Potential Benefit of an Agonistic Anti IGFIR Antibody (scFv-Fc) as an Effective Breast Cancer Therapy.

Abstract

Abstract Multiple monoclonal antibodies targeting the type-1 insulin-like growth factor receptor (IGFIR) are currently in different phases of clinical trials. All the reported antibodies inhibit biochemical activation of IGFIR and block cell proliferation. In contrast, we have reported an agonistic anti-IGFIR antibody scFv-Fc that stimulates IGFIR and its downstream signaling of PI3K and MAPK pathways to promote cell proliferation in vitro. Like the purely antagonistic antibodies, our previous work has shown that scFv-Fc can down regulate IGFIR levels, partially inhibit xenograft growth of MCF-7 cells in athymic mice, and render MCF-7 cells refractory to the mitogenic effects of IGF-I after the initial wave of agonistic activity. MCF-7 cells maintained long term in scFv-Fc have low levels of IGFIR expression, yet the remaining receptor is activated and inhibited by an IGFIR tyrosine kinase inhibitor (TKI) AEW541. In this study, we have further explored the future potential of using this antibody as breast cancer therapy. The common characteristic effect of anti-IGFIR antibodies is to down regulate IGFIR. Since scFv-Fc can activate IGFIR signaling in a manner different than the natural ligand IGF-I, we examined if this antibody could render cells more sensitive to TKI. In MCF-7 cells, IC50 of the IGF1R tyrosine kinase inhibitor AEW541 was decreased 5 to 10 fold when cultured in scFv-Fc. ER negative MDA-MB-231 cells are insensitive to both inhibitory antibody (AVE1642) and TKI (AEW541) in the presence or absence of IGF-I, which may due to the very low levels of IGF1R that are weakly activated by IGF-I. MDA-MB-231 cells were not affected by AEW541 in monolayer growth assays. After chronic treatment of MDA-MB-231 with scFv-Fc for 2 months, AEW541 significantly inhibited monolayer cell growth by 30% in the presence or absence of IGF-I. We also examined the effect of scFv-Fc's effect on AEW541 inhibition of cell motility in MDA-MB-231 cells. Both acute and chronic treatment of scFv-Fc dramatically inhibited cell migration by 90%.Inhibitory antibodies AVE 1642 and MK 0646 had no effect on cell migration. Both IGF-I and excess amounts of AVE 1642/MK 0646 did not reverse scFv-Fc inhibition on cell migration, suggesting other cell signaling system may be involved. In MDA231-BO, a metastatic variant of MDA-MB-231, scFv-Fc had less inhibitory effect on basal cell migration, but in combination of AEW541 treatment, cell migration was significantly decreased by 70%. In conclusion, our data suggests an antibody with agonistic activity may have different properties than purely inhibitory antibodies. Specifically, initiating biochemical signaling followed by inhibition of tyrosine kinase activity and receptor downregulation may be a potent way to disrupt IGF mediated breast cancer cell biology. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3125.