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Diabodies Targeting Epithelial Membrane Protein 2 Reduce Tumorigenicity of Human Endometrial Cancer Cell Lines

Authors' Affiliations: ¹ Molecular Biology Institute and ² Jules Stein Eye Institute, University of California; ³ Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging; ⁴ Department of Pathology and Laboratory, David Geffen School of Medicine at the University of California at Los Angeles; ⁵ Department of Surgery, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California; and ⁶ Anesthesia and Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California

Requests for reprints: Madhuri Wadehra, Department of Pathology and Laboratory, David Geffen School of Medicine at the University of California at Los Angeles, 14-127 Center for Health Sciences, Los Angeles, CA 90095. Phone: 310-825-1590; Fax: 310-825-5674; E-mail: mwadehra{at}mednet.ucla.edu.

Purpose: Endometrial cancer is the most common gynecologic malignancy. One promising biomarker is epithelial membrane protein 2 (EMP2), and its expression is an independent prognostic indicator for tumors with poor clinical outcome expression. The present study assesses the suitability of EMP2 as a therapeutic target.

Experimental Design: Human monovalent anti-EMP2 antibody fragments were isolated from a human phage display library and engineered as bivalent antibody fragments (diabodies) with specificity and avidity to both EMP2 peptides and native cell-surface EMP2 protein. Diabodies were assessed using cell death and apoptosis assays. In addition, the efficacy of EMP2 diabodies on endometrial cancer tumors was determined using mouse xenograft models.

Results: Treatment of human endometrial adenocarcinoma cell lines with anti-EMP2 diabodies induced significant cell death and caspase-3 cleavage in vitro. These responses correlated with cellular EMP2 expression and were augmented by progesterone, which physiologically induces EMP2 expression. In vivo, treatment of subcutaneous human xenografts of HEC-1A cell lines with anti-EMP2 diabodies suppressed tumor growth and induced cell death in the xenograft.

Conclusions: These findings suggest that EMP2 may be a potential pharmacologic target for human endometrial cancer.