Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function

Mol Cancer Ther. 2006 Jan;5(1):114-20. doi: 10.1158/1535-7163.MCT-05-0252.

Abstract

The insulin-like growth factor (IGF) system plays an important role in a variety of physiologic processes and in diseases such as cancer. Although the role of the IGF system in cancer has been recognized many years ago, components of the system have only recently been targeted and shown to affect cell transformation, proliferation, survival, motility, and migration in tissue cultures and in mouse models of cancer. We have been hypothesizing that targeting IGF-II in addition to blocking its interaction with the IGF receptor type I (IGF-IR) would also allow to block that portion of the signal transduction through the insulin receptor that is due to its interaction with IGF-II. Lowering its level may also not induce up-regulation of its production as for IGF-I. Finally, targeting a diffusable ligand as IGF-II may not require penetration of the antibody inside tumors but could shift the equilibrium to IGF-II complexed with antibody so the ligand concentration would decrease in the tumor environment without the need for the antibody to penetrate the tumor. Here, we describe the identification and characterization of three novel anti-IGF-II fully human monoclonal antibodies. They bound with high (subnanomolar) affinity to IGF-II, did not cross-react with IGF-I and insulin, and potently inhibited signal transduction mediated by the IGF-IR interaction with IGF-II. The most potent neutralizer, IgG1 m610, inhibited phosphorylation of the IGF-IR and the insulin receptor, as well as phosphorylation of the downstream kinases Akt and mitogen-activated protein kinase with an IC(50) of the order of 1 nmol/L at IGF-II concentration of 10 nmol/L. It also inhibited growth of the prostate cancer cell line DU145 and migration of the breast cancer line cells MCF-7. These results indicate an immunotherapeutic potential of IgG1 m610 likely in combination with other antibodies and anticancer drugs but only further experiments in mouse models of cancer and human clinical trials could evaluate this possibility.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Movement / drug effects
  • Cross Reactions
  • Female
  • Humans
  • Insulin-Like Growth Factor I / immunology
  • Insulin-Like Growth Factor II / immunology*
  • Male
  • Molecular Sequence Data
  • Oncogene Protein v-akt / drug effects
  • Oncogene Protein v-akt / metabolism
  • Peptide Library
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Receptor, IGF Type 1 / drug effects*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / drug effects
  • Receptor, Insulin / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Peptide Library
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Oncogene Protein v-akt