Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts
Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts
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DOI：
10.1158/1078-0432.ccr-05-1793
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发表时间：
2006-02-15
影响因子：
11.5
通讯作者：
Laterra, J
中科院分区：
文献类型：
--
作者：
Kim, KJ;Wang, LH;Laterra, J
目的：肝细胞生长因子（HGF）及其受体Met参与许多全身和中枢神经系统肿瘤的发生、进展和转移。因此，能够阻断HGF-Met相互作用的抗HGF单克隆抗体(mAb)在癌症治疗中具有广泛的应用性。 实验设计：通过杂交瘤技术产生阻断HGF与Met结合的抗HGF单克隆抗体(mAb)，并通过体外测定测量其抑制HGF各种生物活性的能力。 L2G7 抑制肿瘤生长的能力是通过建立 s.c. 来确定的。以及裸鼠中人U87和U118神经胶质瘤细胞系的颅内异种移植物，并用100μg L2G7或对照给予腹腔注射处理。每周两次。结果：MAb L2G7 强烈抑制体外测量的 HGF 的所有生物活性，包括细胞增殖、细胞分散和内皮小管形成。用 L2G7 处理完全抑制了已建立的皮下细胞的生长。裸鼠异种移植。此外，从第5天开始全身施用L2G7可诱导颅内U87异种移植物的消退，并显着延长荷瘤小鼠的存活时间，从中值39天延长至>90天。从第 18 天开始，L2G7 治疗大型颅内肿瘤（平均肿瘤大小，26.7 mm(3)），到第 29 天诱导肿瘤显着消退（对照组，134.3 mm(3)；L2G7 治疗组，11.7 mm(3)），并再次延长动物存活时间。 结论：这些发现表明，用全身给予的抗 HGF mAb 阻断 HGF-Met 相互作用，即使在中枢神经系统内，也能产生深远的抗肿瘤作用。神经系统，以前认为该部位对基于抗体的全身疗法具有抵抗力。
Purpose: Hepatocyte growth factor (HGF) and its receptor Met are involved in the initiation, progression, and metastasis of numerous systemic and central nervous system tumors. Thus, an anti-HGF monoclonal antibody (mAb) capable of blocking the HGF-Met interaction could have broad applicability in cancer therapy.Experimental Design: An anti-HGF mAb L2G7 that blocks binding of HGF to Met was generated by hybridoma technology, and its ability to inhibit the various biological activities of HGF was measured by in vitro assays. The ability of L2G7 to inhibit the growth of tumors was determined by establishing s.c. and intracranial xenografts of human U87 and U118 glioma cell lines in nude mice, and treatment with 100 mu g of L2G7 or control given i.p. twice per week.Results: MAb L2G7 strongly inhibited all biological activities of HGF measured in vitro, including cell proliferation, cell scattering, and endothelial tubule formation. Treatment with L2G7 completely inhibited the growth of established s.c. xenografts in nude mice. Moreover, systemic administration of L2G7 from day 5 induced the regression of intracranial U87 xenografts and dramatically prolonged the survival of tumor-bearing mice from a median of 39 to >90 days. L2G7 treatment of large intracranial tumors (average tumor size, 26.7 mm(3)) from day 18 induced substantial tumor regression (control group, 134.3 mm(3); L2G7 treated group, 11.7 mm(3)) by day 29 and again prolonged animal survival.Conclusions: These findings show that blocking the HGF-Met interaction with systemically given anti-HGF mAb can have profound antitumor effects even within the central nervous system, a site previously believed to be resistant to systemic antibody-based therapeutics.