated by the cell fusion method. During 2-year period from April 1999 to March 2001, we made research in the following matters. 1. We made additional 4 human monoclonal antibodies that recognize tumor related antigens. The further investigation to characterize these antibodies is now underway. 2. We evaluated the safety, toxicity and preliminary efficacy of escalating dosages of purified SK-1 in patients with advanced colon cancer. SK-1 was administered intravenously at 2, 4 or 10 mg three times to three groups of patients with recurrent colon cancer. Slight fever that subsided without medication was noted in one patient. No other severe side effects were noted. The mean rate of serum CEA level increase declined significantly during the eight weeks following the treatment (ref.1, 4). 3. We generated murine antiidiotypic monoclonal antibody (Ab2) and rabbit anti-anti-idiotypic antisera (Ab3) to SK1. Using these antibodies we showed that, in four patients, serum titer of antiidiotypic IgG antibodies to SK-1 (Ab2) continued to increase following the treatment. It was suggested that SK-1 natural antibody may have induced carcinoma-related, antiidiotypic antibody responses (ref.1, 4). 4. We identified the gene encoding the SK1-antigenic peptide. A cDNA expression library constructed in λgt22A using mRNA from the colon cancer cell line was screened (ref.3). 5. Adoptive immunotherapy using in vitro activated CD8-positive cytotoxic T lymphocyte was conducted. We showed that, although difficult, CTL can be induced in vitro using autologous tumor cell as an antigen. Once it is induced successfully, favorable clinical effects were seen by the adoptive transfer of such cell populations (ref.6, 7).