Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF-1 receptor

Int J Cancer. 2009 May 15;124(10):2281-93. doi: 10.1002/ijc.24186.


IGF-1 receptor (IGF-1R) plays a key role in the development of numerous tumors. Blockade of IGF-1R axis using monoclonal antibodies constitutes an interesting approach to inhibit tumor growth. We have previously shown that h7C10, a humanized anti-IGF-1R Mab, exhibited potent antitumor activity in vivo. However, mechanisms of action of h7C10 are still unknown. Here, we showed that h7C10 inhibited IGF-1-induced IGF-1R phosphorylation in a dose-dependent manner. Also, h7C10 abolished IGF-1-induced activation of PI3K/AKT and MAPK pathways. Cell cycle progression and colony formation were affected in the presence of h7C10 probably because of the inhibition of IGF-1-induced cyclin D1 and E expression. In addition, we demonstrated that h7C10 induced a rapid IGF-1R internalization leading to an accumulation into cytoplasm resulting in receptor degradation. Using lysosome and proteasome inhibitors, we observed that the IGF-1R alpha- and beta-chains could follow different degradation routes. Thus, we demonstrated that antitumoral properties of h7C10 are the result of IGF-1-induced cell signaling inhibition and down-regulation of IGF-1R level suggesting that h7C10 could be a candidate for therapeutic applications.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Base Sequence
  • Cyclins / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Lysosomes / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Microscopy, Fluorescence
  • Phosphorylation
  • RNA, Small Interfering
  • Receptor, IGF Type 1 / immunology*
  • Receptor, IGF Type 1 / metabolism
  • Retinoblastoma Protein / metabolism
  • Transplantation, Heterologous
  • Ubiquitination


  • Antibodies, Monoclonal
  • Cyclins
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • Receptor, IGF Type 1