Neutralizing Anti-Insulin-like Growth Factor Receptor 1 Antibodies Inhibit Receptor Function and Induce Receptor Degradation in Tumor Cells

Abstract

Insulin-like growth factor receptor 1 (IGFR1) plays a crucial role in oncogenic transformation [C. Sell et al., Mol. Cell. Biol., 14: 3604–3612, 1994]. Compared with the normal human mammary epithelial cell line MCF12A, MCF7 human mammary carcinoma cells overexpress IGFR1 on the cell surface. To measure the effects of IGFR1 inhibition on tumor cells, we tested two mouse neutralizing antibodies against human IGFR1 in cell-based assays. Both MAB391 and anti-IR3 antibodies inhibit IGFR1 autophosphorylation upon IGF-I ligand stimulation with IC₅₀s of 0.58 and 0.80 nm, respectively. When cells were treated with neutralizing anti-IGFR1 antibodies for ≥4 h, the total receptor level was dramatically decreased. IGF-I-stimulated activation of AKT was also inhibited by anti-IGFR1 antibodies. Furthermore, MAB391 and anti-IR3 inhibited the growth of MCF7 cells in soft agar. In addition to MCF7 cells, MAB391 also inhibited IGFR1 autophosphorylation and induced IGFR1 down-modulation in HT29 colorectal and Du145 prostate cancer cells. Therefore, neutralizing antibodies against IGFR1 represent a valid approach to inhibit growth of tumor cells.