The IGF-Trap: Novel Inhibitor of Carcinoma Growth and Metastasis

• Published in: Molecular cancer therapeutics 2015-04, Vol.14 (4), p.982-993
• Main Authors: Wang, Ni, Rayes, Roni F, Elahi, Seyyed Mehdy, Lu, Yifan, Hancock, Mark A, Massie, Bernard, Rowe, Gerald E, Aomari, Hafida, Hossain, Sazzad, Durocher, Yves, Pinard, Maxime, Tabariès, Sébastien, Siegel, Peter M, Brodt, Pnina
• Format: Article
• Language: English
• Subjects: Animals; Antibody Specificity; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - mortality; Carcinoma - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; CHO Cells; Cricetulus; Disease Models, Animal; Humans; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor II - metabolism; Kinetics; Mice; Neoplasm Metastasis; Protein Binding; Receptor, IGF Type 1 - antagonists & inhibitors; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - isolation & purification; Recombinant Fusion Proteins - pharmacology; Signal Transduction - drug effects; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-0751

The IGFI receptor promotes malignant progression and has been recognized as a target for cancer therapy. Clinical trials with anti-IGFIR antibodies provided evidence of therapeutic efficacy but exposed limitations due in part to effects on, and the compensatory function of, the insulin receptor system. Here, we report on the production, characterization, and biologic activity of a novel, IGF-targeting protein (the IGF-Trap) comprising a soluble form of hIGFIR and the Fc portion of hIgG1. The IGF-Trap has a high affinity for hIGFI and hIGFII but low affinity for insulin, as revealed by surface plasmon resonance. It efficiently blocked IGFIR signaling in several carcinoma cell types and inhibited tumor cell proliferation, migration, and invasion in vitro. In vivo, the IGF-Trap showed favorable pharmacokinetic properties and could suppress the growth of established breast carcinoma tumors when administered therapeutically into tumor-bearing mice, improving disease-free survival. Moreover, IGF-Trap treatment markedly reduced experimental liver metastasis of colon and lung carcinoma cells, increasing tumor cell apoptosis and reducing angiogenesis. Finally, when compared with an anti-IGFIR antibody or IGF-binding protein-1 that were used at similar or higher concentrations, the IGF-Trap showed superior therapeutic efficacy to both inhibitors. Taken together, we have developed a targeted therapeutic molecule with highly potent anticancer effects that could address limitations of current IGFIR-targeting agents.