Flavell D J, Boehm D A, Noss A, Flavell S U
The Simon Flavell Leukaemia Research Laboratory, University Department of Pathology, Southampton General Hospital, UK.
Br J Cancer. 1997;75(7):1035-43. doi: 10.1038/bjc.1997.177.
Immunotoxins that carry two toxin molecules to the target cell should in theory have a greater anti-tumour effect than those that carry just one. We have investigated the therapeutic efficacy of two anti-CD7-saporin immunotoxins constructed with one saporin (HB2-Sap 1-mer) or two saporin molecules (HB2-Sap 2-mer) per immunotoxin molecule. In vitro, the 2-mer immunotoxin was 5.6 times more effective than the 1-mer immunotoxin at inhibiting protein synthesis in the CD7+ human T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2 and was also more effective at inhibiting HSB-2 cell proliferation. Flow cytometry revealed that the 2-mer immunotoxin had a reduced binding capacity to HSB-2 cells compared with the 1-mer immunotoxin or native HB2 antibody. In therapy studies in SCID mice with disseminated HSB-2 human leukaemia, the 2-mer immunotoxin performed marginally better than the 1-mer immunotoxin, but log-rank analysis did not reveal any significant differences between the two therapy groups. We therefore conclude that, although the 2-mer immunotoxin performed better than the 1-mer immunotoxin against target HSB-2 cells in vitro, this improved performance was not reflected as an improved in vivo therapeutic outcome in the SCID mouse model.
理论上，携带两个毒素分子至靶细胞的免疫毒素应比仅携带一个毒素分子的免疫毒素具有更强的抗肿瘤作用。我们研究了两种抗CD7-皂草素免疫毒素的治疗效果，这两种免疫毒素分别是每个免疫毒素分子携带一个皂草素分子（HB2-Sap 单聚体）或两个皂草素分子（HB2-Sap 二聚体）。在体外，二聚体免疫毒素在抑制CD7+人T细胞急性淋巴细胞白血病（T-ALL）细胞系HSB-2的蛋白质合成方面比单聚体免疫毒素有效5.6倍，在抑制HSB-2细胞增殖方面也更有效。流式细胞术显示，与单聚体免疫毒素或天然HB2抗体相比，二聚体免疫毒素与HSB-2细胞的结合能力降低。在携带播散性HSB-2人白血病的SCID小鼠的治疗研究中，二聚体免疫毒素的表现略优于单聚体免疫毒素，但对数秩分析未显示两个治疗组之间有任何显著差异。因此，我们得出结论，尽管二聚体免疫毒素在体外对靶HSB-2细胞的表现优于单聚体免疫毒素，但在SCID小鼠模型中，这种改善的表现并未转化为体内治疗效果的提高。
