Inhibition of the Biologic Response to Insulin-like Growth Factor I in MCF-7 Breast Cancer Cells by a New Monoclonal Antibody to the Insulin-like Growth Factor-I Receptor. The Importance of Receptor Down-regulation

P.-G. Jackson-Booth; C. Terry; B. Lackey; M. Lopaczynska; P. Nissley

doi:10.1055/s-2004-814144

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2003; 35(11/12): 850-856
DOI: 10.1055/s-2004-814144

Original

Inhibition of the Biologic Response to Insulin-like Growth Factor I in MCF-7 Breast Cancer Cells by a New Monoclonal Antibody to the Insulin-like Growth Factor-I Receptor. The Importance of Receptor Down-regulation

P.-G. Jackson-Booth¹ , C. Terry¹ , B. Lackey¹ , M. Lopaczynska¹ , P. Nissley¹

¹Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA

Abstract

We developed a mouse monoclonal antibody (4G11) against insulin-like growth factor I receptor by immunizing mice with mouse embryo fibroblasts overexpressing the human insulin-like growth factor-I receptor. Not only did the 4G11 antibody inhibit the binding of [¹²⁵I]insulin-like growth factor-I to the fibroblast receptor, but 4G11 antibody also potently down-regulated the insulin-like growth factor-I receptor. 4G11 Fab fragment inhibited ligand binding, but did not down-regulate the receptor, suggesting that receptor aggregation is required for down-regulation. 4G11 antibody also down-regulated the receptor in MCF-7 breast cancer cells, a panel of colon cancer cells and MG-63 osteosarcoma cells. Receptor recovery in MCF-7 cells after down-regulation by 4G11 antibody was slow, requiring 32 - 48 h for full recovery. Receptor down-regulation in MCF-7 cells by 4G11 antibody was confirmed by FACS analysis of intact and permeabilized cells. In contrast to 4G11 antibody, insulin-like growth factor-I did not down-regulate the receptor in MCF-7 cells. Down-regulation of the receptor by 4G11 antibody in MCF-7 cells resulted in inhibition of Akt and MAPK activation by insulin-like growth factor-I. We conclude that the ability of a monoclonal antibody to down-regulate the receptor may be an important antibody property in targeting the insulin-like growth factor-I receptor for the treatment of certain cancers.

Key words

Colon cancer cells - Akt - MAPK

Full Text

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P. Nissley

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