BIIB022, a human antibody targeting human insulin-like growth factor-1 receptor (IGF-1R), enhances the anti-tumor activities of Tarceva in non-small cell lung carcinoma (NSCLC) and Rapamycin in sarcoma cell lines

4002 Antibodies to IGF-1R as inhibitors of PI3K/AKT survival pathway have shown evidence of objective responses in early clinical trials. BIIB022 is a fully human antibody specific to IGF-1R, constructed as a nonglycosylated IgG4P with G1-like hinge antibody, and currently in clinical trials for the treatment of patients with solid tumors. BIIB022 allosterically blocks interaction of IGF-1R with its ligands IGF-1 and IGF-2, and inhibits IGF-1R mediated signaling and tumor cell growth. In human pancreatic, lung and breast tumor xenograft models, BIIB022 exhibits single-agent anti-tumor activity. Previous studies have demonstrated cross-talk between IGF-1R and EGFR pathways and activation of IGF-1R pathway has been incriminated as one of the mechanisms of resistance to EGFR inhibitors. We therefore investigated the effect of BIIB022 in combination with Tarceva, an EGFR inhibitor approved for NSCLC. In a panel of NSCLC lines, BIIB022 as a single agent inhibited in vitro cell growth and in combination enhanced the growth inhibitory activity of Tarceva in approximately 50% of the cell lines tested. BIIB022 significantly increased the sensitivity of A549 cells to Tarceva with a >5 fold change in IC 50 , where the IC 50 values for combination of Tarceva and BIIB022, and for Tarceva alone, were 0.99µM and 5.41µM respectively. Further signaling pathway analysis indicated that BIIB022 and Tarceva also additively inhibited phosphorylation of AKT. In A549 disseminated tumor model the combination of BIIB022 and Tarceva showed enhanced anti-tumor efficacy compared to single agent alone. In addition, effect of BIIB022 on other molecular targeted therapies was explored. Several rapamycin analogues targeting mTOR, a target downstream of PI3K/AKT, are in clinical trials and being evaluated as treatment for Sarcoma and other cancer types. Since inhibition of mTOR has been shown to induce IRS-1/IGF-1R signaling dependent feed-back activation of AKT, the effect of BIIB022 in combination with rapamycin was determined. In a panel of sarcoma and renal carcinoma lines tested, BIIB022 enhanced the anti-tumor activity of rapamycin by blocking the AKT phosphorylation induced by mTOR inhibition. Currently we are examining this combination in pre-clinical models. Taken together, our results support the evaluation of BIIB022 in combination with other molecular targeted therapies in the clinic.