Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member

Abstract

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED 50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC 50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG-treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in f100 cancer cell lines and f300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers. (Cancer Res 2006; 66(18): 9162-70)

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

“…Various studies have shown that therapeutic antibodies and TKIs specific to RON inhibit tumor growth mediated by pancreatic, colon, and breast cancer cells in mouse tumor xenograft models (7,12,13,31). Studies using BMS-777607 to target MET have shown the effectiveness in inhibiting MET-mediated tumor cell migration, matrix invasion, and distance metastasis (32,33).…”

“…Aberrant RON expression also has been molecularly targeted in mouse xenograph models of pancreatic ductal adenocarcinoma (PDAC; refs. [5][6][7]. PDAC is a highly malignant disease with limited treatment options (8).…”

“…Targeted inhibition of RON to treat PDAC is currently under investigation (6,7,12,13). Both tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies (mAb) have been tested in preclinical models (7,14).…”

“…Both tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies (mAb) have been tested in preclinical models (7,14). Moreover, anti-RON antibodies have been used as a drug delivery method to improve chemotherapeutic efficacy (13).…”

RON - The Con in Colorectal Carcinoma

“…These effects were found to be dependent on hypoxic RON expression further strengthening the utility of targeting RON signaling pathway in CRC. Another RON binding antibody IMC41A10 developed by ImClone Systems has been shown to block the interaction between RON and its ligand MSP with a high affinity [63]. The efficacy of RON kinase has been demonstrated in several cancers including HT29 colon cancer cells wherein IMC41A10 has been shown to inhibit MSP induced phosphorylation and downstream signaling events.…”