Efficacy of anti-insulin like growth factor I receptor (IGF-IR) monoclonal antibody cixutumumab in mesothelioma is highly correlated with IGF-IR sites/cell

摘要

Insulin growth factor-I receptor (IGF-IR) is expressed in mesothelioma and therefore an attractive target for therapy. The anti-tumor activity of cixutumumab, a humanized monoclonal antibody to IGF-IR, in mesothelioma and relationship to IGF-IR expression was investigated using eight early passage tumor cells obtained from patients, nine established cell lines and an in vivo human mesothelioma tumor xenograft model. Although IGF-IR expression at the mRNA and protein level was present in all mesothelioma cells, using a quantitative ELISA immunoassay there was considerable variability of IGF-IR expression ranging from 1 to 14 ng/mg of lysate. Using flow cytometry the number of IGF-IR surface receptors varied from ≈2,000 to 50,000 sites/cell. Cells expressing >10,000 sites/cell had greater than 10% growth inhibition when treated with cixutumumab (100 μg/mL). Cixutumumab also induced antibody-dependent cell-mediated toxicity (ADCC) (>10% specific lysis) in cell lines, which had >20,000 IGF-IR sites/cell. Treatment with cixutumumab decreased phosphorylation of IGF-IR, Akt and Erk in cell lines, H226 and H28 having 24,000 and 51,000 IGF-IR sites/cell respectively but not in the cell line H2052 with 3,000 IGF-IR sites/cell. In vivo, cixutumumab treatment delayed growth of H226 mesothelioma tumor xenografts in mice and improved the overall survival of these mice compared to mice treated with saline (p< 0.004). Our results demonstrate that the anti-tumor efficacy of cixutumumab including inhibition of IGF-IR downstream signaling is highly correlated with IGF-IR sites/cell. A phase II clinical trial of cixutumumab is currently ongoing for treatment of patients with mesothelioma.