Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer.
Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer.
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DOI：
10.1038/sj.bjc.6603881
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发表时间：
2007-08-06
影响因子：
8.8
通讯作者：
Lindhofer, H.
中科院分区：
文献类型：
--
作者：
Ruf, P.;Gires, O.;Jaeger, M.;Fellinger, K.;Atz, J.;Lindhofer, H.
上皮细胞黏附分子EpCAM是一种跨膜糖蛋白，常在多种肿瘤中过度表达。这种泛癌抗原已经成为过多免疫疗法的靶点。创新的治疗方法包括使用三功能抗体(Trab)，在肿瘤部位招募和激活不同类型的免疫效应细胞。TRAb Catumaxomab对EpCAM和CD3具有双重特异性。在恶性腹水患者中，Catumaxomab显著延长了无穿刺期，证实了这种治疗性抗体的高效性。在这里，我们表征了单抗(MAb)HO-3，即Catumaxomab的EpCAM结合臂。多肽图谱显示，HO-3识别一个不连续的表位，在EpCAM的胞外区有三个结合位点。对糖基化缺陷突变体的研究表明，mAbHO-3识别EpCAM独立于其糖基化状态。TRAb Catumaxomab不仅与单抗HO-3有高亲和力的结合，而且与Catumaxomab的单价EpCAM结合臂也有很高的亲和力，其Kd值为5.6×10−10 M。此外，TRAb Catumaxomab诱导效应者外周血单核细胞对肿瘤细胞的杀灭作用至少是mAbHO-3的1000倍。这些发现表明了TRABS的巨大治疗潜力，并清楚地表明支持EPCAM指导的癌症免疫疗法。
Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein that is frequently overexpressed in a variety of carcinomas. This pan-carcinoma antigen has served as the target for a plethora of immunotherapies. Innovative therapeutic approaches include the use of trifunctional antibodies (trAbs) that recruit and activate different types of immune effector cells at the tumour site. The trAb catumaxomab has dual specificity for EpCAM and CD3. In patients with malignant ascites, catumaxomab significantly increased the paracentesis-free interval, corroborating the high efficacy of this therapeutic antibody. Here, we characterised the monoclonal antibody (mAb) HO-3, that is, the EpCAM-binding arm of catumaxomab. Peptide mapping indicated that HO-3 recognises a discontinuous epitope, having three binding sites in the extracellular region of EpCAM. Studies with glycosylation-deficient mutants showed that mAb HO-3 recognised EpCAM independently of its glycosylation status. High-affinity binding was not only detected for mAb HO-3, but also for the monovalent EpCAM-binding arm of catumaxomab with an excellent KD of 5.6 × 10−10 M. Furthermore, trAb catumaxomab was at least a 1000-fold more effective in eliciting the eradication of tumour cells by effector peripheral blood mononuclear cells compared with mAb HO-3. These findings suggest the great therapeutic potential of trAbs and clearly speak in favour of EpCAM-directed cancer immunotherapies.
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影响因子：
168.9
作者：
Gastl, G;Spizzo, G;Mikuz, G
通讯作者：
Mikuz, G
EP-CAM：人类上皮抗原是一种同粒细胞粘附分子。
影响因子：
7.8
作者：
Litvinov, S V;Velders, M P;Bakker, H A;Fleuren, G J;Warnaar, S O
通讯作者：
Warnaar, S O
影响因子：
6.4
作者：
Heiss, MM;Ströhlein, MA;Lindhofer, H
通讯作者：
Lindhofer, H
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.4
作者：
Gutzmer, R;Li, W;Marks, MS
通讯作者：
Marks, MS