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Departments of ¹ Tumor Biology and ² Biotechnology Development, Schering-Plough Research Institute, Kenilworth, New Jersey; ³ Department of Biological Research, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California; and ⁴ Medarex, Milpitas, California

Requests for reprints: Yan Wang, Department of Oncology, Schering-Plough Research Institute, 2015 Galloping Hill Road, K15-4600, Kenilworth, NJ 07033. Phone: 908-740-7326; Fax: 908-740-3918. E-mail: yan.wang{at}spcorp.com

Insulin-like growth factor-I receptor (IGF-IR) plays an important role in tumor cell growth and survival. On ligand stimulation, IGF-IR, a receptor tyrosine kinase, phosphorylates tyrosine residues on two major substrates, IRS-1 and Shc, which subsequently signal through the Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways. Here, we describe the characterization of a fully human anti–IGF-IR monoclonal antibody 19D12 that inhibits IGF binding and autophosphorylation of both IGF-IR/IGF-IR homodimers and IGF-IR/insulin receptor heterodimers. 19D12 does not recognize insulin receptor homodimers. In addition to inhibiting IGF-IR autophosphorylation, 19D12 also inhibits IRS-1 phosphorylation and activation of the major downstream signaling molecules AKT and extracellular signal-regulated kinase 1/2. Furthermore, the antibody down-regulates the total IGF-IR protein level and can exhibit antibody-dependent cellular cytotoxicity activity against a non–small cell adenocarcinoma cell line in vitro in the presence of isolated human natural killer cells. 19D12 binds tightly to the receptor, with an affinity of 3.8 pmol/L as measured by KinExA. In cell culture, 19D12 inhibits proliferation and soft agar growth of various tumor cell lines. In vivo, 19D12 inhibits the tumor growth of a very aggressive human ovarian tumor xenograft model A2780. These data support the development of this anti–IGF-IR monoclonal antibody as a promising anticancer agent.

Note: Current address of J.A. Pachter is Cancer Biology, OSI Pharmaceuticals, Inc., Farmingdale, New York.

Received 2/17/05; revised 4/14/05; accepted 6/ 1/05.