Institute of Physiology and Pathophysiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Cancer Immunol Immunother. 2010 Nov;59(11):1675-84. doi: 10.1007/s00262-010-0894-1. Epub 2010 Jul 21.
Catumaxomab is an intact trifunctional bispecific antibody targeting human EpCAM (epithelial cell adhesion molecule) and CD3 with further binding to Fcgamma receptor type I, IIa and III. We choose multicellular tumor spheroids (MCTS) of human EpCAM-positive FaDu tumor cells in co-culture with human peripheral blood mononuclear cells as an adequate three-dimensional in vitro model for pharmacological testing of catumaxomab. We found a strong dose-dependent antitumor response mediated by catumaxomab, with volume-decreased or completely destroyed tumor spheroids together with a massive immune cell infiltration and decreased signals for cancer cell viability and clonogenicity. In control experiments with F(ab')2 fragments of catumaxomab and the parental antibodies alone or in combination the effects in spheroid volume reduction were less than that of catumaxomab. All binding partners of the postulated tricell complex have to be present to exert catumaxomab's full mode of action. These distinct effects of catumaxomab are based on the unique composition of the trifunctional bispecific antibody. Since, in general, many cancers are treated by chemotherapy in combination with immunological tumor therapy, we additionally analyzed the effects of cisplatin alone and in combination with catumaxomab. For cisplatin alone we detected a dose-dependent response relating to decrease of spheroid volume. The combined approach resulted in a synergistic spheroid volume decrease and the colony formation was reduced to non-detectable levels.
卡特木单抗是一种针对人 EpCAM（上皮细胞黏附分子）和 CD3 的完整三功能双特异性抗体，进一步与 Fcγ 受体 I 型、IIa 型和 III 型结合。我们选择人 EpCAM 阳性 FaDu 肿瘤细胞与人类外周血单个核细胞共培养的多细胞肿瘤球体（MCTS）作为药理学测试卡特木单抗的合适三维体外模型。我们发现卡特木单抗介导的抗肿瘤反应具有强烈的剂量依赖性，肿瘤球体的体积减小或完全破坏，伴随着大量免疫细胞浸润和癌症细胞活力和克隆形成信号降低。在卡特木单抗 F(ab')2 片段和单独或组合使用亲本抗体的对照实验中，球体体积减小的效果小于卡特木单抗。发挥卡特木单抗的全部作用模式必须存在推测的三细胞复合物的所有结合伙伴。卡特木单抗的这些独特作用基于三功能双特异性抗体的独特组成。由于一般来说，许多癌症通过化疗联合免疫肿瘤治疗进行治疗，我们还分析了顺铂单独和与卡特木单抗联合使用的效果。对于顺铂单独，我们检测到与球体体积减少相关的剂量依赖性反应。联合方法导致协同的球体体积减少，并且集落形成减少到不可检测的水平。
