Therapeutic Discovery Human Monoclonal Antibody Fragments Binding to Insulin-like Growth Factors I and II with Picomolar Affinity

The type 1 insulin-like growth factor receptor (IGF1R) and its ligands (IGF-I and IGF-II) have been implicated inavarietyofphysiologicprocessesand indiseases suchas cancer. Inaddition to IGF1R, IGF-II alsoactivates the insulin receptor (IR) isoformA, and therefore, antibodies against IGF-II can inhibit cell proliferation mediated by the signaling through both IGF1R and IR triggered by IGF-II. We identified a new human monoclonal antibody (mAb),m708.2,which is bound to IGF-I and IGF-II but not to insulin.m708.2 potently inhibited signal transduction mediated by the interaction of IGF-I or IGF-II with the IGF1R and IGF-II with the IR. It also inhibited the growth of the breast cancer cell line MCF-7. An affinity-matured derivative of m708.2, m708.5, bound to IGF-I with equilibrium dissociation constant, KD 1⁄4 200 pmol/L and to IGF-II with KD 1⁄4 60 pmol/L. m708.5 inhibited signal transduction mediated by IGF-I and IGF-II and cancer cell growth more potently than m708.2. These results suggest thatm708.5 could have potential as a candidate therapeutic for cancers driven by the IGF-I and IGF-II interactions with IGF1R and IR. Mol Cancer Ther; 10(9); 1–9. 2011 AACR.