Diabodies targeting epithelial membrane protein 2 reduce tumorigenicity of human endometrial cancer cell lines.
OBJECTIVE
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.


METHODS
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.
Shimazaki
Kaori
K
Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Lepin
Eric J
EJ
Wei
Bo
B
Nagy
Agnes K
AK
Coulam
Catherine P
CP
Mareninov
Sergey
S
Fu
Maoyong
M
Wu
Anna M
AM
Marks
James D
JD
Braun
Jonathan
J
Gordon
Lynn K
LK
Wadehra
Madhuri
M
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C486403:EMP2 protein, human; D007128:Immunoglobulin Fragments; D008562:Membrane Glycoproteins