De Jonge J, Heirman C, de Veerman M, Van Meirvenne S, Moser M, Leo O, Thielemans K
Vrije Universiteit Brussel, Medical School, Laboratory of Physiology-Immunology, Belgium.
J Immunol. 1998 Aug 1;161(3):1454-61.
As demonstrated in several preclinical models, bispecific Abs are attractive immunotherapeutic agents for tumor treatment. We have previously reported that a bacterially produced anti-CD3 x antitumor bispecific single chain variable fragment of Ab fragment (BsscFv), which is capable of retargeting CTLs toward BCL1 tumor cells, exhibits antitumor activity in vitro. To further facilitate BsscFv production, the coding sequence was subcloned in a eukaryotic expression vector and introduced into Chinese hamster ovary cells for large-scale production. In this report, we have determined the serum stability and the clearance rate from the circulation of BsscFv. Most important, we prove here the therapeutic value of BsscFv in the treatment of BCL1 lymphoma, a murine model for human non-Hodgkin's lymphoma. Tumor-bearing mice that were treated with rscFv in combination with staphylococcal enterotoxin B superantigen, human rIL-2, or murine rIL-12 showed long-term survival, whereas untreated mice all died. This is the first report of the successful in vivo use of BsscFv as an immunotherapeutic agent. Furthermore, long-term survival was the result of complete tumor removal and was not due to the induction of dormancy.
正如在多个临床前模型中所证明的那样，双特异性抗体是用于肿瘤治疗的有吸引力的免疫治疗剂。我们之前曾报道，一种细菌产生的抗CD3×抗肿瘤双特异性单链可变片段抗体（BsscFv），能够将细胞毒性T淋巴细胞（CTL）重新靶向BCL1肿瘤细胞，在体外表现出抗肿瘤活性。为了进一步促进BsscFv的生产，将编码序列亚克隆到真核表达载体中，并导入中国仓鼠卵巢细胞进行大规模生产。在本报告中，我们测定了BsscFv的血清稳定性及其从循环中的清除率。最重要的是，我们在此证明了BsscFv在治疗BCL1淋巴瘤（一种人类非霍奇金淋巴瘤的小鼠模型）中的治疗价值。用重组单链抗体片段（rscFv）联合葡萄球菌肠毒素B超抗原、人重组白细胞介素-2（rIL-2）或小鼠重组白细胞介素-12（rIL-12）治疗的荷瘤小鼠显示出长期存活，而未治疗的小鼠全部死亡。这是首次成功将BsscFv作为免疫治疗剂用于体内的报告。此外，长期存活是完全清除肿瘤的结果，而不是由于诱导休眠所致。
