Abstract A208: Pharmacodynamic properties and antitumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody.

Abstract

Abstract Insulin-like growth factor (IGF) signaling is thought to play an important role in the development of tumors and resistance to existing cancer therapies. The proliferative and pro-survival signals driven by the IGF ligands, IGF-1 and IGF-2, are transmitted through their binding to the IGF-1 receptor (IGF-1R). In addition, IGF-2 activates the insulin receptor variant A (IR-A) that is expressed during embryonic development as well as in many cancers. To target IGF signaling for cancer therapy we have developed BI 836845, a fully human IgG1 antibody derived from an antibody phage display library that can bind to and neutralize the functions of both IGF-1 and IGF-2. Surface plasmon resonance (Biacore) analysis demonstrated that BI 836845 has an affinity (KD) of 0.07 nM and 0.8 nM for human IGF-1 and IGF-2, respectively. BI 836845 also shows comparable affinities to mouse as well as rat IGF-1 and IGF-2, allowing a comprehensive pre-clinical characterization of the pharmacodynamic properties of the antibody in these species. Cell-based ELISA assays were used to demonstrate that BI 836845 potently neutralizes the ability of IGF-1 and IGF-2 to phosphorylate the human IGF-1R. Similarly, BI 836845 inhibits phosphorylation of IR-A driven by IGF-2. BI 836845 was also shown to completely and potently inhibit IGF bioactivity in human serum samples ex vivo. Pharmacodynamic effects of BI 836845 were studied in growing rats treated intravenously once weekly with 20, 60, or 200 mg/kg antibody. Inhibition of IGF bioactivity as determined by ex vivo IGF-1R phosphorylation potential in the plasma was observed at all dose levels, despite a corresponding increase in total IGF-1 levels. An increase in total IGF-1 levels has also been seen with IGF-1R targeted antibodies in clinical studies and is thought to be due to blockade of a growth hormone mediated physiological feedback mechanism. Treatment with BI 836845 resulted in a marked dose dependent reduction of rat body weight gain at all dose levels, consistent with the known role for IGFs in normal growth and development. BI 836845 potently inhibits the in vitro proliferation of cell lines derived from various cancers, with mesenchymal-derived cancer cell lines being particularly sensitive (EC50 values in the low nanomolar range). In a model of Ewing s sarcoma, using immunodeficient nude mice subcutaneously transplanted with human RD-ES cells, twice-weekly treatment with BI 836845 resulted in partial inhibition of tumor growth. Treatment in combination with rapamycin resulted in improved efficacy at tolerated doses. In conclusion, BI 836845 is a potent IGF ligand neutralizing antibody whose pharmacological profile warrants further investigation in clinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A208.