Inhibition of tumor growth by poly(ethylene glycol) derivatives of anti-ErbB2 antibodies
Inhibition of tumor growth by poly(ethylene glycol) derivatives of anti-ErbB2 antibodies
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DOI：
10.1007/s002620000112
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发表时间：
2000-07-01
影响因子：
5.8
通讯作者：
Sela, M
中科院分区：
文献类型：
--
作者：
Hurwitz, E;Klapper, LN;Sela, M
具有抗肿瘤活性的物质的聚（乙二醇）（PEG）修饰显示出增强对生长的实体瘤的渗透并延长抗肿瘤作用。因此，将PEG作为修饰剂引入对ErbB 2（HER 2）癌蛋白特异的两种类型的单克隆抗体（N12和L26）。这些抗体抑制过表达ErbB 2的肿瘤（例如N87人肿瘤）的生长，并且评价了PEG对其抗肿瘤活性的影响。在抗体的铰链区与巯基缀合的甲氧基-PEG-马来酰亚胺削弱了它们与N87肿瘤细胞的抗体结合，并且没有增强荷瘤小鼠中的抗肿瘤抑制活性。通过蛋白质的氨基缀合的支链N-羟基琥珀酰亚胺活化的PEG（PEG 2）用于结合整个抗体（Ab）或其单体Fab'片段。当在体外针对N87细胞测试时，Ab-PEG 2的结合活性和抗肿瘤细胞毒性作用大部分被保留。PEG 2修饰似乎没有改变抗体在体内的肿瘤抑制活性，并且在施用后的前几周期间观察到相同的肿瘤发展模式。然而，在肿瘤生长的后期观察到PEG的刺激作用，因为肿瘤发展减缓或完全停止。此外，与注射未修饰抗体的小鼠的结果相比，在该后期阶段植入相同小鼠的第二肿瘤被显著或完全抑制。Fab ′-PEG 2单体衍生物也显示有效抑制第二肿瘤的生长。PEG对针对ErbB 2的抗体或Fab'片段的抗肿瘤活性的延长和延长的增强作用在治疗ErbB 2过表达肿瘤中可能是重要的。
Poly(ethylene glycol) (PEG) modification of substances with antitumor activity was shown to enhance penetration into growing solid tumors and extend antitumor effects. Accordingly, PEG was introduced as a modifier to two types of monoclonal antibodies (N12 and L26) specific to the ErbB2 (HER2) oncoprotein. These antibodies suppress the growth of tumors overexpressing ErbB2 (e.g. N87 human tumor) and the effect of PEG on their antitumor activity was evaluated. Methoxy-PEG-maleimide conjugated to sulfhydryl groups at the hinge region of the antibodies impaired their antibody binding to N87 tumor cells and did not enhance the antitumor inhibitory activity in tumor-bearing mice. A branched N-hydroxysuccinimide-activated PEG (PEG2), conjugated through amino groups of the protein, was used for binding to the whole antibody (Ab) or to its monomeric Fab' fragment. When tested against N87 cells in vitro, the binding activity and antitumor cytotoxic effects of Ab-PEG2 were mostly preserved. PEG2 modification did not seem to alter the tumor-inhibitory activity of the antibodies in vivo and the same pattern of tumor development was observed during the first few weeks following administration. However, the stimulating effects of PEG were observed at later stages of tumor growth since tumor development was either slowed down or completely arrested. Furthermore, a second tumor implanted into the same mice during this later stage was significantly or completely inhibited, as compared to results in mice injected with the unmodified antibody. The Fab'-PEG2 monomeric derivative was also shown to be effective in inhibiting the growth of a second tumor. The extended and prolonged enhancing effect of PEG on the antitumor activity of antibodies or Fab' fragments directed against ErbB2 may be of importance in the treatment of ErbB2-overexpressing neoplasms.