Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody.
BACKGROUND
Uterine serous papillary carcinoma (USPC) was an aggressive and chemotherapy resistant variant of endometrial cancer. The authors evaluated the expression of human trophoblast-cell-surface-marker (Trop-2) and the potential of hRS7, a humanized anti-Trop-2 monoclonal antibody, as a novel therapeutic strategy against USPC.


METHODS
Trop-2 expression was evaluated by immunohistochemistry (IHC) in a total of 23 USPC. Six primary USPC cell lines were assessed by flow cytometry and real-time polymerase chain reaction (PCR) for Trop-2 expression. Sensitivity to hRS7 (Immunomedics, Inc.) antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in standard 5-hour ⁵¹Cr-release assays against primary USPC cell lines.


RESULTS
Expression of Trop-2 was found in 15 of 23 (65%) of the tumor tissues tested by IHC and in 50% (3 of 6) of the USPC cell lines tested by real-time PCR and flow-cytometry (Trop-2 expression in USPC versus normal endometrial cells; P < .005). USPC cell lines overexpressing Trop-2, regardless of their intrinsic resistance to natural killer cytotoxicity, were highly sensitive to hRS7-mediated ADCC in vitro (range of killing, 28.2% to 64.4%) (P < .001). Negligible cytotoxicity against USPC was seen in the absence of hRS7 or in the presence of rituximab control antibody (range of killing, 1.1% to 12.4%). Incubation with interleukin-2 (50 IU/mL) in addition to hRS7 further increased the cytotoxic activity against USPC cell lines overexpressing Trop-2 (P = .008).


CONCLUSIONS
Trop-2 was highly expressed in uterine serous carcinoma at mRNA and protein levels. Primary USPC cell lines are highly sensitivity to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for USPC refractory to standard treatment modalities.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.
Joyce
J
Varughese
Emiliano
E
Cocco
Stefania
S
Bellone
Maria
M
de Leon
Marta
M
Bellone
Paola
P
Todeschini
Peter E
PE
Schwartz
Thomas J
TJ
Rutherford
Sergio
S
Pecorelli
Alessandro D
AD
Santin
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D007376:Interleukin-2; C499380:TACSTD2 protein, human
J Clin Oncol. 2006 Oct 10;24(29):4783-91
17028294
Science. 1997 May 23;276(5316):1268-72
9157888
Curr Opin Oncol. 2006 Sep;18(5):494-9
16894299
Cancer Res. 2008 Oct 1;68(19):8113-21
18829570
Gynecol Oncol. 1992 Dec;47(3):298-305
1473741
J Clin Invest. 1993 Jan;91(1):123-32
7678599
Clin Cancer Res. 1995 Jan;1(1):63-70
9815888
Int J Gynaecol Obstet. 2008 Aug;102(2):128-31
18555254
Br J Cancer. 2008 Oct 21;99(8):1290-5
18813308
Gynecol Oncol. 1994 Sep;54(3):264-8
8088602
Mol Cancer Ther. 2008 Feb;7(2):280-5
18281513
Int J Cancer. 2004 Dec 20;112(6):1029-35
15386348
Eur J Cancer. 2010 Mar;46(5):944-53
20060709
J Clin Pathol. 2009 Feb;62(2):152-8
18930986
J Immunol. 1987 May 15;138(10):3566-72
2437198
Mod Pathol. 2008 Feb;21(2):186-91
18084248
Br J Cancer. 2005 Apr 25;92(8):1561-73
15785748
Biochim Biophys Acta. 2009 Dec;1796(2):309-14
19683559
Int J Gynecol Cancer. 2006 Sep-Oct;16(5):1897-902
17009989
Gynecol Oncol. 2004 Dec;95(3):593-6
15581969
Cancer. 2005 Oct 1;104(7):1391-7
16116605
Clin Cancer Res. 1999 Oct;5(10 Suppl):3079s-3087s
10541347
Int J Cancer. 1987 Mar 15;39(3):297-303
2434438
CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
20610543
Am J Surg Pathol. 1982 Mar;6(2):93-108
7102898
Br J Cancer. 2010 Jan 5;102(1):134-43
19920829
Int J Cancer. 1993 Dec 2;55(6):938-46
8253531
Am J Obstet Gynecol. 2010 Aug;203(2):162.e1-8
20417484
Int J Colorectal Dis. 2009 Aug;24(8):875-84
19421758
Proc Natl Acad Sci U S A. 1981 Aug;78(8):5147-50
7029529
Hybridoma. 1992 Oct;11(5):539-45
1459581
Gynecol Oncol. 2005 Jul;98(1):24-30
15894362
Breast Cancer Res Treat. 2004 Mar;84(2):173-82
14999147