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Expression of &agr;V-Integrins in Uterine Serous Papillary Carcinomas; Implications for Targeted Therapy With Intetumumab (CNTO 95), a Fully Human Antagonist Anti-&agr;V-Integrin Antibody

Objective: Uterine serous papillary carcinoma (USPC) is an aggressive variant of endometrial cancer characterized by an innate resistance to chemotherapy and poor prognosis. In this study, we evaluated the expression of &agr;V-integrins in primary USPC cell lines and the in vitro ability of intetumumab (CNTO 95), a fully human monoclonal antibody against &agr;V-integrins, to inhibit USPC cell adhesion and migration. Materials and Methods: The surface expression of integrins belonging to the &agr;V-family, including &agr;V&bgr;3, &agr;V&bgr;5, and &agr;V&bgr;6, was evaluated in 6 primary USPC cell lines using flow cytometry analysis. To test the ability of intetumumab to inhibit USPC cell adhesion and migration, adhesion assays in the presence of vitronectin and migration assays through an 8.0-&mgr;m pore polycarbonate membrane also were performed. Results: We found high expression of the &agr;V-subunit on the cell surface of all 6 primary USPC cell lines tested (100% positive cells; mean fluorescence intensity range, 13.1-39.5). When the expression of single heterodimeric integrins was evaluated, &agr;V&bgr;3, &agr;V&bgr;5, and &agr;V&bgr;6 were expressed on 37.5%, 32.0%, and 16.3% of cells (mean fluorescence intensity range, 6.5-16.2, 9.2-32.5, and 6.2-11.5, respectively). Importantly, in functional assays, low doses of intetumumab were effective in inhibiting adhesion (0.15 &mgr;g/mL, P = 0.003) and migration (1.25 &mgr;g/mL P = 0.02) of primary USPC cell lines. Conclusions: The &agr;V-integrins are overexpressed on the cell surface of primary USPC cell lines. Intetumumab may significantly inhibit USPC cell adhesion and migration pathways and may therefore represent a novel treatment option for patients harboring this rare but highly aggressive variant of endometrial cancer.