ImClone Systems Inc (formerly IMCL)

[biophud]

EORTC link--Multiple IMCL abstracts presented. An impressive and diverse collection of pipeline molecules.

http://www.ecco-org.eu/Conferences-and-Events/EORTC-NCI-AACR-2008/page.aspx/268

Also of note-->data from AMGN on their anti ErbB-3 antibody (developed with ABGX and U3). Interesting because the study looks at combination therapy with c225.

Fully human anti-HER3 mAb U3-1287 (AMG 888) demonstrates unique in vitro and in vivo activities versus other HER family inhibitors in NSCLC models M. Treder1, S. Ogbagabriel2, R. Moor1, U. Schulze-Horsel1, T. Hettmann1, M. Rothe1, R. Radinsky2, D. Freeman2. 1U3 Pharma, Research, Munich, Germany; 2Amgen Inc, Oncology Research, Thousand Oaks, CA, USA

Background: HER3 is a member of the Human Epidermal Growth Factor Receptor (HER) family and is an important component of HER family driven tumorigenesis. Though HER3 lacks intrinsic kinase activity, it is a scaffold for PI3K/AKT signaling for the HER family via heterodimeric interactions. HER3 signaling may be a resistance mechanism for EGFR and HER2 inhibitors. We report unique in vitro and in vivo activities of U3-1287 (AMG 888), the first fully human Anti-HER3 mAb vs. current HER family inhibitors in NSCLC models. Combinations with EGFR inhibitors are also explored. Methods: To determine the inhibition of HER3 oncogenic signaling, A549, Calu-3 and H1975 NSCLC cells were treated with up to 10 mg/ml of U3-1287 (AMG 888), C225 (Anti-EGFR), c2C4 (Anti-HER2) or control mAbs 1 hour prior to heregulin-beta (HRG) or vehicle stimulation. Since HER3 is a heterodimerization partner for HER family members, U3-1287 (AMG 888) was combined with EGFR inhibitors in vitro. To determine in vivo efficacy, mice bearing ~200mm3 A549 NSCLC xenografts were treated 2×/week with anti-HER or control Abs. A549 xenograft tumors were analyzed for the inhibition of pHER3 by Western blotting. The anti-tumor effects of U3-1287 (AMG 888) with an EGFR inhibitor was tested in the Calu-3 and H1975 NSCLC xenograft models. Results: Treatment with U3-1287 (AMG 888) resulted in an inhibition of ligand-induced pHER3, basal pHER3 and pAkt in A549, Calu-3 and H1975 NSCLC cell lines, respectively. In NCI-H1975 cells, combining U3-1287 (AMG 888) with the anti-EGFR mAb C225 resulted in greater pHER3 and pAkt inhibition in vitro than with either single agent alone. Administration of U3-1287 (AMG 888) resulted in tumor stasis in the (EGFR TKI resistant) A549 NSCLC xenograft model vs control and other HER mAbs and tumor inhibition in Calu-3 and NCI-H1975 xenografts compared to IgG treated mice (p < 0.05). Combinations with the anti-EGFR mAb C225 resulted in tumor growth inhibition that was greater than either single agent alone in CaLu-3 (p < 0.001) and NCI-H1975 (p < 0.001) xenografts. Conclusions: U3-1287 (AMG 888) inhibits basal and ligand-induced HER3 oncogenic signaling in NSCLC cell lines in vitro and basal pHER3 in vivo. NSCLC xenografts are sensitive to U3-1287 (AMG 888) treatment as single agent or in combination with an anti-EGFR mAb, including an EGFR TKI resistant model. These data provide preclinical evidence for the potential clinical application of U3-1287 (AMG 888) in NSCLC.