The monoclonal antibody Zt/f2 targeting RON receptor tyrosine kinase as potential therapeutics against tumor growth-mediated by colon cancer cells

Mol Cancer. 2011 Jul 12;10:82. doi: 10.1186/1476-4598-10-82.

Abstract

Background: Overexpression of the RON receptor tyrosine kinase contributes to epithelial cell transformation, malignant progression, and acquired drug resistance. RON also has been considered as a potential target for therapeutic intervention. This study determines biochemical features and inhibitory activity of a mouse monoclonal antibody (mAb) Zt/f2 in experimental cancer therapy.

Results: Zt/f2 is a mouse IgG2a mAb that is highly specific and sensitive to human RON and its oncogenic variants such as RON160 (ED(50) = 2.3 nmol/L). Receptor binding studies revealed that Zt/f2 interacts with an epitope(s) located in a 49 amino acid sequence coded by exon 11 in the RON β-chain extracellular sequences. This sequence is critical in regulating RON maturation and phosphorylation. Zt/f2 did not compete with ligand macrophage-stimulating protein for binding to RON; however, its engagement effectively induced RON internalization, which diminishes RON expression and impairs downstream signaling activation. These biochemical features provide the cellular basis for the use of Zt/f2 to inhibit tumor growth in animal model. Repeated administration of Zt/f2 as a single agent into Balb/c mice results in partial inhibition of tumor growth caused by transformed NIH-3T3 cells expressing oncogenic RON160. Colon cancer HT-29 cell-mediated tumor growth in athymic nude mice also was attenuated following Zt/f2 treatment. In both cases, ~50% inhibition of tumor growth as measured by tumor volume was achieved. Moreover, Zt/f2 in combination with 5-fluorouracil showed an enhanced inhibition effect of ~80% on HT-29 cell-mediated tumor growth in vivo.

Conclusions: Zt/f2 is a potential therapeutic mAb capable of inhibiting RON-mediated oncogenesis by colon cancer cells in animal models. The inhibitory effect of Zt/f2 in vivo in combination with chemoagent 5-fluorouracil could represent a novel strategy for future colon cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / pathology*
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Cell Growth Processes / drug effects*
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / pathology*
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • Molecular Targeted Therapy
  • NIH 3T3 Cells
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • RON protein
  • Receptor Protein-Tyrosine Kinases