SUPPRESSION AND PROMOTION OF TUMOR-GROWTH BY MONOCLONAL-ANTIBODIES TO ERBB-2 DIFFERENTIALLY CORRELATE WITH CELLULAR UPTAKE
SUPPRESSION AND PROMOTION OF TUMOR-GROWTH BY MONOCLONAL-ANTIBODIES TO ERBB-2 DIFFERENTIALLY CORRELATE WITH CELLULAR UPTAKE
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DOI：
10.1073/pnas.92.8.3353
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发表时间：
1995-04-11
影响因子：
11.1
通讯作者：
YARDEN, Y
中科院分区：
文献类型：
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作者：
HURWITZ, E;STANCOVSKI, I;YARDEN, Y
erbB-2/neu原癌基因的扩增和过表达经常与某些人腺癌的侵袭性临床过程相关，因此编码的表面糖蛋白被认为是免疫治疗的候选靶点。我们以前产生了一系列的抗ErbB-2单克隆抗体（mAb），无论是加速或抑制erbB-2转化鼠成纤维细胞的致瘤性生长。本研究将这一观察结果扩展到在无胸腺小鼠中作为异种移植物生长的人肿瘤细胞系，并解决了两类mAb之间的生化差异。我们表明，在抗体混合物的抑制作用是占主导地位的，它取决于抗体的二价。通过使用放射性标记的单克隆抗体，我们发现，所有三种肿瘤抑制性单克隆抗体与肿瘤细胞孵育时，酸处理迅速变得不可接近。然而，肿瘤刺激性mAb仍然可以接受细胞外治疗，表明它没有发生内吞作用。此外，观察到抑制性mAb的细胞内片段，但未观察到刺激性mAb的细胞内片段。胶体金-抗体缀合物的电子显微镜证实了不存在刺激性mAb的内吞作用，但检测到含有抑制性mAb的内吞囊泡。我们得出结论，ErbB-2的细胞生长加速与细胞表面定位相关，而肿瘤生长的抑制与抗ErbB-2单克隆抗体诱导内吞作用的内在能力相关。这些结论与选择最佳的单克隆抗体用于免疫治疗有关，并可能对过度表达的erbB-2基因的细胞转化机制产生影响。
Amplification and overexpression of the erbB-2/neu protooncogene are frequently associated with aggressive clinical course of certain human adenocarcinomas, and therefore the encoded surface glycoprotein is considered a candidate target for immunotherapy. We previously generated a series of anti-ErbB-2 monoclonal antibodies (mAbs) that either accelerate or inhibit the tumorigenic growth of erbB-2-transformed murine fibroblasts. The present study extended this observation to a human tumor cell line grown as xenografts in athymic mice and addressed the biochemical differences between the two classes of mAbs. We show that the inhibitory effect is dominant in an antibody mixture, and it depends on antibody bivalency. By using radiolabeled mAbs we found that all of three tumor-inhibitory mAbs became rapidly inaccessible to acid treatment when incubated with tumor cells. However, a tumor-stimulatory mAb remained accessible to extracellular treatments, indicating that it did not undergo endocytosis. In addition, intracellular fragments of the inhibitory mAbs, but not of the stimulatory mAb, were observed. Electron microscopy of colloidal gold-antibody conjugates confirmed the absence of endocytosis of the stimulatory mAb but detected endocytic vesicles containing an inhibitory mAb. We conclude that acceleration of cell growth by ErbB-2 correlates with cell surface localization, whereas inhibition of tumor growth is associated with an intrinsic ability of anti-ErbB-2 mAbs to induce endocytosis. These conclusions are relevant to the selection of optimal mAbs for immunotherapy and may have implications for the mechanism of cellular transformation by an overexpressed erbB-2 gene.