Abstract LB-238: Antitumor activity of mini-IGFBP-3, a protease-resistant derivative of human IGF binding protein-3

Abstract

Abstract Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic properties that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. Consequently, targeting the IGF axis has become an area of intense preclinical and clinical research through the development of 3 major classes of therapeutic compounds: antibodies that target IGF-IR, dual IGF-IR and IR tyrosine kinase inhibitors (TKI), and IGF ligands (IGF-I and IGF-II) neutralizing antibodies. Due to their high affinities for IGF-I and IGF-II, six IGFBPs regulate IGF bioavailability and IGFBP-3 is the main carrier of circulating IGFs in postnatal serum. In order to efficiently neutralize the excess of free IGF ligand maintaining tumor progression, we have produced, using the baculovirus insect cell system, a protease-resistant mutein of human IGFBP-3 with conserved affinities towards both IGF-I and IGF-II that was fused to the human IgG1 Fc fragment. In vitro, the resulting immunoadhesin (mIGFBP-3-Fc), evaluated in both regular and 3D culture, was found to block proliferation, arrest cell cycle and induce apoptosis in various types of cancer cell lines (Colon Adenocarcinoma, Ewing's Sarcoma, Adrenocortical Carcinoma and Multiple Myeloma (MM). mIGFBP-3-Fc antitumor activity was evaluated in vivo using RPMI-8226 luciferase-expressing MM cells xenografts. When MM cells were grafted subcutaneouly, daily mIGFBP-3-Fc injections drastically reduced tumor growth and induced tumor cell apoptosis. Similarly, after iv tumor cell injection, bone marrow localization of MM cells was substantially reduced in the mIGFBP-3-Fc-treated group. Furthermore, when used in association with the proteasome inhibitor Bortezomib, mIGFBP-3-Fc was shown to enhance the antitumor effect of Bortezomib used as single agent. Altogether, these data support the concept that mIGFBP-3-Fc could improve MM treatment either as a single agent or in association with proteasome inhibitors. Citation Format: François Godeau, Patricia Leneuve, Laetitia Da Costa, Yves Le Bouc, Jack-Michel Renoir. Antitumor activity of mini-IGFBP-3, a protease-resistant derivative of human IGF binding protein-3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-238. doi:10.1158/1538-7445.AM2014-LB-238