Effects of an ErbB-3 antibody, MP-RM-1, on tumor growth and ligand-dependent and -independent activation of ErbB-3/akt signaling.

Abstract

e13538 Background: The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand binding molecule that abrogates ErbB-3 mediated signaling. Methods: we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. The ability of the antibody to suppress NRG-1b-dependent and independent ErbB-3 signaling was evaluated in vitro by western blotting using a panel of human tumor cell lines (breast, melanoma, stomach and prostate) as well as early passage tumor cells obtained from patients. The effect on tumor growth in vitro was evaluated with clonogenic assay and in vivo using human tumor xenograft nude mouse models. Results: MP-RM-1 effectively inhibited NRG-1b stimulated and basal ErbB-3/Akt activation. Treatment with the antibody led, in most instances, to a decreased ErbB-3 expression. In addition, MP-RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in human melanoma and prostate carcinoma xenografts. Tumors from animals treated with the antibody displayed a lower ErbB-3/Akt phosphorylation that was accompanied by a decreased ErbB-3 expression. Conclusions: MP-RM-1 has the potential to interfere with signaling by ErbB-3/Akt signaling and can be regarded as a potential candidate for clinical development.