Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody

被引:124
作者
Wang, Y
Hailey, J
Williams, D
Wang, YL
Lipari, P
Malkowski, M
Wang, XY
Xie, L
Li, GH
Saha, D
Lam, W
Ling, W
Cannon-Carlson, S
Greenberg, R
Ramos, RA
Shields, R
Presta, L
Brams, P
Bishop, WR
Pachter, JA
机构
[1] Schering Plough Res Inst, Dept Tumor Biol, Kenilworth, NJ 07033 USA
[2] Schering Plough Res Inst, Dept Biotechnol Dev, Kenilworth, NJ 07033 USA
[3] DNAX Res Inst Mol & Cellular Biol, Dept Biol Res, Palo Alto, CA USA
[4] Medarex, Milpitas, CA USA
关键词
D O I
10.1158/1535-7163.MCT-05-0048
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 heterodinners. 19D12 does not recognize insulin receptor homodimers. In addition to inhibiting IGF-IR autophosphorylation, 191312 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. 191312 binds tightly to the receptor, with an affinity of 3.8 pmol/L as measured by KinExA. In cell culture, 191312 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.
引用
收藏
页码:1214 / 1221
页数:8
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