Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies.
Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies.
复制标题
DOI：
--
复制
发表时间：
1999-02
期刊：
影响因子：
--
通讯作者：
F. Matsuno;Y. Haruta;M. Kondo;H. Tsai;M. Barcos;B. Seon
中科院分区：
文献类型：
--
作者：
F. Matsuno;Y. Haruta;M. Kondo;H. Tsai;M. Barcos;B. Seon
内皮糖蛋白（EDG，CD 105）是内皮细胞上的增殖相关抗原。在这项研究中，产生了两种新的抗EDG单克隆抗体（mAb）Y 4 - 2F 1（或称为SN 6 j）和P3- 2G 8（SN 6 k），并用于治疗不同的预先形成的肿瘤。这两种mAb（均为IgG 1-κ抗体）与小鼠内皮细胞的交叉反应较弱，但所确定的表位不同于先前报道的抗EDG mAb K4- 2C 10（B. K. Seon等人，临床癌症研究，3：1031-1044，1997）。SN 6 j和SN 6 k与人内皮细胞和恶性肿瘤组织的血管内皮细胞反应强烈，但与肿瘤细胞本身无明显反应。这两种单抗的去糖基化蓖麻毒素A链（dgRA）缀合物在体外对小鼠内皮细胞显示出微弱但特异的细胞毒活性。在治疗研究中，严重联合免疫缺陷小鼠皮下接种。与MCF-7人乳腺癌细胞接触，并保持不处理，直到出现明显尺寸的肿瘤（直径4-6 mm）。通过静脉内施用单独的抗EDG缀合物、未缀合的mAb或对照缀合物来治疗具有不同肿瘤的小鼠。当通过尾静脉给药三次40 μ g单独的缀合物时，在大多数荷瘤小鼠（每种缀合物n = 8）中诱导肿瘤的持久完全消退。值得注意的是，只要对小鼠进行随访，肿瘤就保持消退而没有进一步治疗（即，100天）。对照偶联物未诱导任何治疗小鼠的肿瘤消退，尽管在一些小鼠（n = 8）中观察到弱的非特异性效应。未缀合的mAb的作用随着所用剂量而变小，即，34微克三次。抗EDG缀合物在小鼠背气囊测定中显示出抗血管生成活性。结果表明，这些共轭物具有良好的临床应用潜力。
Endoglin (EDG, CD105) is a proliferation-associated antigen on endothelial cells. In this study, two new anti-EDG monoclonal antibodies (mAbs) Y4-2F1 (or termed SN6j) and P3-2G8 (SN6k) were generated and used for treating distinct preformed tumors. These mAbs, both IgG1-kappa antibodies, cross-reacted weakly with mouse endothelial cells but defined epitopes different from the epitope defined by a previously reported anti-EDG mAb K4-2C10 (B. K. Seon et al., Clin. Cancer Res., 3: 1031-1044, 1997). SN6j and SN6k reacted strongly with human endothelial cells and vascular endothelium of malignant human tissues but showed no significant reactivity with tumor cells per se. The deglycosylated ricin A chain (dgRA) conjugates of the two mAbs showed a weak but specific cytotoxic activity against murine endothelial cells in vitro. In the therapeutic studies, severe combined immunodeficient mice were inoculated s.c. with MCF-7 human breast cancer cells and left untreated until palpable tumors of distinct size (4-6 mm in diameter) appeared. Mice with the distinct tumors were treated by i.v. administration of individual anti-EDG conjugates, unconjugated mAbs, or a control conjugate. Long-lasting complete regression of the tumors was induced in the majority of tumor-bearing mice (n = 8 for each conjugate) when 40 microg of the individual conjugates were administered three times via the tail vein. It is remarkable that the tumors remained regressed without further therapy for as long as the mice were followed (i.e., 100 days). Control conjugate did not induce regression of the tumors in any of the treated mice, although weak nonspecific effects were observed in some of the mice (n = 8). The effects of unconjugated mAbs were small with the dose used, i.e., 34 microg three times. The anti-EDG conjugates showed antiangiogenic activity in the dorsal air sac assay in mice. The results suggest good potential of these conjugates for the clinical application.