Fjeld J G, Benestad H B, Stigbrand T, Nustad K
Central Laboratory, Norwegian Radium Hospital, Montebello, Oslo.
Br J Cancer. 1992 Jul;66(1):74-8. doi: 10.1038/bjc.1992.219.
Exploring the fundamental mechanisms behind the low tumour uptake of labelled monoclonal antibodies (MoAbs) during in vivo immunotargeting, experiments were performed to estimate the in vivo value of the association constant (Ka) in an experimental targeting reaction. An artificial tumour model was utilised, based on diffusion chambers (DC) filled with antigen-coated polymer particles, implanted i.p. in normal, immunocompetent mice (NMRI/BOM). The MoAb H7 with specificity for placental alkaline phosphatase (PLALP) was chosen for this experiment. Each mouse carried two DC, one target DC filled with PLALP-coated particles, and a second control DC with the same amount of uncoated particles. The DC contained escalating doses of particles, ranging from 0.1 mg to 16 mg per DC, with groups of 6-12 animals per dose level. The next day after the implantation, a constant dose of 125I-labelled Fab fragments of H7 was injected i.v. in each mouse. The association constant Ka as measured from the binding data obtained in vivo was not significantly different from the value measured in vitro when the same target DC were incubated with the 125I-Fab in test tubes. This indicates that in vivo impairment of the antibody avidity is not the reason why a relatively low tumour uptake is generally experienced in immunotargeting studies.
为探究体内免疫靶向过程中标记单克隆抗体（MoAbs）肿瘤摄取率低背后的基本机制，进行了实验以评估实验靶向反应中结合常数（Ka）的体内值。采用了一种人工肿瘤模型，该模型基于充满抗原包被聚合物颗粒的扩散室（DC），经腹腔注射植入正常、具有免疫活性的小鼠（NMRI/BOM）体内。本实验选用了对胎盘碱性磷酸酶（PLALP）具有特异性的单克隆抗体H7。每只小鼠携带两个扩散室，一个为靶标扩散室，充满PLALP包被的颗粒，另一个为对照扩散室，含有等量的未包被颗粒。每个扩散室中颗粒剂量递增，范围为每扩散室0.1毫克至16毫克，每个剂量水平有6 - 12只动物。植入后的第二天，每只小鼠经静脉注射恒定剂量的125I标记的H7 Fab片段。当将相同的靶标扩散室与试管中的125I - Fab一起孵育时，根据体内获得的结合数据测得的结合常数Ka与体外测得的值无显著差异。这表明在免疫靶向研究中普遍观察到的肿瘤摄取率相对较低并非是由于抗体亲和力在体内受损所致。
