A Fully Human Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor Blocks Ligand-Dependent Signaling and Inhibits Human Tumor Growth in Vivo

摘要: The insulin-like growth factor I receptor (IGF-IR) is overexpressed in many diverse tumor types and a critical signaling molecule for cell proliferation survival. Therapeutic strategies targeting the IGF-IR may therefore be effective broad-spectrum anticancer agents. Through screening of Fab phage display library, we have generated fully human antibody (A12) that binds to with high affinity (4.11 x 10(-11) M) inhibits ligand binding an IC(50) 0.6-1 nM. Antibody-mediated blockade inhibited downstream two major (IGF) pathways, mitogen-activated protein kinase phosphatidylinositol 3'-kinase/Akt, MCF7 breast cancer cells. As result, mitogenic proliferative potential IGF-I IGF-II were significantly reduced. A12 did not block insulin but could atypical In addition, was shown induce internalization degradation on specific cells, resulting significant reduction surface density. xenograft models vivo, by occur rapidly, inhibition breast, renal, pancreatic tumors. Histological analysis sections demonstrated marked increase apoptotic cells antibody-treated animals. These results demonstrate possesses strong antitumor activity vitro vivo therapeutic candidate treatment cancers are dependent