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