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

Abstract

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.