Abstract #LB-151: Identification and in vitro characterization of a human monoclonal antibody against IGF-II

Elevated expression of insulin-like growth factor-II (IGF-II) is frequently observed in a variety of human malignancies including breast, colon and liver cancer. As IGF-II can deliver a mitogenic signal through both the IGF-IR and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is a potential alternative option to IGF-IR directed agents. Utilizing a Fab-displaying phage library and a biotinylated precursor form of IGF-II (1-104aa) as a target, we isolated Fabs specific for the E-domain C-terminal extension form of IGF-II and for mature IGF-II. One of these Fabs which bound to both forms of IGF-II was reformatted into a full-length IgG, expressed, purified and subjected to further analysis. This antibody (DX-2647) displayed a very high affinity for mature IGF-II (K D value of 23 pM). The antibody blocked binding of IGF-II to the IGF-IR and IR-A, to a panel of insulin-like growth factor binding proteins (IGFBPs), and the mannose-6-phosphate receptor. A crystal complex of the parental Fab of DX-2647 bound to IGF-II was resolved to 2.4A o . DX-2647 inhibited IGF-II-induced 1) receptor tyrosine phosphorylation, 2) cellular proliferation, and 3) anchorage-dependent as well as anchorage-independent colony formation in various cell lines. The efficacy of DX-2647 in blocking the progression of human tumor xenografts is currently under study. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-151.