Isolation of Fully Human Antagonistic RON Antibodies Showing Efficient Block of Downstream Signaling and Cell Migration

被引：10

作者：

Gunes, Zeynep ^{[1
]}

Zucconi, Adriana ^{[1
]}

Cioce, Mario ^{[1
]}

Meola, Annalisa ^{[1
]}

Pezzanera, Monica ^{[1
]}

Acali, Stefano ^{[1
]}

Zampaglione, Immacolata ^{[1
]}

De Pratti, Valeria ^{[1
]}

Bova, Luca ^{[1
]}

Talamo, Fabio ^{[1
]}

Demartis, Anna ^{[1
]}

Monaci, Paolo ^{[1
]}

La Monica, Nicola ^{[1
]}

Ciliberto, Gennaro ^{[1
]}

Vitelli, Alessandra ^{[1
]}

机构：

[1] Ist Ric Biol Mol P Angeletti, Rome, Italy

来源：

TRANSLATIONAL ONCOLOGY | 2011年 / 4卷 / 01期

关键词：

RECEPTOR TYROSINE KINASE; MACROPHAGE-STIMULATING PROTEIN; GROWTH-FACTOR RECEPTOR; CROSS-TALK; ONCOGENIC PHENOTYPES; PANCREATIC-CANCER; MET; TARGET; OVEREXPRESSION; EXPRESSION;

D O I：

10.1593/tlo.10211

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

RON belongs to the c-MET family of receptor tyrosine kinases. As its well-known family member MET, RON and its ligand macrophage-stimulating protein have been implicated in the progression and metastasis of tumors and have been shown to be overexpressed in cancer. We generated and tested a large number of human monoclonal antibodies (mAbs) against human RON. Our screening yielded three high-affinity antibodies that efficiently block ligand-dependent intracellular AKT and MAPK signaling. This effect correlates with the strong reduction of ligand-activated migration of T47D breast cancer cell line. By cross-competition experiments, we showed that the antagonistic antibodies fall into three distinct epitope regions of the RON extracellular Sema domain. Notably, no inhibition of tumor growth was observed in different epithelial tumor xenografts in nude mice with any of the antibodies. These results suggest that distinct properties beside ligand antagonism are required for anti-RON mAbs to exert antitumor effects in vivo.

引用

页码：38 / U50

页数：11

共 43 条

[1] The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation [J].