Antitumor activity of mannan-binding protein in vivo as revealed by a virus expression system: Mannan-binding proteindependent cell-mediated cytotoxicity

Mannan-binding protein (MBP), a Ca(2+)-dependent mammalian lectin specific for mannose and N-acetylglucosamine, is an important serum component associated with innate immunity. MBP activates complement and functions as a direct opsonin on binding to mannooligosaccharide-bearing pathogens. We have found that MBP recognizes and binds specifically to oligosaccharide ligands expressed on the surfaces of a human colorectal carcinoma. Interestingly, the recombinant vaccinia virus carrying human MBP gene was demonstrated to possess a potent growth-inhibiting activity against human colorectal carcinoma cells transplanted in KSN nude mice when administered by intratumoral or subcutaneous injection. Moreover, a significant prolongation of life span of tumor-bearing mice resulted from the treatment. This effect appears to be a consequence of local production of MBP. Unexpectedly, the mutant MBP, which had essentially no complement-activating activity, was nearly as active as wild-type MBP. These results indicated that MBP has a previously undescribed cytotoxic activity, which we propose to term MBP-dependent cell-mediated cytotoxicity(MDCC). In addition, this study provides a model for the development of an effective and specific host defense factor for cancer gene therapy.

甘露聚糖结合蛋白（Mannan-binding protein, MBP）是一种钙离子依赖性的哺乳动物凝集素，特异性识别甘露糖与N-乙酰葡糖胺，是参与固有免疫的重要血清组分。MBP可激活补体系统，并在结合携带甘露寡糖的病原体时发挥直接调理素功能。本研究发现，MBP可特异性识别并结合人结直肠癌表面表达的寡糖配体。有趣的是，携带人MBP基因的重组痘苗病毒，经瘤内或皮下注射给药后，可对接种于KSN裸小鼠体内的人结直肠癌细胞展现出强效生长抑制活性。此外，该治疗可显著延长荷瘤小鼠的生存期。该效应似乎源于MBP的局部表达。出乎意料的是，几乎丧失补体激活活性的突变型MBP，其抗肿瘤活性几乎与野生型MBP相当。上述结果表明，MBP具有此前未被报道的细胞毒活性，我们将其命名为MBP依赖性细胞介导的细胞毒作用（MBP-dependent cell-mediated cytotoxicity, MDCC）。此外，本研究为开发用于癌症基因治疗的高效特异性宿主防御因子提供了实验模型。