Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201).
We evaluated the expression of epithelial cell adhesion molecule (EpCAM) and the potential of MT201 (adecatumumab), a human monoclonal antibody against EpCAM, in uterine serous papillary carcinoma (USPC). EpCAM expression was evaluated by real-time PCR and immunohistochemistry in a total of 56 USPC fresh-frozen biopsies and paraffin-embedded tissues. EpCAM surface expression was also evaluated by flow cytometry and immunohistochemistry in six USPC cell lines. Sensitivity to MT201 antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity was tested against a panel of primary USPC cell lines expressing different levels of EpCAM in standard 5-h (51)Cr release assays. EpCAM transcript was significantly overexpressed in fresh-frozen USPC when compared with normal endometrial cells (NEC). Median (minimum-maximum) copy number was 943.8 (31.5-1568.3) in tumor samples versus 12.9 (1.0-37.0) in NEC (P < 0.001). By immunohistochemistry, EpCAM expression was found in 96% (26 out of 27) of USPC samples with significantly higher expression compared with NECs (P < 0.001). High surface expression of EpCAM was found in 83% (five out of six) of the USPC cell lines tested by flow cytometry. EpCAM-positive cell lines were found highly sensitive to MT201-mediated antibody-dependent cellular cytotoxicity in vitro, whereas primary USPC cell lines were resistant to natural killer cell-dependent cytotoxicity. Human plasma IgG did not significantly inhibit MT201-mediated cytotoxicity against USPC. EpCAM is highly expressed in uterine serous carcinoma at mRNA and protein levels, and primary USPC are highly sensitivity to MT201-mediated cytotoxicity. MT201 might represent a novel therapeutic strategy in patients harboring advanced/recurrent or metastatic USPC refractory to standard treatment modalities.
El-Sahwi
Karim
K
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Bellone
Stefania
S
Cocco
Emiliano
E
Casagrande
Francesca
F
Bellone
Marta
M
Abu-Khalaf
Maysa
M
Buza
Natalia
N
Tavassoli
Fattaneh A
FA
Hui
Pei
P
Rüttinger
Dominik
D
Silasi
Dan-Arin
DA
Azodi
Masoud
M
Schwartz
Peter E
PE
Rutherford
Thomas J
TJ
Pecorelli
Sergio
S
Santin
Alessandro D
AD
D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007150:Immunohistochemistry; D007167:Immunotherapy; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007074:Immunoglobulin G; D007376:Interleukin-2; D012333:RNA, Messenger; C460839:adecatumumab