Monoclonal antibodies to fibroblast growth factor receptor 2 effectively inhibit growth of gastric tumor xenografts.
Monoclonal antibodies to fibroblast growth factor receptor 2 effectively inhibit growth of gastric tumor xenografts.
复制标题
DOI：
10.1158/1078-0432.ccr-10-0531
复制
发表时间：
2010-12-01
期刊：
影响因子：
--
通讯作者：
Kim KJ
中科院分区：
文献类型：
--
作者：
Zhao WM;Wang L;Park H;Chhim S;Tanphanich M;Yashiro M;Kim KJ
成纤维细胞生长因子受体2(FGFR2)的过度表达可能是许多人类肿瘤，特别是低分化型胃癌的致病因素之一。我们研究了针对FGFR2的单抗是否能抑制异种移植模型中肿瘤的生长。我们制备并鉴定了三种识别FGFR2上不同表位的单抗：GAL-FR21、GAL-FR22和GAL-FR23。测定了单抗识别FGFR2的FGFR2IIIb和FGFR2IIIc亚型的能力，以及它们阻断FGFR2与FGFR2的结合的能力。此外，我们还研究了单抗抑制成纤维细胞生长因子诱导的FGFR2磷酸化和下调FGFR2表达的能力。最后，通过建立SNU-16和OCUM-2M人胃癌细胞株裸鼠移植瘤模型，观察抗FGFR2单抗对肿瘤生长的抑制作用。每周两次)，并监测肿瘤大小。在三种单抗中，GAL-FR21仅与FGFR2IIIb亚型结合，而GAL-FR22和GAL-FR23同时与FGFR2IIIb和FGFR2IIIc结合，结合区分别位于FGFR2的D3、D2-D3和D1区。GAL-FR21和GAL-FR22可阻断FGF2、FGF7和FGF10与FGFR2IIIb的结合。Gal-FR21抑制FGF2和Fgf7诱导的FGFR2的磷酸化，两种单抗均下调SNU-16细胞FGFR2的表达。这些单抗能有效抑制已建立的小鼠SNU-16和OCUM-2M异种移植瘤的生长。抗FGFR2单抗GAL-FR21和GAL-FR22有可能用于治疗胃和其他肿瘤。
Overexpression of Fibroblast Growth Factor Receptor 2 (FGFR2) may be a causative factor of a number of human tumors, especially gastric tumors of the poorly differentiated type. We investigated whether monoclonal antibodies (mAbs) directed against FGFR2 can inhibit the growth of tumors in xenograft models. We generated and characterized three mAbs that recognize different epitopes on FGFR2: GAL-FR21, GAL-FR22 and GAL-FR23. The ability of the mAbs to recognize the FGFR2IIIb and FGFR2IIIc isoforms of FGFR2 was determined, as was their ability to block binding of FGF ligands to FGFR2. The capability of the mAbs to inhibit FGF-induced FGFR2 phosphorylation and to down-modulate FGFR2 expression was also investigated. Finally, the ability of the anti-FGFR2 mAbs to inhibit tumor growth was determined by establishing xenografts of SNU-16 and OCUM-2M human gastric tumor cell lines in nude mice, treating with each mAb (0.5 – 5 mg/kg i.p. twice weekly), and monitoring tumor size. Of the three mAbs, GAL-FR21 binds only the FGFR2IIIb isoform, whereas GAL-FR22 and GAL-FR23 bind to both the FGFR2IIIb and FGFR2IIIc forms, with binding regions respectively in the D3, D2-D3 and D1 domains of FGFR2. GAL-FR21 and GAL-FR22 blocked the binding of FGF2, FGF7 and FGF10 to FGFR2IIIb. GAL-FR21 inhibited FGF2 and FGF7 induced phosphorylation of FGFR2, and both mAbs down-modulated FGFR2 expression on SNU-16 cells. These mAbs effectively inhibited growth of established SNU-16 and OCUM-2M xenografts in mice. Anti-FGFR2 mAbs GAL-FR21 and GAL-FR22 have potential for the treatment of gastric and other tumors.