Fjeld J G, Bruland O S, Benestad H B, Schjerven L, Stigbrand T, Nustad K
Central Laboratory, Norwegian Radium Hospital, Montebello, Oslo.
Br J Cancer. 1990 Oct;62(4):573-8. doi: 10.1038/bjc.1990.332.
A tumour model system is reported that for many purposes may be an alternative to xenografted nude mice. The model allows immunotargeting of human tumour cells in immunocompetent animals. The target cells are contained in i.p. diffusion chambers (DC) with micropore membrane walls that are permeable to molecules, including the cell specific monoclonal antibodies (MoAb), but impermeable to cells. Thus, the tumour cells are protected from the host immunocompetent cells. In the work here presented the model was tested in immunocompetent mice and pigs, with tumour cells and antibody preparations that had demonstrated specific targeting in the nude mouse xenograft model. Hence, the DC were filled with cells from the human cell lines Hep-2 (expressing placental alkaline phosphatase, PLALP), or OHS (a sarcoma cell line), and the MoAb preparations injected i.v. were a 125I-labelled Fab fragment of the PLALP specific antibody H7, or a 125I-labelled F(ab')2 fragment of the sarcoma specific antibody TP-1. Specific targeting of the human tumour cells was demonstrated in both mice and pigs. The target: blood ratios were comparable in the two species, reaching a maximum of about 15 after 24 h with the Fab preparation, and a ratio of 25 after 72 h with the F(ab')2. The target uptake relative to injected dose was lower in pigs than in mice, but the difference between the two species was smaller than expected, presumably due to a slower antibody clearance in the pigs than in the mice. An artificial cell targeting system like this has several advantages in the search for solutions to many of the fundamental problems experienced in immunotargeting. Firstly, parallel binding experiments can be carried out in vitro with the same target. Because in vitro results are only influenced by the diffusion into the DC and the immunological binding characteristics of the antibodies, targeting differences between antibody preparations due to these factors can then be distinguished from differences due to pharmacokinetical properties. Secondly, the animals can be implanted with any type and number of target cells, or with antigen negative control cells. Thirdly, and perhaps most important, the system opens a possibility for evaluation of the murine MoAb in xenogenic species, and this may predict the clinical targeting potential better than experiments on mice.
据报道，一种肿瘤模型系统在许多方面可替代异种移植裸鼠。该模型可在具有免疫活性的动物体内对人肿瘤细胞进行免疫靶向。靶细胞置于腹腔内扩散小室（DC）中，小室的微孔膜壁可使包括细胞特异性单克隆抗体（MoAb）在内的分子透过，但细胞不能透过。因此，肿瘤细胞受到保护，免受宿主免疫活性细胞的攻击。在本文介绍的工作中，使用在裸鼠异种移植模型中已证明具有特异性靶向作用的肿瘤细胞和抗体制剂，在具有免疫活性的小鼠和猪体内对该模型进行了测试。因此，DC中填充有人细胞系Hep-2（表达胎盘碱性磷酸酶，PLALP）或OHS（一种肉瘤细胞系）的细胞，静脉注射的MoAb制剂是PLALP特异性抗体H7的125I标记Fab片段，或肉瘤特异性抗体TP-1的125I标记F(ab')2片段。在小鼠和猪体内均证明了对人肿瘤细胞的特异性靶向。两种物种的靶标与血液的比率相当，Fab制剂在24小时后最高可达约15，F(ab')2在72小时后可达25。相对于注射剂量的靶标摄取在猪体内低于小鼠，但两种物种之间的差异小于预期，可能是由于猪体内抗体清除速度比小鼠慢。这样一种人工细胞靶向系统在寻找免疫靶向中遇到的许多基本问题的解决方案方面具有几个优点。首先，可以在体外对相同靶标进行平行结合实验。因为体外结果仅受扩散进入DC以及抗体的免疫结合特性影响，所以由于这些因素导致的抗体制剂之间的靶向差异可以与由于药代动力学特性导致的差异区分开来。其次，可以给动物植入任何类型和数量的靶细胞，或抗原阴性对照细胞。第三，也许也是最重要的，该系统为评估异种动物体内的鼠源MoAb提供了可能性，这可能比在小鼠身上进行的实验更好地预测临床靶向潜力。
