Abstract 646: Anti-tumor efficacy of IMC-A12, a fully human anti-insulin like growth factor 1 receptor (IGF-1R) antibody, against malignant mesothelioma (MM)

Abstract

Abstract Introduction: MM is an aggressive cancer with limited treatment options and poor prognosis. Previous studies have shown that the interaction between IGF-1R and its ligands IGF-1 and IGF-2 play an important role in MM tumorogenesis. To exploit IGF-1R as a target for mesothelioma therapy we investigated the activity of IMC-A12 against early passage mesothelioma tumor cells, established MM cell lines and an in vivo human mesothelioma tumor xenograft model. Material and methods: Eight early passage mesothelioma tumor cells obtained from patients with mesothelioma and eight established MM cell lines were evaluated for IGF-1R expression by real time PCR, Western blotting, and a quantitative immunoassay. The cell surface IGF-IR expression (sites/cell) was analyzed by flow cytometry using QuantiBRITE-PE bead assay. The anti-proliferative effect of IMC-A12 and its ability to induce antibody mediated cell cytoxicity (ADCC) was evaluated in vitro using both early passage tumor cells as well as established cell lines. For our in vivo experiment, the mesothelioma cell line NCI-H226, stably transfected with the luciferase gene, was inoculated intraperitoneally (i.p) into athymic nude mice. Three days after tumor cell inoculation, mice received either IMC-A12 (50 mg/kg) or saline by i.p. injection twice weekly for 8 weeks and tumor growth was monitored using bioluminescence imaging. Results: All early passage as well as established MM cell lines showed IGF-1R expression at the mRNA and protein levels. Using a quantitative electrochemiluminescence immunoassay we determined that there is considerable variability of IGF-1R expression ranging from 1-12 ng/mg of cell lysate. Using flow cytometry we evaluated the number of IGF-1R cell surface receptors, which varied from ≈ 2,000-50,000 sites/cell. Cells expressing >10,000 sites/cell had greater than 10% (range, 10% -60%) growth inhibition when treated with IMC-A12 (100 μg/mL). Similarly, IMC-A12 treatment induced ADCC (> 10% specific lysis) in those cell lines with IGF-1R expression of > 10,000 sites/cell. In vivo IMC-A12 treatment delayed tumor growth in athymic nude mice bearing H226 tumors and improved the overall survival when compared to the control group (p< 0.05). Conclusion: Our results show that both early passage mesothelioma cells as well as established MM cell lines express IGF-1R but that there is a wide variability in the degree of IGF-1R expression. IMC-A12 exhibits anti-proliferative activity against these cell lines as well as induces ADCC, both of which are strongly co-related with IGF-1R cell surface expression. Single agent IMC-A12 also has significant in vivo anti-tumor activity. These results suggest IMC-A12 may be useful for treatment of MM. A phase II clinical trial of IMC-A12 has just opened for patient accrual. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 646. doi:10.1158/1538-7445.AM2011-646