Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake.

Abstract

The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through IGF-I receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-II binding and by inducing cell surface receptor down-regulation via internalization and degradation, with the extracellular and intracellular domains of IGF-IR being differentially affected by the proteasomal and lysosomal inhibitors. In vitro, h10H5 exhibits antiproliferative effects on cancer cell lines. In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti-vascular endothelial growth factor antibody. Antitumor activity of h10H5 is associated with decreased AKT activation and glucose uptake and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors and furthermore illustrate a new method of monitoring its activity noninvasively in vivo via 2-fluoro-2-deoxy-d-glucose-positron emission tomography imaging.

• Authors: Yonglei Shang, Yifan Mao, Jennifer Batson, Suzie J Scales, Gail Phillips, Mark R Lackner, Klara Totpal, Simon Williams, Jihong Yang, Zhijun Tang, Zora Modrusan, Christine Tan, Wei-Ching Liang, Siao Ping Tsai, Alexander Vanderbilt, Kenji Kozuka, Klaus Hoeflich, Janet Tien, Sarajane Ross, Congfen Li, Sang Hoon Lee, An Song, Yan Wu, Jean-Philippe Stephan, Avi Ashkenazi, Jiping Zha
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 9 Pg. 2599-608 (Sep 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18790743 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Biomarkers
• Proteasome Inhibitors
• Protein Subunits
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• Glucose

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Biomarkers (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Drug Synergism
• Endocytosis (drug effects)
• Enzyme Activation (drug effects)
• Female
• Gene Expression Profiling
• Glucose (metabolism)
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Lysosomes (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Neoplasms (enzymology, genetics, pathology)
• Proteasome Inhibitors
• Protein Subunits (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays