Abstract 335: Therapeutic targeting of EphB4 with a novel monoclonal antibody

Abstract

Abstract Objective: EphB4 is a transmembrane receptor tyrosine kinase that plays an important role in neural plasticity and angiogenesis. Its biological and clinical relevance in ovarian cancer is the focus of this study. Methods: Benign ovarian (ML5 and ML10) and ovarian cancer (Hey, SKOV3ip1, A2780-par, A2780-cp20, and IGROV-af1) cell lines, 7 normal ovarian and 85 invasive ovarian cancer samples were evaluated for EphB4 expression by Western blot or immunohistochemistry. Univariate and multivariate analyses were performed for clinical correlation. EphB4 blockade was accomplished using a novel EphB4-targeted monoclonal antibody (EphB4-131). Systemic delivery of EphB4-131 antibody was utilized in vivo to target EphB4 in orthotopic mouse models of ovarian cancer. Results: By Western blot analysis, all five malignant cell lines overexpressed EphB4, whereas the two benign cell lines had low EphB4 expression. All of the normal ovarian tissues had low or absent EphB4 expression. Among the invasive ovarian carcinomas (mean age of patients was 59.4 years), 73 (86%) had some level of EphB4 expression and overexpression (moderate or strong) was noted in 58% of all samples. EphB4 overexpression significantly correlated with advanced stage (III or IV; p<0.001) and presence of ascites (p<0.001). In multivariate analysis, EphB4 overexpression (p=0.04) and stage (p=0.03) were independent predictors of poor survival. EphB4-131 antibody led to decreased EphB4 expression in A2780-cp20 and IGROV-af1 cell lines, lasting for over 5 days. Compared to controls, EphB4-131 antibody alone significantly decreased tumor growth in A2780-cp20 (83%, p<0.01) and IGROV-af1 (80%, p<0.001) orthotopic ovarian cancer models. Combination therapy with EphB4-131 antibody and docetaxel resulted in the greatest tumor reduction in both A2780-cp20 and IGROV-af1 cell lines (94-98% reduction versus controls; p<0.01). Conclusions: EphB4 overexpression is predictive of poor clinical outcome in ovarian cancer patients and is associated with aggressive features. Therapeutic targeting of EphB4 with the novel antibody EphB4-131 is an attractive strategy for further development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 335.