Abstract 1757: MEDI-573, an IGF-I/II neutralizing human antibody inhibits both IGF-1R and IR-A signaling pathways

Abstract

Abstract Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). Overexpression of IGF-II and IR-A has been reported in multiple types of cancer, and has also been proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R targeting therapy. MEDI-573 is a dual targeting human antibody that neutralizes both IGF-I and IGF-II. We have shown previously that this antibody inhibits IGF-1R activation by IGF and demonstrated potent in vivo tumor growth inhibition activity in IGF driven xenograft models. Here we show that MEDI-573 inhibits IGF-II activated IR-A signal pathways without cross reactivity to insulin, and therefore has minimum impact on glucose metabolism, which is mediated mainly by insulin/IR interaction. MEDI-573 blocks the binding of IGF-II to, and inhibits the subsequent phosphorylation of IR-A and IRS-1. MEDI-573 inhibited IGF-II-induced in vitro growth of IR-A overexpressing cells with or without the presence of up to 10uIU of insulin in the medium. In addition, MEDI-573 inhibited IGF-II-induced proliferation of IR-A-overexpressing cells as effectively as it inhibited the IGF-1R-overexpressing cells. The anti-proliferative activity of MEDI-573 is not changed across heterogeneous mixed cell populations with various ratios of IR-A- versus IGF-1R-expressing cells. In contrast, an IGF-1R specific antibody was most active at inhibiting the proliferation of a pure IGF-1R expressing homogenous population, but lost activity when the heterogeneous cell population contained increasing percentages (25-50%) of IR-A-expressing cells. We also examined the relative abundance of IR-A versus IR-B (insulin receptor isoform B) mRNA in multiple cancer cell lines using a previously published quantitative RT-PCR method. The results show that IR-A is frequently the dominant isoform overexpressed in these cancer cells. Taken together, these results demonstrate that by neutralizing IGF-I and IGF-II ligands, MEDI-573 is a dual targeting antibody that offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways and potentially overcome IGF-1R targeting resistance. 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 1757. doi:10.1158/1538-7445.AM2011-1757