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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
Author(s) -
Varughese Joyce,
Cocco Emiliano,
Bellone Stefania,
de Leon Maria,
Bellone Marta,
Todeschini Paola,
Schwartz Peter E.,
Rutherford Thomas J.,
Pecorelli Sergio,
Santin Alessandro D.
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.25891
Subject(s) - medicine , antibody dependent cell mediated cytotoxicity , monoclonal antibody , cancer research , flow cytometry , immunohistochemistry , cytotoxicity , antibody , pathology , serous fluid , cell culture , immunotherapy , immunology , in vitro , cancer , biology , biochemistry , genetics
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 51 Cr‐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. Cancer 2011. © 2011 American Cancer Society.